Alcor: FAQ – Technical

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Index - 1.General - 2.Technical - 3.Ethical - 4.Spiritual 5.Financial - 6.Membership - 7.Misinformed See also Scientists' Cryonics FAQ

Q: What are nanotechnology and nanomedicine?

A: Molecular nanotechnology is an emerging technology for manufacturing and manipulating matter at the molecular level. The concept was first suggested by Richard Feynman in 1959. The theoretical foundations of molecular nanotechnology were developed by K. Eric Drexler, Ralph Merkle, and others in the 1980s and 1990s. More recently the future medical applications of nanotechnology have been explored in detail by Robert Freitas in his books, Nanomedicine Vol. I (Basic Capabilities) and Nanomedicine Vol. IIA (Biocompatibility). These scientists have concluded that the mid to late 21st century will bring an explosion of amazing capabilities for analyzing and repairing injured cells and tissues, similar to the information processing revolution that is now occurring. These capabilities will include means for repairing and regenerating tissue after almost any injury provided that certain basic information remains intact. A non-technical overview of nanotechnology, including an excellent chapter on cryonics ("biostasis"), is available in Eric Drexler's book, Engines of Creation.

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Q: Won't memories be lost if brain electrical activity stops?

A: Short-term memory depends on electrical activity. However long-term memory is based on durable molecular and structural changes within the brain. Quoting from the Textbook of Medical Physiology by Arthur C. Guyton (W.B. Saunders Company, Philadelphia, 1986):

We know that secondary memory does not depend on continued activity of the nervous system, because the brain can be TOTALLY INACTIVATED (emphasis added) by cooling, by general anesthesia, by hypoxia, by ischemia, or by any method, and yet secondary memories that have been previously stored are still retained when the brain becomes active once again.

This is known from direct clinical experience with surgical deep hypothermia, for which complete shutdown of brain electrical activity (electrocortical silence) is not only permissible, but desirable for good neurological outcome.

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Global Contrast Media Market with (Covid-19) Impact Analysis: In-depth Analysis, Global Market Share, Top Trends, Professional & Technical…

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Redox-responsive nanoplatform for codelivery of miR-519c and gemcitabine for pancreatic cancer therapy – Science Advances

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INTRODUCTION

Pancreatic cancer is one of the most chemotherapy-resistant cancers and a leading cause of cancer-related mortality with a dismal 5-year survival rate of 8 to 10% (https://seer.cancer.gov/statfacts/html/pancreas.html). Gemcitabine (GEM) is a first-line therapy for pancreatic cancer either alone or in combination with other drugs such as nanoparticle albumin-bound paclitaxel or nab-paclitaxel (1). However, the clinical effect of single-agent GEM is modest due to its rapid metabolism, inefficient delivery to the desmoplastic tumor, and development of chemoresistance (2, 3). The combination therapy of GEM and nab-paclitaxel versus GEM alone increases survival along with an increase in grade 3 neutropenia, fatigue, and neuropathy (4). The use of FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin combination), as compared to GEM, significantly prolongs survival but at the expense of higher grade 3 or 4 toxicities (5).

Most patients with pancreatic cancer are present with metastatic or inoperable disease, and therefore, systemic polychemotherapy remains the treatment of choice. The median survival of patients with metastatic pancreatic cancer is still less than a year with either FOLFIRINOX or GEM and nab-paclitaxel (6, 7). Therefore, safer and more effective combination of GEM and novel drugs further need to be developed particularly for older or less fit patients or those with significant comorbidities, who cannot tolerate intensive chemotherapy.

Chemotherapy resistance in pancreatic cancer involves multiple mechanisms. GEM-resistant cells mainly represent cancer stem cells and epithelial-to-mesenchymal transformation (EMT) phenotype (8, 9). Desmoplasia produces hypoxic microenvironment, stimulating hypoxia-inducible factor-1 (HIF-1), which, in turn, modulates tumor metabolism, induces profibrotic and angiogenic responses, and mediates the overexpression of adenosine triphosphatebinding cassette superfamily G member 2 (ABCG2). As a member of the ABC transporter superfamily, ABCG2 functions as a drug efflux pump and has been reported to play a role in GEM resistance in pancreatic cancer (10, 11). Because of an increase in high-glucose metabolism in GEM-resistant cells, the flux of glycolytic intermediates is directed toward nonoxidative pentose phosphate pathway (PPP), leading to an increase in pyrimidine biosynthesis and pool of deoxycytidine triphosphate (dCTP). The structural similarity between dCTP and GEM, a nucleoside analog, results in a molecular competition to bind the replicating DNA, reducing the efficacy of GEM. Hypoxia is responsible for an increase in sonic hedgehog (SHH) signaling and smoothened (SMO) expression in pancreatic cancer and activation of the transcription factor glioma-associated oncogene (GLI) (12). These changes result in further generation of fibrosis and a decrease in blood flow, creating a desmoplasia-hypoxia vicious cycle.

MicroRNAs (miRNAs) regulate gene expression by the degradation of target mRNAs, repressing of mRNA translation, or up-regulating of target genes. Aberrant expressions of miRNAs correlate with altered expression of genes responsible for stemness, metastasis, tumor metabolism, hypoxia, and chemoresistance (13). We previously reported differential down-regulation of miR-205 and miR-let7b in human pancreatic cancer tissues and cells (14). Further, we demonstrated that the combination of GEM-conjugated polymeric micelles and miR-205 significantly inhibited pancreatic tumor growth in mice after systemic administration, as miR-205 sensitized resistant pancreatic cells to GEM (8, 15). miR-519c is of particular interest in pancreatic cancer, as it is down-regulated in pancreatic cancer, binds to HIF-1 mRNA, and can inhibit HIF-1 expression, leading to sensitization of pancreatic cancer cells (16, 17). We hypothesize that a combination of GEM and miR-519c can target HIF-1 and ABCG2, resensitize resistant pancreatic cancer cells to GEM, and result in decreased desmoplasia. Moreover, 2-O-methyl phosphorothioate (2-OMe-PS) modification of RNA based on our previous study (18) was applied to miR-519c to increase its stability, binding affinity, and functional potential and decrease immunostimulatory properties.

Nanoparticulate delivery systems have shown distinct advantages in increasing drug accumulation at the tumor site after systemic administration. GEM delivery is limited by its poor pharmacokinetic profiles and dense desmoplasia, which may be overcome by a GEM-conjugated delivery system. We recently developed methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate)-graft-gemcitabine-graft-dodecanol (mPEG-b-PCC-g-GEM-g-DC), which conjugates GEM via stable amide bonds and self-assembles into micelles, with 12% (w/w) GEM loading and 2.5-fold higher GEM accumulation in orthotopic pancreatic cancer compared to free GEM (2). Redox-sensitive polymeric micelles are very promising due to their controlled drug release inside the tumor cells in the presence of intracellular stimuli, including glutathione (GSH) (19). GSH concentration in tumor cells is several times higher than that in the extracellular microenvironment and normal tissues (20). Epidermal growth factor receptor (EGFR) has been overexpressed in 40 to 80% of pancreatic cancers. Cells that overexpress EGFR will accumulate the functionalized particles, resulting in greater cytotoxicity. We hypothesized that EGFR targeted GE11 peptide mixed micelles system based on tetraethylene pentamine (TEPA) for complex formation with miRNA and GSH-sensitive polypeptide for GEM conjugation via disulfide bond for targeted delivery of GEM and OMe-PSmiR-519c will result in a synergistic inhibition of pancreatic cancer without excess toxicity. Our in vitro and in vivo studies confirmed that mixed OMe-PSmiR-519ccomplexed and GEM-conjugated mixed micelles effectively inhibit pancreatic tumor growth.

We first established a GEM-resistant pancreatic ductal adenocarcinoma (PDAC) cell model by incubating wild-type MIA PaCa-2 cells with increasing concentrations of GEM over 2 months. The resulting GEM-resistant MIA PaCa-2R cells were 25-fold more resistant compared to the wild-type MIA PaCa-2 cells, as reflected by the pronounced increase in the median inhibitory concentration value from 2 to 50 M. Our immunohistochemical analysis demonstrated a high expression of HIF-1 protein in patient-derived pancreatic cancer tissues but a negligible expression in adjacent healthy patient tissues (fig. S1A). Western blot analysis of MIA PaCa-2R cells demonstrated that the expression level of HIF-1 was very low under normoxic conditions but significantly increased, reaching the highest level at 4 hours after incubation of MIA PaCa-2R cells under hypoxic condition (fig. S1B).

miR-519c was significantly down-regulated in pancreatic cancer tissue compared to adjacent normal tissues, as determined by real-time reverse transcription polymerase chain reaction (RT-PCR) (Fig. 1A). Similarly, we observed a significantly low miR-519c expression level in pancreatic cancer cell lines such as HPAF-II, Capan-1, and MIA PaCa-2R, compared to nonmalignant pancreatic cells HPDE (human pancreatic duct epithelial) (Fig. 1B). With target prediction by miRTarBase, we confirmed that miR-519c directly targets HIF-1 and ABCG2, indicating its potential utility to reverse hypoxia-induced chemoresistance.

miR-519c was down-regulated in patient tissues (A) and pancreatic cancer cell lines (B), compared to paired normal tissues and normal pancreatic cells such as HPDE. Further, miR-519c inhibited the expression of HIF-1 and Hh ligands such as SHH, SMO, and GLI1 after the transfection of MIA PaCa-2R cells with Lipofectamine/miR-519c under hypoxic condition (C and D). (E) miR-519c also inhibited cell migration under hypoxic condition when MIA PaCa-2R cells were cultured on Transwell chamber with human pancreatic stellate cells (hPSCs). *P < 0.05, two-paired t test.

Expression of SHH, SMO, and GLI1 was significantly higher under hypoxic versus normoxic conditions, as determined by Western blot analysis. Transfection of pancreatic cancer cells with Lipofectamine/miR-519c complexes significantly inhibited the expression of HIF-1 and Hh ligands, such as SHH, GLI1, and SMO (Fig. 1, C and D). We observed that addition of human pancreatic stellate cells (hPSCs)conditioned medium to MIA PaCa-2R cells induced tumor cell invasion, especially under hypoxic condition (Fig. 1E), indicating that the exposure of MIA PaCa-2R cells to desmoplastic microenvironment enhances their invasion capacity. Additional treatment of MIA PaCa-2R cells with miR-519c inhibited cell migration under hypoxic condition and desmoplasia (Fig. 1E).

Flow cytometry data demonstrated an up-regulation of glucose transporter 1 (GLUT1) expression in MIA PaCa-2R cells under hypoxic conditions. Transfection of these cells with miR-519c, but not scrambled miRNA, significantly inhibited GLUT1 expression under hypoxic conditions (Fig. 2A and fig. S2). As a glucose analog, the uptake of 2-deoxyglucose (2-DG) by MIA PaCa-2R cells was significantly increased under hypoxic conditions even when these cells were transfected with scrambled miRNA. This is expected, as GLUT1 is a well-known HIF-1 target. Transfection of these cells with miR-519c resulted in a significant decrease in 2-DG uptake under hypoxic conditions (Fig. 2B), suggesting that miR-519c negates hypoxia-induced elevation in glucose uptake, using 2-DG as a GLUT1 substrate. The concentration of dCTP was significantly higher under hypoxic conditions but declined following the transfection of MIA PaCa-2R cells with Lipofectamine/miR-519c complexes (Fig. 2C), indicating that the intracellular level of dCTP is severely suppressed by miR-519c. Hypoxia is known to increase glycolytic influx and pyrimidine biosynthesis in tumor cells. The mRNA expression levels of several known targets of HIF-1 were up-regulated under the hypoxic condition. These targets included NME/NM23 nucleoside diphosphate kinase (NME4) involved in PPP and nucleotide biosynthesis pathways, as well as lactate dehydrogenase (LDH), hexokinase 2 (HKII), and transketolase (TKT) involved in glucose metabolism. The expression level of these targets genes was significantly inhibited after the transfection of MIA PaCa-2R cells with miR-519c but not by scrambled miRNA (Fig. 2D). Together, these results provide strong evidence that miR-519c repletion attenuates glucose metabolism and reduces intracellular dCTP pool.

(A and B) miR-519c inhibited 2-DG uptake, as well as expression of GLUT1 and dCTP, but not scrambled miRNA under hypoxic condition after transfection of MIA PaCa-2R cells with Lipofectamine miR-519c. Cells transfected with Lipofectamine/scrambled miRNA complexes were used as the control. (C) miR-519c decreased dCTP level under hypoxic condition. (D) In addition, miR-519c but not scrambled miRNA inhibited NME4, HKII, LDHA, and TKT expressions under hypoxic condition. Results are presented as the mean SD (n = 3). *P < 0.05 and **P < 0.001, two-paired t test.

Because of an increase in high-glucose metabolism in GEM-resistant cells, the flux of glycolytic intermediates is directed toward nonoxidative PPP, leading to an increase in pyrimidine biosynthesis and pool of dCTP. As GEM is a nucleoside analog, its efficacy is affected by both nucleoside synthesis and their cellular uptake. The presence of dC resulted in a dose-dependent decrease in cytotoxicity after treatment with GEM (Fig. 3A), suggesting that treatment with dCTP increased GEM resistance in MIA PaCa-2R cells. The combination of miR-519c and GEM demonstrated a dose-dependent synergistic effect on cell killing. In contrast, treatment with scrambled miRNA had little effect on cell killing (Fig. 3B). Apoptosis assay further confirmed these observations (fig. S3A). The effect of miR-519c on cell cycle of MIA PaCa-2R cells was determined by flow cytometry after the transfection of MIA PaCa-2R cells with miR-519c under normoxic and hypoxic conditions. Treatment with miR-519c compared to scrambled miRNA under hypoxic conditions resulted in a significant increase in the percentage of cells in the G2 phase (Fig. 3C and fig. S3A). These data suggest that miR-519c inhibited pancreatic cancer cell proliferation by inducing G2 phase cell cycle arrest.

(A) Coincubation of GEM with 100 M dC-reduced drug potency. (B) Significant decrease in cell viability when MIA PaCa-2R cells were transfected with a combination of GEM and miR-519c under the hypoxic condition for 48 hours, but GEM combination with scrambled miRNA was less effective. (C) miR-519c inhibited viability by arresting cell cycle in the G2-M phase. (D and E) miR-519c inhibits ABCG2, c-Myc, and programmed death-ligand 1 (PD-L1) expressions, which are up-regulated under hypoxic condition, but scrambled miRNA had little effect. (F) Combination of miR-519c and GEM was more effective in apoptotic cell death of tumor spheroids generated using MIA PaCa-R cells than either of them alone. The confocal laser scanning microscopy images were captured at a depth of 15 m. *P < 0.05 and **P < 0.001, two-paired t test.

The Western blot analysis demonstrated that drug resistancerelated protein ABCG2 and transcription factor c-MYC (which promotes cancer cell proliferation) and programmed death-ligand 1 (PD-L1) were up-regulated under hypoxic condition. These data indicated that the hypoxic-dependent up-regulation of ABCG2- and c-MYCmagnified GEM resistance and PD-L1 can promote immune escape of tumor cells from cytotoxic T lymphocytes and contribute to the immunosuppression in tumors under hypoxia. Then, the apoptosis rate was investigated by the coculturing of MIA PaCa-2R and peripheral blood lymphocytes with or without miR-519c treatment under normoxic and hypoxic conditions (fig. S4). We observed a significant increase in apoptosis of MIA PaCa-2R cells in the coculture system with miR-519c transfection under hypoxia. Treatment of MIA PaCa-2R cells with miR-519c but not scrambled miRNA inhibited expression of ABCG2, c-MYC, and PD-L1 (Fig. 3, D and E). These data suggest that miR-519c has the potential to improve the cytotoxicity of activated T cells and immunotherapy.

Three-dimensional (3D) desmoplastic tumor spheroids were developed to mimic the hypoxic microenvironment in pancreatic cancer by mixing and culturing hPSCs and MIA PaCa-2R cells in hanging drop plates. Live and dead assay was carried out after treatment with miR-519c and GEM for 48 hours by confocal laser scanning microscopy. Fluorescein isothiocyanatelabeled calcein and propidium iodide binding to nucleic acids presented live and dead cells, respectively. Treatment with the combination of miR-519c and GEM for 9 days exhibited a significantly higher inhibition of tumor growth, leading to the collapse of tumor spheroids. In contrast, treatment with miR-519c or GEM alone failed to destroy tumor spheroids (Fig. 3F). These results suggest that miR-519c facilitates the resensitization of pancreatic cancer cells to GEM.

Chemical modifications can protect miRNA against nuclease degradation and affect their nonspecific interaction with plasma proteins and cell membrane components. Therefore, modification of its 3 end with OMe-PS stabilized miR-519c, which in good agreement with our previous study (18). We determined the effect of nucleases on miRNA stability by incubating unmodified miR-519c and OMe-PSmiR-519c in 50% fetal bovine serum (FBS). miR-519c was degraded within an hour in 50% FBS at 37C. When three-terminal nucleotides at the 3 end of miR-519c guide strand were modified, with 2-OMe-PS, its stability was substantially increased, resulting in significant levels of intact miRNA remained even after 24 hours of incubation at 37C (Fig. 4A). Further, there was no loss of activity in cell killing due to this chemical modification. Incubation of MIA PaCa-2R cells with the combination of 100 nM OMe-PSmiR-519c or miR-519c and increasing concentrations of GEM demonstrated a dose-dependent synergistic effect on cell killing, with OMe-PSmiR-519c being more potent than miR-519c (Fig. 4B).

(A) Synergistic effect of OMe-PSmiR-519c and GEM on cell viability after transfection of MIA PaCa-2R cells with 100 M OMe-PSmiR-519c and increasing concentrations of GEM for 48 hours under hypoxic conditions. (B) Stability of OMe-PSmiR-519c and unmodified miR-519c in 50% FBS. (C and D) Effect of miR-519c and OMe-PSmiR-519c on proinflammatory cytokines interleukin-2 (IL-2) and IL-4, as analyzed by enzyme-linked immunosorbent assay. (E) Association of OMe-PSmiR-519c with endogenous AGO2 protein. (F) HIF-1 and ABCG2 expression levels after miR-519c and OMe-PSmiR-519c treatment for 48 hours under hypoxic conditions, as determined by Western blot analysis. *P < 0.05 and **P < 0.001, two-paired t test.

To examine whether the chemical modification of miR-519c induces proinflammatory cytokine production, we determined the levels of interleukin-2 (IL-2) and IL-4 after incubating OMe-PSmiR-519c and unmodified miR-519c with human peripheral blood mononuclear cells (hPBMCs) for 24 hours and measured cytokines released in hPBMC cultures using a cytokine multianalyte ELISArray kit. The antigen standard cocktail was added to the plate as the positive control. There was a little induction of cytokines due to miRNA treatment. Compared to miR-519ctreated groups, OMe-PSmiR-519ctreated hPBMCs showed the lower release of cytokines, including IL-2 and IL-4 (Fig. 4, C and D).

Argonaute 2 (AGO2) protein is a ribonuclease (RNase) and is an essential component of the RNA-induced silencing complex (RISC) where one strand of the mature miRNA duplex is first loaded onto AGO2 protein. AGO2-bound miRNA interacts with complementary regions of target mRNA and leads to either AGO2-mediated endonuclease cleavage of the mRNA or reduction in its translation efficiency. Therefore, we assessed the effect of chemical modification of miR-519c on its association with AGO2 compared to unmodified miR-519c and OMe-PSmiR-519c in the cytoplasm. As shown in Fig. 4E, the transfection of MIA PaCa-2R with miR-519c and OMe-PSmiR-519c was resulting in 3- and 16-fold higher RISC loading than that of the control group. Consequently, higher RISC loading resulted in improved inhibition of HIF-1 and ABCG2 (Fig. 4F). Notably, the AGO2 association did not differ between normoxic and hypoxic conditions.

On the basis of the results above, we selected OMe-PSmiR-519c over miR-519c for in vivo studies due to its higher stability, enhanced RISC loading, and affinity. We used our mPEG-co-P(Asp)-g-TEPA-g-DC cationic copolymer for complex formation with miRNA and used for preparing mixed micelles with mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC for codelivery of OMe-PS-miR-591c and GEM. 1H nuclear magnetic resonance (NMR) of mPEG-co-P(Asp)-g-TEPA-g-DC and mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC is shown in Fig. 5 (A and B). The percentage of GEM loading in mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC was calculated to be 14% on the basis of the integration of peak at 3.5 parts per million (ppm) for the CH2 of mPEG (f) and peaks at 7.8 to 8.22, 7.09, 5.29 to 6.16, 4.36, 4.27, 3.0, and 2.93 ppm (a, b, c, d, e, g, and h), respectively (protons on GEM-S-S-NH2). The rest of the carboxylic acid groups in the polymer were also reacted with dodecylamine (DC) to provide sufficient hydrophobicity for micelle formation, as indicated by the peaks at 0.85, 0.98, and 1.23 ppm (i, j, and k), respectively. In TEPA polymer, the broad peak at 2.98 ppm for TEPA and the characteristic peaks at 1.38, 1.24, and 0.85 ppm (e, f, and g) for DC chain suggest their successful conjugation (Fig. 5B). 1H NMR spectra of intermediate products, such as mPEG-PBLA (Poly--benzyl-L-aspartate) in dimethyl sulfoxide (DMSO)d6, Boc-Ala-SS-OH in CDCl3, Diboc-GEM in DMSO-d6, Boc-Ala-SS-Diboc-GEM in CDCl3, Ala-SS-GEM in DMSO-d6, and GE11-PEG-co-P(Asp)-g-DC in DMSO-d6, are also shown in fig. S5.

(A and B) 1H NMR spectra of mPEG-co-P(Asp)-g-TEPA-g-DC and mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC. (C) Particle size distribution of redox-sensitive mixed micelles, as determined by dynamic light scattering. (D) Surface morphology and particle size distribution of mixed micelles determined by atomic force microscopy. (E) mPEG-co-P(Asp)-g-TEPA-g-DC forms complexes with miRNA at the N:P (TEPA:miRNA) ratio of 4:1 and above, as determined by gel electrophoresis. (F) GEM and miRNA release profiles from micelles with or without miR-519c demonstrate GSH-responsive GEM release and controlled release of miRNA in the presence of GSH.

The particle size distribution of miR-519ccomplexed and GEM-conjugated redox-sensitive mixed micelles was prepared using mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC and mPEG-b-PCC-g-DC-g-TEPA (Fig. 5C). As determined by atomic force microscopy, these mixed micelles were spherical in shape and narrow particle size distribution, with the mean particle size of 129.5 5 nm (Fig. 5D). GEM loading was 14% in the polymer conjugate, as determined after alkaline hydrolysis and analysis with high-performance liquid chromatographyultraviolet (HPLC-UV), which was consistent with the NMR calculation. Micelles prepared using mPEG-co-P(Asp)-g-TEPA-g-DC had the mean particle size of 77.18 nm and formed a complex with miRNA at a very low N:P ratio (4:1) (fig. S6). The particle size of mixed micelles based on the above two polymers was 160 nm. Drug-polymer conjugates and miRNA were analyzed for their drug release profiles at different conditions. In the absence of GSH, GEM conjugates were stable and released only up to 5% of GEM within 4 days. Disulfide conjugates released significant amounts of GEM within an hour in 10 mM GSH. These results confirmed that disulfide conjugates were stable at physiological conditions but rapidly released GEM in the reducing environment. The release profile demonstrated a controlled release of miRNA from GEM conjugates/TEPA micelles over 2 days (Fig. 5F).

To optimize GE11 peptide concentration for enhanced EGFR receptormeditated endocytosis, we determined the effect of GE11 peptide on the cellular uptake of micelles after incubation of MIA PaCa-2R cells with coumarin G6loaded mixed micelles prepared at 10:90, 20:80, and 30:70 ratios of GE11 peptidedecorated micelles and nontargeted micelles. There was an increase in cellular uptake with increasing GE11 peptide concentration, but the level of cellular uptake for the mixed micelles at 20:80 and 30:70 ratios was similar (fig. S7A). To avoid the effect of high GE11 peptide concentration on micellar stability and systemic toxicity, we did not formulate targeted micelles beyond 30:70 ratio. Preincubation of cells with excess of free GE11 peptide significantly reduced the cellular uptake of the mixed micelles, indicating that the uptake was receptor mediated (fig. S7A). Then, we determined the biodistribution of GEM to the tumor at 6 and 24 hours after systemic administration of nontargeted and EGFR-targeted GE11-decorated GEM-conjugated OMe-PSmiR-519c mixed micelles into desmoplastic pancreatic tumorbearing nonobese diabetic/severe combined immunodeficientgamma null (NSG) mice at the doses of GEM (20 mg/kg) and miRNA (1 mg/kg). Desmoplastic orthotopic mouse model recapitulates hypoxic tumor microenvironment responsible for decreased drug delivery and chemoresistance in pancreatic cancer. At 6 and 24 hours after administration, GEM and miRNA were extracted from the tumor, and the liver and their concentrations were determined by liquid chromatographytandem mass spectrometry (LC-MS/MS) (using 5-Aza-2-dC as an internal standard) and real-time PCR, respectively. We observed significantly higher GEM and miR-519c concentrations in the tumor at 6 and 24 hours after administration of GE11 peptidedecorated combination mixed micelles compared to nontargeted combination mixed micelles (Fig. 6A). In contrast, GEM concentrations in the liver at 6 and 24 hours after administration of GE11 peptidedecorated combination mixed micelles were significantly lower than those of the mice injected with nontargeted combination mixed micelles (fig. S8A). The relative levels of miR-519c were higher in the tumor at 6 and 24 hours after administration of GE11 peptidedecorated combination mixed micelles compared to nontargeted combination mixed micelles (fig. S8C).

(A) Biodistribution of GEM and OMe-PSmiR-519c at 6 and 24 hours after injection of nontargeted (NT) and GE11-targeted micelles following intravenous injection at GEM dose of 20 mg/kg and miR-519c dose of 1 mg/kg. GEM concentration was determined by LC-MS/MS using 5-Aza-2-dC as an internal standard for GEM quantification. miR-519c concentration was determined by real-time PCR. (B) Bioluminescence images of tumors and isolated tumor images at the end of the experiment. (C) Tumor weight after treatment and (D) body weight. (E) Representative microscopic pictures of immunohistochemical staining for HIF-1, -SMA, Ki-67, and cleaved caspase-3. Scale bars (10), 200 m. Photo credit: Xiaofei Xin, University of Nebraska Medical Center. *P < 0.05 and *P < 0.001, two-paired t test.

Desmoplastic orthotopic mouse model recapitulates hypoxic tumor microenvironment responsible for decreased drug delivery and chemoresistance in pancreatic cancer. Micelles were injected intravenously three times a week for 2 weeks, and tumor growth was monitored by in vivo imaging system (IVIS) bioluminescence imaging. The rationale of doses and schedules of individual drugs were designed on the basis of previous studies (21). Notably, the combination therapy had lower doses of individual drug and miRNA. GEM micelles and OMe-PSmiR-519c micelles separately controlled tumor growth significantly more than saline or free GEM. Nontargeted combination micelles demonstrated synergy and had greater tumor growth inhibition than either GEM-conjugated micelles or OMe-PSmiR-519ccomplexed micelles, reflecting the ability of OMe-PSmiR-519c to down-regulate HIF-1 and resensitize pancreatic cancer to GEM. EGFR-targeted GE11 peptidedecorated mixed micelles were even more effective than nontargeted mixed micelles in controlling tumor growth (Fig. 6B). The tumor weight was the lowest for GE11 peptidedecorated combination micellestreated group compared to all treated groups (Fig. 6C). We did not observe a decrease in body weight or morbidity in mice (Fig. 6D).

Hematoxylin and eosin (H&E) staining of tumor tissues confirmed the extensive apoptotic and necrotic cells throughout the tumor in the control group and the inhibition of proliferation of tumor cells in the treated groups. Compared to the control and free GEM group, the tumor samples from GEM conjugated redox-sensitive micellestreated group exhibited with limited metastatic cells (Fig. 6E). Coinjection of hPSCs with MIA PaCa-2R cells stimulated tumor growth by inducing fibrosis, as evidenced by the overexpression of smooth muscle actin (-SMA) in the tumor of the saline-treated group (Fig. 6E). Treatment of the mice with GEM-conjugated redox-sensitive micelles or miR-519ccomplexed micelles showed a significantly less -SMApositive fibrotic area (Fig. 6E). However, the mice treated with the combination therapy showed the least -SMApositive staining in the tumor.

Ki-67 protein is an excellent marker for determining the cell proliferation. Ki-67 staining of tumor tissues confirmed the extensive cell proliferation in the nontreated control group compared to the free GEM-treated group. Tumor tissues treated with GEM-conjugated redox-sensitive micellestreated group showed a significantly lower number of cells Ki-67positive cells (Fig. 6E). Furthermore, cleaved caspase-3 staining of tumor tissues indicated the induction of significant apoptosis by treatment with GEM redox-sensitive micelles and miR-519c micellestreated groups, compared to free GEM- and saline-treated group. GE11 peptidedecorated combination micellestreated group showed the lowest Ki-67 and highest cleaved caspase-3 expression compared to all other treatment groups (Fig. 6E). In addition, we determined the systemic toxicity of GE11-decorated combination micellestreated groups and saline-treated control group by histological analysis of the major organs. There were no noticeable histological changes observed in the livers, spleens, kidneys, and hearts from the treatment groups (fig. S9), suggesting that the mice tolerated GE11 peptidedecorated combination micellar formulation of GEM and miR-519c treatment well.

These findings indicated that EGFR-targeted micelles were able to deliver miR-519c and GEM to the tumor sites and release the antitumor agents via redox responsiveness, thus resulting in maximum synergy against pancreatic cancer without additional toxicities.

PDAC is a recalcitrant disease characterized by highly aggressive cancer cells, extensive desmoplastic reaction, and hypovascularization. These unique features endow PDAC tumors with an array of resistance mechanisms against standard-of-care chemotherapy treatments (22). It is, therefore, urgent to identify novel targets that can sensitize tumor cells. Desmoplastic and hypoxic pancreatic tumor microenvironments play multifaceted roles in inducing chemotherapy resistance, promoting distant metastasis, and serving as a barrier to drug delivery (23). Hypoxic microenvironment activates quiescent PSCs in extracellular matrix (ECM) by up-regulation of Hh signaling ligands (Fig. 1D). Strong desmoplasia severely affects vascular function, resulting in hypovascularization of the tumor, which up-regulates HIF-1 expression (fig. S1). Therefore, a cycle of hypoxia and desmoplasia is amplifying each other. This cycle could be blocked by HIF-1 inhibition, which was found sufficient enough to impede Hh signaling (24).

Aberrant expression of miRNA correlates with altered expression of genes responsible for stemness, metastasis, cancer metabolism, hypoxia, and chemoresistance (25). The advantage of miRNAs lies in their ability to modulate multiple cellular pathways simultaneously, which are difficult to target by small molecules and therapeutic proteins. miR-519c is down-regulated in pancreatic cancer patient tissues and different cell lines (Fig. 1, A and B) but can target HIF-1 and Hh ligands such as SHH and GLI, as determined by Western blotting (Fig. 1, C and D). Therefore, miR-519c could be a promising strategy in the inhibition of desmoplasia of pancreatic cancer and other hypoxia-related genes. The presence of miR-519c prevented migration of MIA PaCa-2R cells in the presence of hPSC-conditioned medium (Fig. 1E), indicative of miR-519cmediated inhibition of tumor cellstromal metabolic interactions. The tumor microenvironment promotes the interactions between cancer cells and their surrounding cancer-associated fibroblasts (CAFs; PSCs in this case). This feedback is reciprocal, and CAFs can both promote and impair cancer progression, while cancer cells promote PSC activation, proliferation, migration, and ECM remodeling capability via the Hh pathway. Activated PSCs secrete numerous growth factors including platelet-derived growth factor, transforming growth factor, and inflammatory cytokines in the tumor (26). Many reports suggest that HIF-1 induces migration in pancreatic cancer cells by regulating genes such as EMT regulators Snail, chemokine (C-X3-C motif) receptor 1 (CX3CR1), and glucose metabolism (27, 28). We have shown that inhibiting HIF-1 decreased several metabolism-related genes such as GLUT1, NME4, LDHA, HKII, and TKT (Fig. 2, A and D), thus providing the rationale for reduced migration of MIA PaCa-2R cells in the presence of miR-519c.

Resistance to chemotherapeutic drugs in pancreatic cancer could have many causes, such as intrinsic resistance mechanisms and desmoplastic microenvironments that promotes cancer cell resistance by providing an environment that hampers drug delivery. HIF-1mediated metabolic alterations that facilitate GEM resistance in pancreatic cancer cells have been recently reported (29). GEM-resistant pancreatic cancer cells maintain a higher dC pool. Increased glucose metabolism fuels GEM resistance in pancreatic cancer cells, supporting de novo synthesis of dC through nonoxidative PPPs. Here, we show that GEM resistance in hypoxic pancreatic cancer cells can be reversed by miR-519c repletion. The coordinated transcription induction of genes encoding glycolytic enzymes and pyrimidine synthesis in response to hypoxia is mediated by HIF-1. Consistent with HIF-1 down-regulation by miR-519c, we found that miR-519c may counteract hypoxia-induced increase in glycolytic influx and intracellular dCTP level (Figs. 2 and 3).

Hypoxia up-regulates glucose metabolism, angiogenesis, and drug-resistant genes (30). HIF-1 signaling transactivates a multitude of target genes that enhance glucose uptake, as determined by an increase in 2-DG (Fig. 2B), glycolysis, and oxidative phosphorylation, thus facilitating cancer cell survival under oxygen- and glucose-deprived microenvironments. HIF-1 also results in an increase in pancreatic cancer, leading to increased dCTP pool and GEM resistance (Figs. 2D and 3A). Hypoxia and overexpression of HIF-1 ultimately promote induction of an invasive and treatment-resistant phenotype of pancreatic cancer.

We have reported previously that under in vitro conditions, GEM is highly effective in mediating toxicity against human pancreatic cancer cells. In contrast, orthotopic tumors in the pancreas were resistant to systemic therapy of GEM. Many factors affect GEM efficacy in vivo, including higher-rate metabolism, dose-limiting toxicity, competition with cellular dCTP pool, various efflux mechanisms, and poor penetration into the bulk of the tumor.

ABCG2 is an efflux transporter that is often observed in drug-resistant cancer cells and contributes to a multidrug resistance phenotype. ABCG2 may help provide a survival advantage during conditions of hypoxia and allow cells to escape the toxic effects of chemotherapeutic drugs. HIF-1 binds to the hypoxia response element, and binding of latter to the ABCG2 promoter increases its transcription in pancreatic cancer cells (31). Our data suggest that miR-519c, by inhibiting HIF-1, decreases ABCG2-mediated GEM resistance. Over the decades, researchers faced the technical hurdles associated with bringing a therapeutic oligonucleotide product to market. A key hurdle includes getting small interfering RNA/miRNA molecules into the right cells in vivo. Delivery of miRNAs is difficult because they are relatively large, chemically unstable, immunogenic, and negatively charged molecules that do not cross the cell membrane (32). Previously, we have shown that rationally designed chemically modified miRNA could provide an excellent solution by increasing their stability and decreasing their immunogenicity (18). Here, we chemically modified miR-519c with OMe-PS at its 3 end to enhance stability, in vivo half-life, and loading affinity into the RISC (Fig. 4).

The therapeutic efficacy of GEM depends on its delivery to the tumor site, activation by dC kinase to GEM monophosphate, and evading deactivation by cytidine deaminase. As discussed above in detail, desmoplasia makes it difficult for GEM to achieve adequate accumulation inside the tumor after systemic administration. Previously, we have shown that PEGylation prolongs the circulation of GEM-conjugated micelles and improves its overall therapeutic effect (14).

EGFR overexpression is observed in pancreatic cancer cells (33). EGFR-binding monoclonal antibody cetuximab (C225) blocks the binding of EGFR ligands to the receptor. Although cetuximab can exert an anticancer effect in patients expressing wild-type KRAS, pancreatic cancer that expresses mutated KRAS (Kirsten rat sarcoma) in 95% of cases is resistant to cetuximab therapy. EGFR expression is also high in distant metastatic pancreatic cancer (34), hence provides an ideal candidate for targeted drug delivery. Previously, we demonstrated higher tumor accumulation when cetuximab-conjugated micelles were administered into orthotopic PC (pancreatic cancer)bearing NSG mice, which resulted in low tumor burden compared to immunoglobulin Gtargeted and nontargeted micelles (21). To avoid high mitogenic potential of full-length EGFR antibody cetuximab, we developed GE11 peptide (CYHWYGYTPQNVI)decorated micelles, reported equal target binding capacity as of cetuximab, and showed higher drug accumulation and better efficacy (35). Further, small-sized PEGylated nanoparticles and micelles are preferentially accurate at the tumor and inflammatory sites via passive targeting (2).

To further improve our delivery system, here, we developed a new redox-sensitive therapeutic strategy to enhance the chemotherapeutic efficacy in pancreatic cancer, while reducing systemic side effects at the same time. GEM conjugated with the polymer via an amide bond shows very slow release from the micelles, thus proved to be a bottleneck for effective drug concentration. A conjugate with disulfide bonds, which can be easily cleaved by reducing GSH into sulfhydryl groups, causes the degradation of micelles and facilitates the release of the drug. The disulfide bond in mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC can be readily broken by GSH, the concentration of which is significantly higher in tumor than the normal tissues. That can facilitate the precise release of GEM in the tumor site and limit its toxicity to normal organs.

For codelivery, we synthesized mPEG-co-P(Asp)-g-DC-g-S-S-GEM, mPEG-P(Asp)-g-TEPA-g-DC, and GE11-PEG-P(Asp)-g-DC to load GEM and miR-519c in the hydrophobic core (Fig. 5). Because of the complexity of different components, we formulated mixed micelles using different ratios of these polymers. Our novel formulations offer distinct advantages such as targeted delivery of GEM and miR-519c, prevention of rapid deamination of GEM, and the intratumoral release of GEM based on intracellular stimuli such as GSH (Fig. 5F), thus reducing toxicity to normal tissues, and enhanced stability of miRNA. Moreover, PEG shell can prevent aggregation and impart a high degree of stability and stealth effect, leading to the enhanced mean residence time of the drug and miRNA.

EGFR expression plays an important role in metastasis, especially liver metastasis, and recurrence of human pancreatic cancer (34). EGFR facilitates metastasis in pancreatic cancer through activation of Akt and extracellular signalregulated kinase pathway. Metastatic nodules have higher EFGR expression level than the primary tumor, but we did not observe those nodules in the liver, as evidenced by H&E staining (Fig. 6E). The total mass balance of the injected dose might be the reason for lower accumulation of GE11 combination micelles in the liver than the nontarget micelles (fig. S8, A and B).

The rationale of combination therapy that combines two or more therapeutic agents is to lower the doses of individual drug and miRNA to achieve better therapeutic outcome and minimize dose-related side effects (36). Since miR-519c resensitizes pancreatic cancer cells to GEM, we decreased the dose of GEM from 40 to 20 mg/kg and the dose of OMe-PSmiR-519c from 2 to 1 mg/kg when used in combination to determine whether there is synergism in their therapeutic efficacy. GEM-conjugated OMe-PSmiR-519ccomplexed mixed micelles exhibited the highest synergy in tumor regression after systemic administration in orthotopic pancreatic tumorbearing mice (Fig. 6, B and C), with no weight loss (Fig. 6D) or any sign of toxicity in the vital organs of mice from any group during or after the treatment. We observed a significant decrease in HIF-1, -SMA, and Ki-67 expression and a decrease in the cleaved caspase-3 expressions in the combination treatment group (Fig. 6E). This might be attributed to GE11 peptidedecorated micelles achieving higher concentrations of GEM and OMe-PSmiR-519c in the tumor. High -SMA in pancreatic cancer is associated with dense stroma reaction and worse patient outcome. -SMA is expressed by activated PSCs, in response to hypoxia and Hh signaling.

Particle size distribution, shape, and surface morphology of nanoparticles affect their biodistribution and accumulation at the tumor site (37, 38). The particle size distribution of mPEG-co-P(Asp)-g-TEPA-g-DC/miR-519ccomplexed micelles, GEM-conjugated mPEG-co-P(Asp)-g-Ala-S-S-GEM-g-DC micelles, and their combination micelles was 100 20 nm (Fig. 5, C and D). On the basis of our previous studies (2, 39), small particle size and PEGylated surface prolong the blood circulation of these micelles after systemic administration. However, stroma acts as a barrier for nanoparticle delivery to the pancreatic tumor. Since miR-519c targets hypoxia and reduces the desmoplastic barrier, we observed a decrease in -SMA expression in the tumor (Fig. 6E). Therefore, there was significant accumulation of miR-519c and GEM in the tumor after systemic administration of combination micelles (Fig. 6A and fig. S8C).

The combination of GEM and miR-519c showed a synergistic effect in the nonmetastatic orthotopic desmoplastic pancreatic cancer mouse model (Fig. 6), which suggests that this treatment could be useful for patients with stage 0 to III pancreatic cancer. Although we did not observe liver metastasis during the therapeutic study, EGFR expression is expected to be higher in hepatic metastatic nodules than in the primary tumor. Hence, GE11-based nanoparticle delivery platform has the potential to target the metastatic nodules in the liver or other distant metastasis in stage IV (34). More data related to the therapeutic effect study in the orthotopic pancreatic tumor mouse model of liver metastasis will be needed to testify this in the future.

In conclusion, the key hurdles of the clinical translation of nanomedicine are biological barriers, large-scale manufacturing, biocompatibility, and safety (40, 41). The characterization of our combination micelles shows sufficient drug loading of GEM and miRNA, redox-responsive release of GEM, and controlled release of miRNA. The GE11-targeting mixed micelle system proposed in this study leads to active EGFR targeting, significant accumulation in desmoplastic pancreatic tumor, precise release of GEM and miR-519c at tumor sites with the disulfide bond, and efficient synergistic therapeutic effect in vivo. In addition, the PEG corona prolonged the circulation time of micelles and has no observed toxicity in major organs, which enhance the biocompatibility and safety of this platform. Further, scale-up of this delivery system is feasible and can support a first-in-human phase 1 clinical trial.

Dulbeccos modified Eagles medium (DMEM) high-glucose medium, 0.25% trypsin, and Dulbeccos phosphate-buffered saline (DPBS) were purchased from HyClone (Logan, UT). Keratinocyte-SFM (serum-free medium) medium, bovine pituitary extract, and human recombinant EGF were purchased from Gibco (Chevy Chase, MD). Heat-inactivated FBS, antibiotic-antimycotic for cell culture, radioimmunoprecipitation assay (RIPA) buffer for cell lysis and phosphatase inhibitor cocktail (100), live and dead assay kit, miR-519c-3p mimics, Pierce BCA (bicinchoninic acid) protein assay kit, RediPlate 96 RiboGreen RNA quantitation kit, and FxCycle PI/RNase staining solution (F10797) were purchased from Thermo Fisher Scientific (Waltham, MA). Hepes buffer was purchased from Millipore Sigma (St. Louis, MO). Human c-Myc primary antibody was purchased from Proteintech (Manchester, UK). GLUT1, GLI1, SHH, -actin, and SMO primary antibodies were purchased from Santa Cruz Biotechnology (Dallas, TX). Laemmli buffer (4), 10 tris/glycine/SDS protein electrophoresis running buffer (pH 8.3), and 10 tris-buffered saline buffer were purchased from Bio-Rad (Hercules, CA). HIF-1 and ABCG2 primary antibodies were purchased from Abcam (Cambridge, MA). HIF-1 primary antibody was purchased from Novus Biologicals LLC (Centennial, CO). AGO2 primary antibody was purchased from Boster Bio (Pleasanton, CA). Glucose uptake cell-based assay kit (item no. 600470) was purchased from Cayman Chemicals (Ann Arbor, MI). RNeasy mini kit, miScipt II RT kit, miScript SYBR Green kit, Hs_miR-519c-3p miScript primer assay, and Hs_RnU6 miScript primer assay were purchased from QIAGEN (Germantown, MD).

MIA PaCa-2 cell line was purchased from the American Type Culture Collection (Manassas, VA), and MIA PaCa-2resistant (MIA PaCa-2R) cells were generated from MIA PaCa-2 by incubating with GEM in a high-glucose DMEM supplemented with 10% FBS and 1% penicillin/streptomycin at 37C, 5% CO2, and 100% humidity and were split when confluent. HPDE cells were cultured in Keratinocyte-SFMsupplemented bovine pituitary extract and human recombinant EGF in an identical atmosphere. hPSCs were cultured in stellate cell basal medium supplemented with 10% FBS, stellate cell growth supplement, and 1% penicillin/streptomycin. A hypoxic chamber filled with 94% nitrogen, 5% CO2, 1% O2, and 100% humidity was used to generate hypoxic conditions as needed.

hPSC-conditioned medium was obtained using the following steps: Subconfluent PSCs were washed with PBS and incubated with stellate cell basal medium under above conditions for 48 hours. Then, the medium was collected and centrifuged for further use.

MIA PaCa-2R cells of 5 105 per well were seeded in six-well plate, and, after 24 hours, cells were treated with PBS, scrambled miRNA, and miR-519c with or without PSC-conditioned medium for 6 hours under normoxia and hypoxia, respectively. Then, 1 105 cells were collected from each well, resuspended with 200 l of serum-free DMEM, and added to Transwell upper chambers. One milliliter of DMEM containing 20% FBS that served as the chemoattractant was in the lower chamber, and the cells were incubated for 24 hours under normoxic and hypoxic conditions. A cotton-tipped swab was used to remove the cells that did not migrate through the pores. The chambers were fixed in 4% paraformaldehyde and stained with crystal violet.

MIA PaCa-2R cells of 5 104 per well were seeded in a 96-well plate. After 24 hours, cells were treated with miR-519c and scrambled miRNA in 100 l of glucose-free culture media for another 24 hours under normoxic and hypoxic conditions. Glucose uptake cell-based assay kit was applied to evaluate glucose uptake in MIA PaCa-2R cells as following: 2-NBDG (2-deoxy-2-((7-nitro-2,1,3-benzoxadiazol-4-yl)amino)-glucose) (150 g/ml) was added in glucose-free medium for 1.5 hours under normoxic and hypoxic conditions. The plates were centrifuged for 5 min at 400g at room temperature. The supernatants were discarded, and 200 l of the cell-based assay buffer was added to each well for washing cells twice. At the end, 100 l of cell-based assay buffer was added, and the plates were analyzed by a fluorescent reader with an excitation/emission of 485/535 nm to quantify 2-NBDG taken up by cells. Samples were normalized by the fluorescence intensity in scrambled miRNA under normoxia. The concentration of dCTP was quantified by LC-MS/MS.

For GLUT1 expression, MIA PaCa-2R cells at a dose of 2 105 per well were seeded in a six-well plate. After 24 hours, cells were incubated under normoxic and hypoxic conditions. Then, cells were harvested, washed with cell staining buffer three times, incubated with GLUT1 primary antibody in cell staining buffer for 1 hour, followed by Cy5-conjugated secondary antibody for another 30 min, and analyzed by flow cytometer.

MIA PaCa-2R cells at a dose of 2 105 per well were plated in a six-well plate overnight and transfected by Lipofectamine/miR-519c under normoxic and hypoxic conditions for 24 hours. Then, all samples were subjected to total RNA isolation by QIAGEN RNeasy mini kit. Reverse transcription PCR was carried out using QIAGEN miScript II reverse transcription kit. MiR-519c and mRNA levels of SHH, GLI1, NME4, LDHA, HKII and TKT were quantitatively assayed in Roche Light Cycler 480 using miScript SYBR Green PCR kit. MiR-519c and mRNA were normalized to U6 small nuclear RNA and glyceraldehyde-3-phosphate dehydrogenase levels, respectively. Primers were designed as follows: HKII-1, 5-GAGCCACCACTCACCCTACT-3 (forward) and 5-ACCCAAAGCACACACGGAAGTT-3 (reverse); TKT-1, 5-TCCACACCATGCGCTACAAG-3 (forward) and 5-CAAGTCGGAGCTGATCTTCCT-3 (reverse); NME4-1, 5-AGGGTACAATGTCGTCCGC-3 (forward) and 5-GACGCTGAAGTCACCCCTTAT-3 (reverse).

For Western blot assay, all samples were isolated with RIPA buffer on ice within 5 min to prevent HIF-1 degradation when reexposed to O2, and the protein concentration was determined with Pierce BCA protein assay kit. After that, cell lysates were mixed with Laemmli loading buffer, boiled at 100C for 5 min, loaded in the wells of 4 to 15% SDSpolyacrylamide gel electrophoresis gel, transferred by electroporation to polyvinylidene difluoride membrane, and incubated with blocking buffer for 1 hour at room temperature first and then with antiHIF-1, antic-Myc, anti-ABCG2, antiHIF-1, and anti-actin primary antibody overnight at 4C. IR-680 fluorescent dyelabeled secondary antibodies were added, followed by imaging in iBright FL1000. HIF-1 and -actin were both used as the loading control.

MIA PaCa-2R cells at a dose of 2 105 per well were plated in a six-well plate and treated with scrambled miRNA and miR-519c under normoxic and hypoxic conditions for 24 hours. Then, cells were harvested, fixed with 70% ethanol in 4C for 1.5 hours, and washed three times with PBS to remove ethanol. Subsequently, cells were centrifuged, a pellet of cells was collected in tubes, and 0.5 ml of FxCycle PI/RNase staining solution was added to each flow cytometry sample for 30 min at room temperature, avoiding any exposure to light. Flow cytometry was used to test samples at an excitation/emission of 532/585 nm.

Cytotoxicity of GEM, miR-519, and their combination was determined by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. MIA PaCa-2R cells were plated at a density of 5000 cells per well in a 96-well plate overnight. Then, GEM, miR-519c-3p, and the combination of GEM and miR-519c were added to 96-well plates with a GEM concentration ranging from 0.1 to 50 M and miR-519c concentration from 5 to 100 nM under hypoxic condition. After 48 hours of incubation, MTT solution at a concentration of 5 mg/ml was added, and cells were cultured for another 3 hours. The supernatant was discarded, and 200 l of DMSO was added to each well. Cell viability was determined using a spectrophotometer.

hPSC and MIA PaCa-2R cells (1:2; a total of 600 cells in 40 l per well) in DMEM with 10% FBS were seeded onto Perfecta3D 96-Well Hanging Drop Plates (3D Biomatrix Inc., Ann Arbor MI) and incubated with 5% CO2 at 37C. On the fourth day, the spheroids were treated with GEM, miR-519c, and their combination. Cells treated with PBS and scrambled miRNA were used as controls. Morphologies of tumor spheroids were observed under a Zeiss microscope on days 6, 8, 10, and 12 to determine cytotoxicity. Live and dead assay kit was applied following the manufacturers protocol to visualize the apoptosis in desmoplastic tumor spheroids by confocal laser scanning microscopy.

Targeting gene silencing by RNA interference requires RISC. AGO protein is a core protein binding to miRNA. We loaded AGO2 with miRNAs by the action of a specialized assembly RISC-loading complex. To assess the difference of miRNA loading between unmodified miR-519c and OMe-PSmiR-519c, MIA PaCa-2R cells at a dose of 2 105 per well were seeded in a six-well plate and then transfected with unmodified miR-519c and OMe-PSmiR-519c using Lipofectamine for 24 hours under normoxic and hypoxic conditions. Cells were washed three times with PBS and lysed using Pierce IP lysis buffer. A Pierce BCA assay kit was applied to quantify protein concentration, and all samples were diluted to 1000 g/ml by cell lysis buffer. Ten micrograms of AGO2 primary antibody and 500 l of cell lysis buffer were mixed and incubated overnight at 4C. Then, the antigen sample/antibody mixture was added to 1.5 ml of microcentrifuge tubes containing prewashed magnetic beads and incubated for 1 hour at room temperature. After that, beads were collected with a magnetic stand and washed twice with tris-buffered saline and ultrapure water, respectively. One hundred microliters of elution buffer was incubated with samples for 10 min at room temperature. The supernatant of miRNA-AGO2 complexes was harvested after separating from beads with a magnetic stand, following which 15 l of neutralization buffer was added. Synthetic miR-39 from Caenorhabditis elegans (Cel-miR-39) was selected as a spike-in control for miRNA quantification by RTquantitative PCR. For this purpose, first, all samples were isolated by QIAGEN RNeasy mini kit, then reverse transcribed by miScript II RT kit, and amplified with miScript SYBR Green PCR kit using Roche LightCycler 480.

Redox-responsive GEM-conjugated copolymer, TEPA-containing copolymer for complex formation with miRNA, and EGFR-targeting GE11 peptideconjugated copolymer were synthesized, as illustrated in Fig. 7 as described below:

GE11 peptide, CYHWYGYTPQNVI. (A) Synthesis of BLA-NCA. (B) Synthesis of mPEG-PBLA. (C-F) Synthesis of Ala-SS-GEM. (G) Synthesis of mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC and mPEG-P(Asp)-g-TEPA-g-DC. (H) Synthesis of GE11-PEG-co-P(Asp)-g-DC. rt: room temperature, EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, HoBt: Hydroxybenzotriazole, TEA: triethylamine.

Step 1: Synthesis of BLA-NCA: We synthesized -benzyl l-aspartate N-carboxy anhydride (BLA-NCA) by reacting l-aspartic acid -benzyl ester with triphosgene in tetrahydrofuran (THF) under N2 atmosphere. (Fig. 7A).

Step 2: Synthesis of amphiphilic polyamino copolymer mPEG-P(Asp): We synthesized mPEG-PBLA by ring-opening polymerization of BLA-NCA using mPEG-NH2 (weight-average molecular weight, 5000) as a macroinitiator in dry N,N-dimethylformamide at 55C under the N2 atmosphere for 48 hours (Fig. 7B).

Step 3: Synthesis of Ala-SS-GEM: We synthesized Ala-SS-GEM using the following four steps: First, Boc--Ala-OH was reacted with bis(2-hydroxyethyl) disulfide using dicyclohexylcarbodiimide (DCC) coupling reaction in the presence of 4-dimethylaminopyridine in THF. The crude product was purified by flash column chromatography to obtain the intermediate Boc-Ala-SS-OH as a colorless liquid (Fig. 7C). Second, Diboc-GEM was synthesized by reacting GEM HCl, and Boc-anhydride was dissolved in a mixture of dioxane and 1.0 M KOH at room temperature. After completion of the reaction, the reaction mixture was extracted with EtOAc (Ethyl acetate) and washed; dried organic layer was concentrated and, again, treated with Boc-anhydride in 1.0 M KOH solution. After completion of the reaction, the mixture was washed and dried, and the combined organic layer was evaporated and purified by column chromatography to give diboc-GEM a white solid product (Fig. 7D). Third, the intermediate Boc-Ala-SS-OH and diboc-GEM were reacted with triphosgene in the presence of pyridine in anhydrous dichloromethane (DCM) for 1 hour at 0C. The reaction mixture was stirred for additional 4 hours at room temperature. The crude product was then purified using column chromatography to afford Boc-Ala-SS-Diboc-GEM as a colorless oil (Fig. 7E). Last, Ala-SS-GEM was synthesized by removing the Boc groups in a mixture of DCM:trifluoroacetic acid (TFA) (1:1) (Fig. 7F).

Step 4: Ala-SS-GEM and DC (DC-NH2) were conjugated to mPEG-PBLA polymer by aminolysis reaction in dry dimethylformamide at room temperature for 48 hours to afford mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC (Fig. 7G). The structure and molecular weight of mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC was determined by 1H NMR and gel permeation chromatography, respectively. Similarly, mPEG-P(Asp)-g-TEPA-g-DC was synthesized by replacing Ala-SS-GEM with TEPA.

Step 5: GE11 peptide (CYHWYGYTPQNVI) and DC were conjugated to MAL-PEG-PBLA polymer in dry dimethylformamide at room temperature overnight to get GE11-PEG-co-P(Asp)-g-DC (GE11-targeting peptide; Fig. 7H).

The mixture of mPEG-co-P(Asp)-g-TEPA-g-DC and mPEG-co-P(Asp)-g-Ala-SS-GEM-g-DC copolymers dissolved in acetone/methanol (1:1, v/v) was added drop by drop to aqueous solution containing miR-519c. To remove residual acetone and methanol, samples were evaporated in a rotary evaporator. The mixture was filtered through polycarbonate syringe filters of 200-nm pore size. Particle size was measured using Malvern Zetasizer. In vitro GEM release from redox-responsive micelles was performed under pH 7.4 with or without 10 mM GSH. Dialysis bags (molecular weight cutoff, 3500 Da) were loaded with 1 ml of redox-responsive micelles, immersed into 30 ml of PBS buffer solutions, and shaken at a speed of 100 rpm at 37C (n = 3). GEM concentration was determined by HPLC-UV under the following conditions: C18 column (5 m, 250 4.6 mm), flow rate (1 ml/min), acetonitirle and water (90:10, v/v) as mobile phase, an injection volume of 20 l, and a wavelength of 267 nm. In vitro miRNA release from TEPA micelles was carried out by suspending the formulation to PBS buffer solutions under pH 7.4 at each time point and shaking at a speed of 100 rpm at 37C (n = 3). The samples were centrifuged, and the supernatants were collected at each time point. The concentration of released miRNA was tested by RiboGreen RNA quantification kit.

All the animal experiments were approved by the Institutional Animal Care and Use Committee of the University of Nebraska Medical Center, Omaha, NE and carried out as per the National Institutes of Health guidelines. The orthotopic human pancreatic cancer mouse model was developed using 6- to 8-week-old male NSG mice (20 to 25 g). Luciferase stably expressing MIA PaCa-2R cells (0.5 106) and hPSCs (0.5 106) were mixed with Matrigel (2:1) using ice-cold instruments and syringes. Then, mice were anesthetized using isoflurane in an induction chamber, and 30 l of Matrigel cell suspension was orthotopically injected into the pancreas tail. Tumor growth was monitored using the Spectrum IVIS (PerkinElmer, Hopkinton, MA) after intraperitoneal administration of luciferin (20 mg/ml) (150 l per mouse). Three weeks after tumor injection, free GEM and OMe-PSmiR-519c, combination micelles, and GE11 combination micelles were injected to mice via the tail vein as a single administration at a dose (or dose equivalent) of GEM (20 mg/kg) and miR-519c (1 mg/kg). Mice were euthanized either at 6 or 24 hours, and major organs such as the tumor, heart, liver, spleen, lung, and kidney were collected for LC-MS/MS analysis (4000 QTRAP, AB, Sciex Inc.). Briefly, 50 mg of tissue samples were homogenized in 1 ml of PBS, spiked with 5-aza-dC as the internal standard and transferred on ice immediately. Subsequently, 3.0 ml of cold acetonitrile was added, followed by vortexing and high-speed centrifugation in 4C. The supernatant was evaporated to dryness, and the residues were reconstituted with 200 l of acetonitrile:water (10:90, v/v). LC-MS/MS data acquisition will be performed using the Analyst software on a QTRAP 4000 mass spectrometer. The mass spectrometer will be operated in the positively selected reaction monitoring for GEM [mass/charge ratio (m/z), 264.0/112.0) and internal standard (m/z, 229.0/113.0). Total RNA from tissue samples were isolated by QIAGEN RNeasy mini kit, and RT-PCR assay was applied for miR-519c quantification.

For therapeutic study, mice were randomly divided into six groups (n = 5 per group) when the bioluminescence reached 1 106. GEM at a dose of 40 mg/kg for free GEM and GEM micelles, miR-519c at the dose of 2 mg/kg for miR-519c micelles, and GEM at a dose of 20 mg/kg and miR-519c at 1 mg/kg for combination micelles were administered via tail vein every 3 days in a total of five injections. Body weights were measured before each dose administration. Three days after the fifth administration, the animals were euthanized to harvest major organs such as the tumor, heart, liver, spleen, lung, and kidney. Examination included H&E staining, immunohistochemical, and Western blot analyses.

Results are presented as the means SD. One-way analysis of variance (ANOVA) was used to assess the statistical significance of differences between groups. A cutoff of P < 0.05 was used to indicate a significant difference.

Acknowledgments: Funding: The NIH (1R01GM113166) and the Faculty Start-up fund of the University of Nebraska Medical Center to R.I.M. are duly acknowledged for providing financial support for this work. V.R.B. is supported by the National Institute of General Medical Sciences, 1 U54 GM115458. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Author contributions: X.X., Virender Kumar, and R.I.M. designed the study. X.X., F.L., Vinod Kumar, and R.B. performed the experiments and collected data. X.X., Virender Kumar, C.T., and R.I.M. analyzed the data. All authors interpreted the study results. X.X. and R.I.M. wrote the manuscript. All authors provided critical feedback and gave their final approval. Competing interests: All the authors except V.R.B. have declared that they have no competing interests. V.R.B. reports receiving consulting fees from Takeda, Omeros, Agios, Abbvie, Partner Therapeutics, and Incyte, research funding (institutional) from Jazz, Incyte, Tolero Pharmaceuticals, and National Marrow Donor Program, and drug support for a trial from Oncoceutics. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Redox-responsive nanoplatform for codelivery of miR-519c and gemcitabine for pancreatic cancer therapy - Science Advances

What is nanomedicine? – Definition from WhatIs.com

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Nanomedicine is the application of nanotechnology (the engineering of tiny machines) to the prevention and treatment of disease in the human body. This evolving discipline has the potential to dramatically change medical science.

Established and near-future nanomedicine applications include activity monitors, chemotherapy, pacemakers, biochip s, OTC tests, insulin pumps, nebulizers, needleless injectors, hearing aids, medical flow sensors and blood pressure, glucose monitoring and drug delivery systems.

Here are a few examples of how nanomedicine could transform common medical procedures:

The most advanced nanomedicine involves the use of nanorobot s as miniature surgeons. Such machines might repair damaged cells, or get inside cells and replace or assist damaged intracellular structures. At the extreme, nanomachines might replicate themselves, or correct genetic deficiencies by altering or replacing DNA (deoxyribonucleic acid) molecules.

In a 2006 publication on the worldwide status of nanomedicine, MedMarket Diligence reported that about 150 of the largest companies in the world are conducting nanotechnology research projects or planning nanotechnology products. According to Patrick Driscoll, President of MMD, there is a $1 billion market for nanotechnology applications, mostly in the area of MEMS (microelectromechanical systems), a figure that is likely to increase a hundred-fold by 2015.

This was last updated in May 2007

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What is nanomedicine? - Definition from WhatIs.com

Tottenham Acquisition I Limited Announces Filing of a Registration Statement on Form S-4 in Connection with its Proposed Business Combination with…

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NEW YORK, Sept. 10, 2020 /PRNewswire/ -- Tottenham Acquisition I Limited (Nasdaq: TOTA, TOTAU, TOTAW, TOTAR) ("Tottenham"), a publicly traded special purpose acquisition company, announced today that its subsidiary, Chelsea Worldwide Inc., has filed with the U.S. Securities and Exchange Commission ("SEC") a registration statement on Form S-4 (the "Registration Statement"), which includes a preliminary proxy statement/consent solicitation statement/prospectus, in connection with its recently-announced proposed business combination with Clene Nanomedicine, Inc. ("Clene"), a clinical-stage biopharmaceutical company developing a potential therapeutic nanocatalyst for the treatment of neurodegenerative diseases in addition to a nanotechnology based-therapy with antiviral applications.

Tottenham's ordinary shares are currently traded on Nasdaq under the symbol "TOTA". In connection with the closing of the transaction, Tottenham intends to change its name to Clene Inc., reincorporate in Delaware (by merging with Chelsea Worldwide Inc.) and remain Nasdaq-listed under a new ticker symbol. Completion of the transaction is subject to approval by Tottenham shareholders, Clene's stockholders, the Registration Statement being declared effective by the SEC, a concurrent closing of private placements and other customary closing conditions.

Chardan is acting as the M&A advisor to Tottenham. LifeSci Capital LLC is acting as the M&A advisor to Clene. Loeb & Loeb LLP is acting as legal advisor to Tottenham. Kirkland & Ellis LLP along with Stoel Rives LLP, Clene's local counsel, are acting as legal advisors to Clene.

About Clene Nanomedicine, Inc.

Clene Nanomedicine, Inc. is a privately held, clinical-stage biopharmaceutical company focused on the development of unique therapeutic candidates for neurodegenerative diseases. Clene has innovated a novel nanotechnology drug platform for the development of a new class of orally-administered neurotherapeutic drugs.Clene has also advanced into the clinic an aqueous solution of ionic zinc and silver for anti-viral and anti-microbial uses. Founded in 2013, the company is based inSalt Lake City, Utahwith R&D and manufacturing operations located inNorth East, Maryland. For more information, please visitwww.clene.com.

About Tottenham Acquisition I Limited

Tottenham Acquisition I Limited is a blank check company formed for the purpose of acquiring, engaging in a share exchange, share reconstruction and amalgamation with, purchasing all or substantially all of the assets of, entering into contractual arrangements with, or engaging in any other similar business combination with one or more businesses or entities. Tottenham's efforts to identify a prospective target business were not limited to a particular industry or geographic region, although the company initially focused on operating businesses in the TMT (Technology, Media, Telecom), education, e-commerce, health-care and consumer goods industries with primary operations inAsia(with an emphasis inChina).

Forward-Looking Statements

This press release contains, and certain oral statements made by representatives of Tottenham, Clene, and their respective affiliates, from time to time may contain, "forward-looking statements" within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Tottenham's and Clene's actual results may differ from their expectations, estimates and projections and consequently, you should not rely on these forward-looking statements as predictions of future events. Words such as "expect," "estimate," "project," "budget," "forecast," "anticipate," "intend," "plan," "may," "will," "could," "should," "believes," "predicts," "potential," "might" and "continues," and similar expressions are intended to identify such forward-looking statements. These forward-looking statements include, without limitation, Tottenham's and Clene's expectations with respect to future performance and anticipated financial impacts of the business combination, the satisfaction of the closing conditions to the business combination and the timing of the completion of the business combination. These forward-looking statements involve significant risks and uncertainties that could cause actual results to differ materially from expected results. Most of these factors are outside the control of Tottenham or Clene and are difficult to predict. Factors that may cause such differences include, but are not limited to: (1) the occurrence of any event, change or other circumstances that could give rise to the termination of the Merger Agreement relating to the proposed business combination; (2) the outcome of any legal proceedings that may be instituted against Tottenham or Clene following the announcement of the Merger Agreement and the transactions contemplated therein; (3) the inability to complete the business combination, including due to failure to obtain approval of the shareholders of Tottenham or other conditions to closing in the Merger Agreement; (4) delays in obtaining or the inability to obtain necessary regulatory approvals (including approval from regulators, as applicable) required to complete the transactions contemplated by the Merger Agreement; (5) the occurrence of any event, change or other circumstance that could give rise to the termination of the Merger Agreement or could otherwise cause the transaction to fail to close; (6) the inability to obtain or maintain the listing of the post-acquisition company's ordinary shares on NASDAQ following the business combination; (7) the risk that the business combination disrupts current plans and operations as a result of the announcement and consummation of the business combination; (8) the ability to recognize the anticipated benefits of the business combination, which may be affected by, among other things, competition, the ability of the combined company to grow and manage growth profitably and retain its key employees; (9) costs related to the business combination; (10) changes in applicable laws or regulations; (11) the possibility that Clene or the combined company may be adversely affected by other economic, business, and/or competitive factors; and (12) other risks and uncertainties identified in the Form S-4 filed by Chelsea Worldwide relating to the business combination, including those under "Risk Factors" therein, and in other filings with the Securities and Exchange Commission ("SEC") made by Tottenham and Clene. Tottenham and Clene caution that the foregoing list of factors is neither exclusive nor exhaustive. Tottenham and Clene caution readers not to place undue reliance upon any forward-looking statements, which speak only as of the date made. Neither Tottenham or Clene undertakes or accepts any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements to reflect any change in its expectations or any change in events, conditions or circumstances on which any such statement is based, subject to applicable law. The information contained in any website referenced herein is not, and shall not be deemed to be, part of or incorporated into this press release.

Important Information

Chelsea Worldwide Inc., Tottenham, and their respective directors, executive officers and employees and other persons may be deemed to be participants in the solicitation of proxies from the holders of Tottenham ordinary shares in respect of the proposed transaction described herein. Information about Tottenham's directors and executive officers and their ownership of Tottenham's ordinary shares is set forth in Tottenham's Annual Report on Form 10-K filed with the SEC, as modified or supplemented by any Form 3 or Form 4 filed with the SEC since the date of such filing. Other information regarding the interests of the participants in the proxy solicitation are included in the Form S-4 pertaining to the proposed transaction. These documents can be obtained free of charge from the sources indicated below.

In connection with the transaction described herein, Chelsea Worldwide Inc. will file relevant materials with the SEC including a Registration Statement on Form S-4. Promptly after the Registration Statement is declared effective, Tottenham will mail the proxy statement and a proxy card to each shareholder entitled to vote at the extraordinary general meeting relating to the transaction. INVESTORS AND SECURITY HOLDERS OF TOTTENHAM ARE URGED TO READ THESE MATERIALS (INCLUDING ANY AMENDMENTS OR SUPPLEMENTS THERETO) AND ANY OTHER RELEVANT DOCUMENTS IN CONNECTION WITH THE TRANSACTION THAT TOTTENHAM WILL FILE WITH THE SEC WHEN THEY BECOME AVAILABLE BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION ABOUT TOTTENHAM, CLENE AND THE TRANSACTION. The proxy statement/consent solicitation/prospectus and other relevant materials in connection with the transaction (when they become available), and any other documents filed by Tottenham with the SEC, may be obtained free of charge at the SEC's website (www.sec.gov).

SOURCE Tottenham Acquisition I Limited

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Tottenham Acquisition I Limited Announces Filing of a Registration Statement on Form S-4 in Connection with its Proposed Business Combination with...

Blood Group Typing Market | Asia Pacific is Expected to Lead at the Fastest Pace in Future – BioSpace

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Blood group typing is a process of identifying type of blood that a person has. The process depends on the level of antigens on Red Blood Cells (RBC) present. Blood group typing is usually conducted during organ and blood donation as organ or blood donation requires blood transfusion and also the knowledge of Rh factor present on the RBC. Identification of blood group is also important during the pregnancy as it prevents the new born from exposure of anemia. The global blood group typing market has seen a rise in growth due to technological advancements in the healthcare sector.

The market is about to grow during the forecast period because of the increasing research and development activities in forensic science, increase in the number of accidents, rising organ donation, and increase number of pregnancy. On the downside, the lack of skilled professional is expected to slug the growth rate of this market, as pure professionals are needed in this area. The world blood group typing market is segmented on the basis of types of test, techniques used, end users, and offerings.

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On the basis of product and services, the market is segmented into instruments, services and consumables. Consumable section held largest share in the global blood typing market in 2016. It accounts for the major contribution in the market. On the basis types of test, the market is classified into antigen typing, antibody screening, human leukocyte, ABO blood tests, and cross matching tests. Rise in increase of identification of the disease at its initial stage has increased the growth in the usage of the antibody screening test.

North America has emerged dominant in the global blood group typing market. Asia Pacific is expected to lead at the fastest pace in future as the development of the medical sector touch sky.

Global Blood Group Typing Market: Overview

Blood group typing consists of various methods and techniques that are used to detect the group of blood. The correct and reliable grouping of blood is vital to fulfil a variety of clinical ends, especially for safe blood transfusion and in organ donation processes. In recent years, there have been marked developments in the conventional detection methods. Constant technological advancements in microarray, polymerase chain reaction (PCR), and other assay-based techniques have improved detection methods. As a result, the market has seen the advent of high-throughput devices that enable clinicians in multiplexed and quantitative detection of various blood group antigens. Advanced methods such as quantum dots (QDs) and magnetic beads in assays improve identification and enhance clinical safety of blood transfusion.

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Global Blood Group Typing Market: Key Trends

The rising number of blood donations and increasing number of patients needing transfusion due to accidents and trauma are the primary factors driving the blood group typing market. The growing demand for blood group typing for pregnancy and prenatal testing has boosted the market. Blood typing is also crucial to detect the condition of hemolytic disease of the newborn (HDN) in pregnant women, thereby stimulating the demand for such tests. Increasing application of blood group typing in forensic sciences is further expected to catalyze the market growth.

The advent of novel molecular diagnostic tools that help in reliable and rapid identification of group in a large blood samples is expected to provide abundant opportunities to market players. For instance, the molecular genotyping of ABO blood groups in large populations can be accomplished with the help of these methods.

Global Blood Group Typing Market: Market Potential

A recent clinical study published in International Journal of Nanomedicine reveals that scientists have developed a novel multiplexed method for the identification of ABO blood groups. The study was approved by the Ethics Committee of Southwest Hospital, Third Military Medical University, a prominent military institution of higher learning in China. Researchers conducting the study, quantified blood group A and B antigens with QD fluorescence assay (QFA). The assay integrates the traditional QD labeling with magnetic beads to make high throughput and quantitative method for rapid detection of antigens present in the ABO blood groups of fairly large volume populations. The scientists evaluated the efficacy of the method by testing the blood samples for 791 people and they confirmed that the accuracy was 100%; in addition, they asserted that when the conditions were optimized, even detection in weak samples produced satisfactory results.

An estimate by the researchers states that the multiplexed detection can be completed within the short span of 35 minutes with over 105 RBCs (red blood cells). This study holds marked significance for blood transfusion safety. The findings of the study show promising prospect for the blood group typing market, since the testing process can be used to devise an effective clinical strategy to improvise on the identification methods for ABO blood groups.

Global Blood Group Typing Market: Regional Outlook

Geographically, North America is a prominent market for blood group typing devices and consumables. The regional market is expected to witness substantial growth in the coming years. The growth of the market is attributed to the constant technological advancements in PCR and assays for blood grouping leading to the design of cost-effective and novel blood-grouping platforms.

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Meanwhile, Asia Pacific is expected to provide lucrative avenues over the forecast period from 2017 to 2025. The impressive pace of growth of the Asia Pacific market for blood group typing is driven by some promising clinical studies in high throughput devices, increasing healthcare spending, and the growing number of blood transfusions.

Global Blood Group Typing Market: Competitive Analysis

Several players are making innovations in their offerings and using advanced technologies to discover novel methods for blood group typing. Key companies operating in the blood group typing market are Novacyt Group, Day medical SA, Rapid Labs, Quotient, Ltd., AXO Science, Bio-Rad Laboratories, Inc., Ortho Clinical Diagnostics, Inc. Immucor, Inc., and Grifols, S.A.

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Blood Group Typing Market | Asia Pacific is Expected to Lead at the Fastest Pace in Future - BioSpace

Nanomedicine Market Size by Top Key Players, Growth Opportunities, Incremental Revenue , Outlook and Forecasts to 2026 – Latest Herald

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Global Nanomedicine Market is Segmented by Application, End-Use, Product Type and Region

Global Nanomedicine Market 2020: This is a latest report, covering the current COVID-19 impact analysis on the market. This has led to several changes in market conditions. The rapidly changing market scenario as well as the first and future impact assessment are covered with in the report.

The Nanomedicine Market research report included analysis of various factors that increase market growth. It contains trends, restrictions and drivers that change the market positively or negatively. The Nanomedicine Market Report includes all key factors that affect global and regional markets, including drivers, detention, threats, challenges, risk factors, opportunities, and industry trends. This business research paper provides an in-depth assessment of all critical aspects of the global market in relation to Nanomedicine market size, market share, market growth factor, main suppliers, sales, value, volume, main regions, industry trends, product demand, capacity, cost structure and Nanomedicine market expansion. The report begins with an overview of the structure of the industry chain and describes the industry environment. Then the size of the market and the Nanomedicine forecasts are analyzed by product type, application, end use and region. The report presents the situation of competition on the market between suppliers and the profile of the company. In addition, this report analyzes the market prices and treated the characteristics of the value chain.

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The major players in the market include:

Global Nanomedicine Market: Competitive Landscape

This section of the report lists various major manufacturers in the market. The competitive analysis helps the reader understand the strategies and collaborations that players focus on in order to survive in the market. The reader can identify the players fingerprints by knowing the companys total sales, the companys total price, and its production by company over the 2020-2026 forecast period.

Global Nanomedicine Market: Regional Analysis

The report provides a thorough assessment of the growth and other aspects of the Nanomedicine market in key regions, including the United States, Canada, Italy, Russia, China, Japan, Germany, and the United Kingdom United Kingdom, South Korea, France, Taiwan, Southeast Asia, Mexico, India and Brazil, etc. The main regions covered by the report are North America, Europe, the Asia-Pacific region and Latin America.

The Nanomedicine market report was prepared after various factors determining regional growth, such as the economic, environmental, technological, social and political status of the region concerned, were observed and examined. The analysts examined sales, production, and manufacturer data for each region. This section analyzes sales and volume by region for the forecast period from 2020 to 2026. These analyzes help the reader understand the potential value of investments in a particular country / region.

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Key Benefits for Stakeholders:

The report provides an in-depth analysis of the size of the Nanomedicine world market, as well as recent trends and future estimates, in order to clarify the upcoming investment pockets.

The report provides data on key growth drivers, constraints and opportunities, as well as their impact assessment on the size of the Nanomedicine market.

Porters 5 Strength Rating shows how effective buyers and suppliers are in the industry.

The quantitative analysis of the Nanomedicine world industry from 2020 to 2026 is provided to determine the potential of the Nanomedicine market.

This Nanomedicine Market Report Answers To Your Following Questions:

Who are the main global players in this Nanomedicine market? What is the profile of your company, its product information, its contact details?

What was the status of the global market? What was the capacity, the production value, the cost and the profit of the market?

What are the forecasts of the global industry taking into account the capacity, the production and the value of production? How high is the cost and profit estimate? What will be the market share, supply, and consumption? What about imports and export?

What is market chain analysis by upstream raw materials and downstream industry?

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Tags: Nanomedicine Market Size, Nanomedicine Market Trends, Nanomedicine Market Growth, Nanomedicine Market Forecast, Nanomedicine Market Analysis

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Nanomedicine Market Size by Top Key Players, Growth Opportunities, Incremental Revenue , Outlook and Forecasts to 2026 - Latest Herald

Nanomedicine Market 2020 Recent Industry Developments and Growth Strategies Adopted by Top Key Players Worldwide and Assessment to 2025 – Bulletin…

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The Nanomedicine Market research report is one of the most comprehensive report about business strategies adopted by different players in this Market. This research study gives the potential headway openings that prevails in the global market. It offers detailed research and analysis of key aspects of the Nanomedicine Market.

The market analysts authoring this report have provided in-depth information on leading growth drivers, restraints, challenges, trends, and opportunities to offer a complete analysis of the Nanomedicine Market. Moreover, the report gives nitty gritty data on different manufacturers, region, and products which are important to understand the market.

Impact of COVID- 19 on Nanomedicine Market

Due to the pandemic, we have included a special section on the Impact of COVID 19 on the Nanomedicine Market, which would mention How the Covid-19 is Affecting the Industry, Market Trends and Potential Opportunities in the COVID-19 Landscape, Key Regions and Proposal Nanomedicine Market Players to battle Covid-19 Impact.

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The authentic processes followed to exhibit various aspects of the market makes the data reliable in context to particular time period and industry. This report is highly informative document with inclusion of comprehensive market data associated with the significant elements and subdivision of the Nanomedicine Market that may impact the growth scenarios of the industry. The report may commendably help trades and decision makers to address the challenges and to gain benefits from highly competitive Nanomedicine Market.

Competitive Landscape:

The competitive analysis of major market players is another notable feature of the Nanomedicine Market industry report; it identifies direct or indirect competitors in the market.

Key CompaniesGE HealthcareJohnson & JohnsonMallinckrodt plcMerck & Co. Inc.Nanosphere Inc.Pfizer Inc.Sigma-Tau Pharmaceuticals Inc.Smith & Nephew PLCStryker CorpTeva Pharmaceutical Industries Ltd.UCB (Union chimique belge) S.A

Key parameters which define the competitive landscape of the Nanomedicine Market:

Revenue and Market Share by Player

Production and Share by Player

Average Price by Player

Base Distribution, Sales Area and Product Type by Player

Concentration Rate

Manufacturing Base

Mergers & Acquisitions, Expansion

Market Segmentation:

The segmentation is used to decide the target market into smaller sections or segments like product type, application, and geographical regions to optimize marketing strategies, advertising technique and global as well as regional sales efforts of Nanomedicine Market.

Geographically, the report includes the research on production, consumption, revenue, market share and growth rate, and forecast of the following regions:

United States

Central and South America (Brazil, Mexico, Colombia)

Europe (Germany, UK, France, Italy, Spain, Russia, Poland)

China

Japan

India

Southeast Asia (Malaysia, Singapore, Philippines, Indonesia, Thailand, Vietnam)

Middle East and Africa (Saudi Arabia, United Arab Emirates, Turkey, Egypt, South Africa, Nigeria)

The Research Report Provides:

An overview of the Nanomedicine Market

Comprehensive analysis of the market

The segment that accounted for a large market share in the past

The segment that is anticipated to account for a dominant market share by forecasted period

Emerging market segments and regional markets

Segmentations up to the second and/or third level

Analyses of recent developments in the market

Events in the market scenario in past few years

Historical, current, and estimated market size in terms of value and volume

Competitive analysis, with company overview, products, revenue, and strategies

Strategic recommendations to help companies increase their market presence

Lucrative opportunities in the market

Key Points Covered in the Table of Content:

Overview: Along with a broad overview of the Nanomedicine Market, this section gives you the details overview, an idea about the nature and contents of the research study.

Analysis on Strategies of Leading Players: Market players can use this analysis to gain competitive advantage over their competitors in the Nanomedicine Market.

Study on Key Market Trends: This section of the report offers deeper analysis of latest and future trends of the market.

Market Forecasts: Buyers of the report will have access to accurate and validated estimates of the total market size in terms of value and volume. This research report also provides consumption, production, sales, and other forecasts for Nanomedicine Market.

Regional Growth Analysis: All major regions and countries have been covered in Nanomedicine Market report. The regional analysis will help you to tap into unexplored regional markets, prepare specific strategies for target regions, and compare the growth of all regional markets.

Segment Analysis: The report provides accurate and reliable forecasts of the market share of important segments of the Nanomedicine Market. Market participants can use this analysis to make strategic investments in key growth pockets of the Nanomedicine Market.

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Doheny and UCLA Stein Eye Institutes Welcome Kaustabh Ghosh, PhD, to the Scientific and Clinical Research Faculty – P&T Community

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LOS ANGELES, Oct. 31, 2019 /PRNewswire/ --Doheny and UCLA Stein Eye Institutes proudly welcome Kaustabh Ghosh, PhD, to the scientific faculty as Associate Professor in basic science at the UCLA David Geffen School of Medicine. Dr. Ghosh is distinguished as an interdisciplinary researcher with expertise in the fields of vascular inflammation, mechanobiology, bioengineering, and nanomedicine.

"I am tremendously proud and honored to begin this position at Doheny-UCLA," says Dr. Ghosh. "I entered the field of biomedical research from an engineering background, which perhaps gave me a new perspective to see things differently. As a biomedical engineer, it allowed me to think about diseases in a way that a typical biomedical researcher and clinician may not."

Dr. Ghosh states that also as a vascular biologist, one such perspective he was able to successfully introduce was the importance of "stiffness" of blood vessels in disease pathogenesis.

"Doheny will be the ideal place for me to realize the true translational potential for my work as it offers strength and resources in ophthalmic imaging," shares Dr. Ghosh. "Doheny also provides the perfect balance between basic science and clinical research."

He adds, "I look forward to developing strong, collaborative relationships with members of Doheny-UCLA engineering, biomedical sciences and clinical infrastructure. Our goal will be to discover effective treatment strategies from a multidisciplinary approach especially in the area of investigating the role of chronic vascular inflammation, a major determinant of various debilitating conditions including macular degeneration and diabetic retinopathy."

Dr. Ghosh was most recently Associate Professor of Bioengineering at University of California, Riverside (UCR) as well as Participating Faculty in the Division of Biomedical Sciences, Stem Cell Center and the Program in Cell, Molecular and Developmental Biology. The Ghosh Research Group at UCR focused on leveraging the principles of mechanobiology to examine and treat inflammationmediated vascular degeneration associated with diabetic retinopathy and agerelated macular degeneration, the leading causes of vision loss in the diabetic and aging population. In 2016, these studies were supported by two R01 grants from the National Eye Institute (NEI), and a macular degeneration grant from the BrightFocus Foundation. Dr. Ghosh has received numerous awards during his research career, including the Hellman Fellowship and the NIH Postdoctoral Training Grant, and has published 24 peer-reviewed papers in highly-regarded journals that include PNAS, The FASEB Journal, Science, and Nano Letters, among others.

In 2011, prior to joining UCR, Dr. Ghosh was a postdoctoral fellow in the laboratory of Donald Ingber, MD, PhD, part of the Vascular Biology Program at Boston Children's Hospital and Harvard Medical School. In 2006, Dr. Ghosh received his PhD in Biomedical Engineering from Stony Brook University, New York. He obtained his undergraduate degree in Chemical Engineering from National Institute of Technology, Warangal, India in 2001.

Dr. Ghosh's dedication to collaborative research and team building is evident in his numerous and illustrious achievements. His distinguished scientific leadership demonstrates an excellence that will contribute greatly to Doheny Eye Institute's research programs.

About Doheny Eye InstituteFor over 70 years, Doheny Eye Institute has been at the forefront of vision science. From seeking new ways to free blockages that prevent fluid drainage in glaucoma, to replacing retinal cells in age-related macular degeneration, to providing colleagues worldwide with standardized analyses of anatomical changes in the eyes of patients, Doheny clinicianscientists and researchers are changing how people see and also how they think about the future of vision. Please visit doheny.org for more information.

Doheny Eye Institute and UCLA Stein Eye Institute have joined forces to offer the best inpatient care, vision research and education. This affiliation combines the strength, reputation and distinction of two of the nation's top eye institutions to advance vision research, education and patient care in Southern California.

CONTACT INFORMATIONMedia Contact:Matthew RabinDirect: (323) 342-7101Email: mrabin@doheny.org

View original content to download multimedia:http://www.prnewswire.com/news-releases/doheny-and-ucla-stein-eye-institutes-welcome-kaustabh-ghosh-phd-to-the-scientific-and-clinical-research-faculty-300949566.html

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MagForce AG Publishes Financial Results for the First Half of 2019 and Operative Highlights – BioSpace

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Berlin, Germany and Nevada, USA, October 31, 2019 - MagForce AG (Frankfurt, Scale, XETRA: MF6, ISIN: DE000A0HGQF5), a leading medical device company in the field of nanomedicine focused on oncology, published today its financial results for the first half of 2019, ending on June 30, 2019, and operative highlights.

During the first half of 2019 we have continued to pass several major milestones and have made significant progress both in the EU with our roll-out strategy and the US with the completion of the first stage in our pivotal clinical US study for the focal ablation of intermediate risk prostate cancer, commented Ben Lipps, CEO of MagForce AG and MagForce USA, Inc. I am steadfast in my belief that by pursuing a strategy of expansion with sustainable partnerships in Europe and providing NanoTherm therapy in the US to patients suffering from prostate cancer, MagForce is well positioned for the future.

Operative Highlights:

Driving forward European roll-out strategy with two additional hospitals offering MagForces NanoTherm therapy for the treatment of brain tumors

In April of 2019, the first hospital outside of Germany, the Independent Public Clinical Hospital No. 4 (SPKS4) in Lublin, Poland, inaugurated its NanoTherm treatment center and is now offering the innovative therapy as an additional treatment option for brain tumor patients from Poland and surrounding countries. The SPSK4 team, led by Prof. Dr. hab. n. med. Tomasz Trojanowski and Prof. Dr. hab. n. med. Radoslaw Rola, have initiated patient treatments for a small Investigator Initiated Trial (IIT) to apply to the Agency for Health Technology Assessment and Tariff System for patient reimbursement of NanoTherm therapy as a supplementary treatment. In addition, private pay treatments with NanoTherm therapy financed by crowd or personal funding are now available. Furthermore, In June, MagForce entered into a cooperation agreement with a further German hospital, the Paracelsus Clinic in Zwickau, where a mobile treatment center has been installed. In the meantime, construction has been completed and, subject to a standard final approval of the competent authority in Germany, the NanoActivator is ready-for-use in the clinic with its renowned neurosurgical team around Prof. Dr. med. habil. Jan-Peter Warnke.

These new cooperations in Germany and Poland cover geographically important regions, and therefore represent another crucial step in MagForces European roll-out strategy. Additionally, the Company continues to see great interest in its therapy from further European countries. In Spain, negotiations with a potential new clinical partner are in an advanced stage, and MagForce is confident to be able to update the market once a cooperation agreement has been successfully concluded. Also, in Italy the Company continues to pursue early stage discussions with specialist clinics.

While a broad geographic coverage to provide greater availability for NanoTherm therapy is at the center of MagForces roll-out strategy, the Company also constantly works to further optimize the therapy and educate medical professionals in its use to provide patients with the best care possible. To this day, 5-years survival rates for patients treated with standard of care have not significantly improved over the last decades and remain very poor at 5 percent. Currently, the best that can be offered applying conventional treatment methods is a modest 14-months overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. Longer survival times are furthermore often limited by a decreased quality of life and to highly selected patient sub-groups with certain favorable prognostic factors. Local tumor ablative treatment modalities, such as NanoTherm therapy, have therefore received increasing interest, as NanoTherm therapy has demonstrated to increase overall median survival to 23.2 months.

In their quest to improve patient care, the neurosurgeons applying NanoTherm therapy for the treatment of brain tumors, continue to find additional strategies to improve efficacy. Prof. Dr. Stummer and his team at the University Hospital of Mnster (UKM) for example, who have been treating brain tumor patients with MagForce's NanoTherm therapy since early 2015, introduced a new nanoparticles application technique called 'NanoPaste' in the clinic in 2016. The method itself and variations thereof are protected by MagForces international patent applications. In previous clinical research, the UKM team demonstrated that a better applicability of heat-focusing nanoparticles around the resection wall after surgical removal of a brain tumor could boost the thermotherapy treatment outcome. In a recent study published in January of 2019 in the Journal of Neuro-Oncology, the team was able to extend the previous findings demonstrating that NanoTherm therapy combined with radiotherapy may result in potent antitumor immune responses leading to long-term stabilization of recurrent GBM patients. The team now plans to further investigate their findings in a prospective study.

MagForce remains committed to providing the highest quality of treatment through ongoing support for physicians. Therefore, the Company announced its newly launched NanoTherm Therapy School in January. NanoTherm Therapy School offers a comprehensive application training series, developed in close collaboration with leading experts in the application of the MagForces therapy and consists of three consecutive modules to certify surgeons in the use of its innovative NanoTherm technology: Module A The Basics; Module B Advanced Course Stereotactic Instillation; and Module C Interaction with New Neurosurgical Techniques. The first session, Module A, took place at the end of January 2019, and was met with great excitement from participants. Building on this success, Module B will be held in Berlin on November 14 and 15. On the Companys website, you will find the program and registration details for the next module in November.

Pivotal US study for a unique focal prostate cancer treatment option completed stage 1; preparations for next study stage initiated

In the US, prostate cancer, is one of the most frequently diagnosed forms of cancer. Fortunately, prostate cancer is treatable, if detected early. Still, there remains an important unmet need for patients who have progressed to the medium-risk stage and for whom the benefits of treatment with current methods come with a significant risk of related side effects. NanoTherm therapy has the potential to significantly change the way prostate cancer is treated, as it allows for a less invasive, less aggressive treatment modality that could cure the cancer or, at a minimum, reduce a patients chances of needing a more aggressive treatment in the future.

The MagForce US pivotal clinical study in the indication of prostate cancer continues to progress well and the Company announced the completion of enrollment, treatment, and the analysis of the results of this first stage. During Stage 1, MagForce USA worked diligently with study investigators, medical technicians and patients, to not only successfully develop a standardized clinical procedure but also demonstrated a favorable safety and tolerability profile.

In summary, Stage 1 of the study has shown the following important successes: Firstly, validation of standardized clinical procedure; secondly, initial findings in this cohort show only minimal treatment-related side effects, which were tolerable and similar to those commonly associated with biopsies; and thirdly, the ablation analysis showed very well defined ablation and cell death in the region of the nanoparticle deposit as we observed with the previous pre-clinical results.

The Stage 1 ablation results also confirm the observations of Knavel and Brace in 2013 that from 42 C to 46 C, irreversible damage occurs, and after 10 minutes, significant necrosis occurs. From 46 C to 52 C, the time to cell death decreases owing to a combination of microvascular thrombosis, ischemia, and hypoxia. By heating from the inside out, as done with focal ablation using the NanoTherm therapy system, minimization of side effects can be achieved. With the encouraging results from Stage 1, MagForce is optimistic that the Company will also be able to successfully manage the treatments in the next stage of the clinical trial. With the high interest in enrollment received from prostate cancer patients and their attending physicians, MagForce is confident to be able to successfully enroll the required number of prostate cancer patients for the last stage of the study.

Results of operations, net assets and financial position

Revenues for the reporting period amounted to EUR 26 thousand compared to EUR 24 thousand in the previous year and resulted mainly from commercial treatments of patients with NanoTherm therapy.

Other operating income amounted to EUR 329 thousand (previous year: EUR 9,199 thousand). The high other operating income in the previous year is attributable to the transfer of shares in MagForce USA, Inc., between group companies, realizing hidden reserves in the amount of EUR 8,769 thousand.

The cost of materials decreased from EUR 364 thousand to EUR 194 thousand which was due in particular to the reduction in expenses for purchased services for the NanoActivators.

Personnel expenses increased to EUR 1,846 thousand (previous year: EUR 1,729 thousand) primarily resulting from the addition of employees in the second half of 2018. Other operating expenses remained at the level of the previous year at EUR 1,608 thousand (previous year: EUR 1,527 thousand).

Consequently, the operating result for the first half of 2019 was negative at EUR 3,610 thousand, whereas the previous year ended with a positive operating result of EUR 5,305 thousand due to the transfer of the shares in MagForce USA, Inc., within the group.

In total, the Company generated a net loss for the period of EUR 4,912 thousand (previous year: net profit of EUR 4,106 thousand)

Cash flows from operating activities amounted to EUR -2,856 thousand (previous year: EUR - 4,009 thousand). The cash outflow from operating activities was derived indirectly from the net loss for the period.

The cash outflows from investing activities amounted to EUR -785 thousand (previous year: EUR - 516 thousand) and related primarily to the contributions made in the reporting period to provide financial support for the subsidiary MT MedTech Engineering GmbH and the completion of the mobile NanoActivator therapy center in Lublin, Poland, as well as the construction of a new mobile NanoActivator therapy center in Zwickau, Germany.

The cash flows from financing activities amounted to EUR 3,325 thousand (previous year: EUR 9,189 thousand) and is mainly attributable to the proceeds from the capital increase from Authorized Capital.

At the end of the reporting period, cash and cash equivalents amounted to EUR 1,178 thousand (December 31, 2018: EUR 1,494 thousand).

Financing transactions of the Company

To improve liquidity and to accelerate the on-going international expansion, the Company executed the following financing measure during the first half of the year.

In June, MagForce AG successfully resolved and completed a capital increase from authorized capital. By issuing 1,176,472 new no-par value bearer shares at a price of EUR 4.25 per share under exclusion of the shareholders' statutory subscription rights, the financing measure has a total volume of EUR 5 million, of which the Company received EUR 1.8 million after the reporting date on July 2, 2019.

The additional capital will primarily be used to accelerate the on-going international expansion of MagForce, in particular in Europe. Based on the highly satisfying treatment results, MagForce expects the European roll-out, combined with reimbursement approval in relevant countries, will significantly speed up revenue generation and profitability of the European business.

Outlook and financial prognosis 2019 and beyond

The outlook for the year 2019, as reported in the 2018 annual report, published on June 20, 2019 was reaffirmed by management.

About MagForce AG and MagForce USA, Inc.MagForce AG, listed in the Scale segment of the Frankfurt Stock Exchange (MF6, ISIN: DE000A0HGQF5), together with its subsidiary MagForce USA, Inc. is a leading medical device company in the field of nanomedicine focused on oncology. The Group's proprietary NanoTherm therapy enables the targeted treatment of solid tumors through the intratumoral generation of heat via activation of superparamagnetic nanoparticles.

NanoTherm, NanoPlan, and NanoActivator are components of the therapy and have received EU-wide regulatory approval as medical devices for the treatment of brain tumors. MagForce, NanoTherm, NanoPlan, and NanoActivator are trademarks of MagForce AG in selected countries.

For more information, please visit: http://www.magforce.comGet to know our Technology: video (You Tube)Stay informed and subscribe to our mailing list

DisclaimerThis release may contain forward-looking statements and information which may be identified by formulations using terms such as "expects", "aims", "anticipates", "intends", "plans", "believes", "seeks", "estimates" or "will". Such forward-looking statements are based on our current expectations and certain assumptions, which may be subject to a variety of risks and uncertainties. The results actually achieved by MagForce AG may substantially differ from these forward-looking statements. MagForce AG assumes no obligation to update these forward-looking statements or to correct them in case of developments, which differ from those, anticipated.

- End of press release -

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Comprehensive Study on Healthcare Nanotechnology (Nanomedicine) Market 2019 | Trends, Drivers, Strategies, Applications and Competitive Landscape…

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New report on Healthcare Nanotechnology (Nanomedicine) Market 2019 focuses on the growth opportunities, which will help the Healthcare Nanotechnology (Nanomedicine) market to expand operations in the existing markets. Healthcare Nanotechnology (Nanomedicine) market research study is significant for manufacturers in the Healthcare Nanotechnology (Nanomedicine) market, including industry stakeholders, distributors, suppliers, and investors, and it can also help them understand applicable strategies to grow in the Healthcare Nanotechnology (Nanomedicine) market.

In Healthcare Nanotechnology (Nanomedicine) Market Report, Following Companies Are Covered:

Healthcare Nanotechnology (Nanomedicine) Market Report Provides Comprehensive Analysis of:

For More Information or Query or Customization Before Buying, Visit at https://www.industryresearch.co/enquiry/pre-order-enquiry/14099195

Key Market Trends:

The Growth of Nanomedicine is Expected to Provide High Opportunities for the Treatment of Neurological Diseases, Over the Forecast Period

A large number of brain disorders with neurological and psychological conditions result in short-term and long-term disabilities. Recent years observed a significant number of research studies being published on methods for the synthesis of nanoparticle-encapsulated drugs within in vivo and in vitro studies. The insufficient absorbance of oral drugs administered for a range of neurological conditions, such as Alzheimers disease, Parkinson disease, tumor, neuro-AIDS, among others, opens up the necessity of nanomedicine with stem cell therapy. Some of the registered nanoparticles for the complex CNS treatment are a gold nanoparticle, lipid nanoparticle, and chitosan nanoparticles.

Other than neurological diseases, research-based progress was found in the treatment of cancers, with the scientific communities identifying new metabolic pathways to find better drug combination using nanomedicine.

North America is Expected to Hold the Largest Share in the Market

In the United States, several companies are closely observing the developments in nanostructured materials across various applications in the healthcare industry, including medical devices, to improve efficiency and efficacy. In the United States, the National Nanotechnology Initiative (NNI), which was initiated in 2000, is among the supreme bodies that manage all nanotechnology-related activities. Under the NNI, several agencies are working in collaboration with companies and universities. For instance, nano-manufacturing in Small Business Innovation Research (SBIR) programs were developed for both commercial and public use. Companies are targeting the treatment of several cancer types and infectious diseases through immunotherapy, where nanoemulsion vaccines and drugs play a significant role. In the United States, one of the major challenges associated with nanotechnology is the ability to integrate nanoscale materials into new devices and systems, along with an application of novel properties at the nano-level. Thus, most of the companies are investing in R&D. Nanotechnology is likely to play a significant role in the delivery of drugs. In the recent strategic plan presented by the NNI in 2016, several programs were identified to further advance the research and development programs, over the forecast period.

Reasons for Buying Healthcare Nanotechnology (Nanomedicine) Market Report:

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Detailed TOC of Healthcare Nanotechnology (Nanomedicine) Market Report 2019-2024:

1 INTRODUCTION1.1 Study Deliverables1.2 Study Assumptions1.3 Scope of the Study

2 RESEARCH METHODOLOGY

3 EXECUTIVE SUMMARY

4 MARKET DYNAMICS4.1 Market Overview4.2 Market Drivers4.2.1 Growing Prevalence of Cancer and Genetic and Cardiovascular Diseases4.2.2 Increasing Advancements in Nanoscale Technologies for Diagnostic Procedures4.2.3 Growing Preference for Personalized Medicines4.3 Market Restraints4.3.1 High Cost4.3.2 Stringent Regulations for Commercial Introduction4.4 Porters Five Forces Analysis4.4.1 Threat of New Entrants4.4.2 Bargaining Power of Buyers/Consumers4.4.3 Bargaining Power of Suppliers4.4.4 Threat of Substitute Products4.4.5 Intensity of Competitive Rivalry

5 MARKET SEGMENTATION5.1 By Application5.1.1 Drug Delivery5.1.2 Biomaterials5.1.3 Active Implants5.1.4 Diagnostic Imaging5.1.5 Tissue Regeneration5.1.6 Other Applications5.2 By Disease5.2.1 Cardiovascular Diseases5.2.2 Oncological Diseases5.2.3 Neurological Diseases5.2.4 Orthopedic Diseases5.2.5 Infectious Diseases5.2.6 Other Diseases5.3 Geography5.3.1 North America5.3.1.1 US5.3.1.2 Canada5.3.1.3 Mexico5.3.2 Europe5.3.2.1 France5.3.2.2 Germany5.3.2.3 UK5.3.2.4 Italy5.3.2.5 Spain5.3.2.6 Rest of Europe5.3.3 Asia-Pacific5.3.3.1 China5.3.3.2 Japan5.3.3.3 India5.3.3.4 Australia5.3.3.5 South Korea5.3.3.6 Rest of Asia-Pacific5.3.4 Middle East & Africa5.3.4.1 GCC5.3.4.2 South Africa5.3.4.3 Rest of Middle East & Africa5.3.5 South America5.3.5.1 Brazil5.3.5.2 Argentina5.3.5.3 Rest of South America

6 COMPETITIVE LANDSCAPE6.1 Company Profiles6.1.1 Sanofi SA6.1.2 Celegene Corporation6.1.3 CytImmune Sciences Inc.6.1.4 Johnson & Johnson6.1.5 Luminex Corporation6.1.6 Merck & Co. Inc.6.1.7 Nanobiotix6.1.8 Pfizer Inc.6.1.9 Starpharma Holdings Limited6.1.10 Taiwan Liposome Company Ltd

7 MARKET OPPORTUNITIES AND FUTURE TRENDS

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Comprehensive Study on Healthcare Nanotechnology (Nanomedicine) Market 2019 | Trends, Drivers, Strategies, Applications and Competitive Landscape...

Market Share in Nanotechnology and Nanomedicine for Treatment of Viral Infections Could Reach Tens of Billion Dollars – P&T Community

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PALM BEACH, Florida, Oct. 29, 2019 /PRNewswire/ -- There is much activity in the nanotechnology & nanomedicine markets as new treatments and human clinical trials are growing at a record pace. And these new treatment are hope they could be key to combating viral infections such as, bacteria, viruses, fungi,HBV, hepatitis C, Influenza, HSV, Human papillomavirus and parasites account for approximately 15million deaths worldwide, with acute respiratory infections and human immunodeficiency virus (HIV) being the leading causes. The National Institutes for Health NCBI Center for Biotechnology Information (NCBI) reports: "Infectious diseases are the leading cause of mortality worldwide, with viruses in particular making global impact on healthcare and socioeconomic development. In addition, the rapid development of drug resistance to currently available therapies and adverse side effects due to prolonged use is a serious public health concern. The development of novel treatment strategies is therefore required. The interaction of nanostructures with microorganisms is fast-revolutionizing the biomedical field by offering advantages in both diagnostic and therapeutic applications. Nanoparticles offer unique physical properties that have associated benefits for drug delivery." Mentioned in today's commentary includes: TG Therapeutics, Inc. (NASDAQ: TGTX), NanoViricides, Inc. (NYSE: NNVC), Matinas BioPharma Holdings, Inc. (NYSE: MTNB), Clovis Oncology, Inc. (NASDAQ: CLVS), Pfizer Inc. (NYSE: PFE).

Nanoparticle-based delivery systems present new opportunities to overcome challenges associated with conventional drug therapies and have therefore attracted enormous interest in the treatment of viral infections. Nanomaterials can be engineered to incorporate conventional antiviral properties with those modifications that are unique to nanosystems (ultra small and controllable size, large surface area to volume ratio, and the ability to tailor the surface with the possibility of multi-functionalization). This is undoubtedly a promising tool for biomedical research and clinical use.

One of the more active companies in the industry includes NanoViricides, Inc. (NYSE American: NNVC). NanoViricides,a leader in nanomedicines with novel platform technology to treat difficult and life-threatening viral diseases, on October 9, 2019 announced that it has initiated bio-analytical studies as part of the required IND-enabling preclinical safety and toxicology studies of NV-HHV-101, moving towards human clinical trials.

The Company has contracted NorthEast BioLab, Hamden CT, to conduct the bio-analytical studies and facilitate the toxicokinetic analyses. These studies and analyses are part of the required general safety and toxicology studies that will go into an Investigational New Drug (IND) Application to the US FDA.

NorthEast BioLab has already performed the bio-analytical assay development and validation and is in the process of determining the concentrations of NV-HHV-101 in blood samples from the general safety and toxicology studies that are required for IND.

The company feels that the market size for its immediate target drugs in the HerpeCide program is variously estimated into Billions to tens of Billions of Dollars. The Company believes that its dermal topical cream for the treatment of shingles rash will be its first drug heading into clinical trials. The Company believes that additional topical treatment candidates in the HerpeCide program, namely, HSV-1 "cold sores" treatment, and HSV-2 "genital ulcers" treatment are expected to follow the shingles candidate into IND-enabling development and then into human clinical trials.

NanoViricidesalso released a report this past August that its first drug candidate, NV-HHV-101, is on track with required preclinical GLP Safety and Toxicology studies moving towards human clinical trials. The Company reports that NV-HHV-101 has been found to be safe and well tolerated in the clinical observation portion of the GLP Safety/Toxicology study of NV-HHV-101 as a dermal treatment.

The Company has previously found that NV-HHV-101 was safe and well tolerated in non-GLP safety/toxicology studies. The GLP studies are an expanded version of the non-GLP studies, with extended treatment, larger number of subjects, and stringent operational requirements as specified by the current Good Laboratory Practices guidelines for such studies.

Additional studies required for the Safety and Toxicology datasets for filing an IND are in progress.

The Company anticipates advancing NV-HHV-101 into human clinical trials for topical dermal treatment of the shingles rash as the initial indication, assuming that these studies are successful. The Company also continues to evaluate this broad-spectrum drug candidate as well as certain variations based on the same candidate, for the treatment of other herpesviruses, namely HSV-1 cold sores and HSV-2 genital herpes. The market size for its immediate target drugs in the HerpeCide program is variously estimated into billions to tens of billions of dollars. The Company believes that its dermal topical cream for the treatment of shingles rash will be its first drug heading into clinical trials. The Company believes that additional topical treatment candidates in the HerpeCide program, namely, HSV-1 "cold sores" treatment, and HSV-2 "genital ulcers" treatment are expected to follow the shingles candidate into IND-enabling development and then into human clinical trials.

In addition, the Company also recently announced that its first clinical drug candidate, NV-HHV-101, for the treatment of the Shingles virus (aka VZV), is on track with required preclinical GLP Safety and Toxicology studies moving towards human clinical trials. The Company has reported that NV-HHV-101 has been found to be safe and well tolerated in the clinical observation portion of the GLP Safety/Toxicology study of NV-HHV-101 as a dermal treatment.

NanoViricides' current programs target a potential market opportunity of over $20 Billion. Investors are urged to view an informative video interview with Anil R. Diwan, PhD, President and Executive Chairman, who was interviewed by broadcast journalist Christine Corrado of Proactive Investors, a leading multi-media news organization, investor portal and events management business with offices in New York, Sydney, Toronto, Frankfurt, and London. Click here to access the video interview.

In other biotech news in the markets this week:

TG Therapeutics, Inc.(NASDAQ: TGTX), a biopharmaceutical company developing medicines for patients with B-cell mediated diseases, announced that the follicular lymphoma (FL) cohort of the UNITY-NHL Phase 2b pivotal trial evaluating single agent umbralisib, the Company's novel, once daily, PI3K delta inhibitor, met the primary endpoint of overall response rate (ORR) as determined by Independent Review Committee (IRC) for all treated patients (n=118) who have received at least two prior lines of therapy including an anti-CD20 monoclonal antibody and an alkylating agent. The results met the Company's prespecified ORR target of 40-50%. Importantly, umbralisib monotherapy appeared to be well tolerated with a safety profile consistent with previous reports.

The Company plans to present the data at a future medical conference as well as discuss the data with the U.S. Food and Drug Administration (FDA).

Matinas BioPharma Holdings, Inc.(NYSE AMER: MTNB), a clinical stage biopharmaceutical company, this month announced that it has initiated its Phase 2 EnACT clinical study, which will explore the use of MAT2203 for both induction and maintenance therapy in HIV-patients with cryptococcal meningitis, a life-threatening fungal infection most commonly observed in immunocompromised individuals.

"We are extremely pleased to advance clinical development of MAT2203 for the treatment of cryptococcal meningitis," commented Theresa Matkovits, Ph.D., Chief Development Officer of Matinas.

Clovis Oncology, Inc.(NASDAQ: CLVS) this month announced that the National Institute for Health and Care Excellence (NICE) has recommended that women with relapsed ovarian cancer in England have access to rucaparib through the Cancer Drugs Fund (CDF).1 Rucaparib is available for use within the CDF as an option for the maintenance treatment of relapsed, platinum-sensitive high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to platinum-based chemotherapy in adults, based on the conditions outlined in the managed access agreement.

"Ovacome welcomes the availability of rucaparib via the CDF as an option for maintenance treatment of platinum-sensitive relapsed high grade serous epithelial ovarian cancer regardless of BRCA status or line of treatment in the relapsed maintenance setting," said Victoria Clare, CEO of Ovacome, a United Kingdom ovarian cancer charity focused on providing support to anyone affected by ovarian cancer.

Pfizer Inc. (NYSE: PFE) reported financial results for third-quarter 2019 and updated certain components of its 2019 financial guidance.Third-Quarter 2019 Revenues of $12.7 Billion, Reflecting 3% Operational Decline; Excluding the Impact from Consumer Healthcare, Third-Quarter 2019 Revenues were Flat Operationally - See the full financial reporting at: https://finance.yahoo.com/news/pfizer-reports-third-quarter-2019-104500229.html

DISCLAIMER:FN Media Group LLC (FNM), which owns and operates Financialnewsmedia.com and MarketNewsUpdates.com, is a third- party publisher and news dissemination service provider, which disseminates electronic information through multiple online media channels.FNM is NOT affiliated in any manner with any company mentioned herein.FNM and its affiliated companies are a news dissemination solutions provider and are NOT a registered broker/dealer/analyst/adviser, holds no investment licenses and may NOT sell, offer to sell or offer to buy any security. FNM's market updates, news alerts and corporate profiles are NOT a solicitation or recommendation to buy, sell or hold securities. The material in this release is intended to be strictly informational and is NEVER to be construed or interpreted as research material. All readers are strongly urged to perform research and due diligence on their own and consult a licensed financial professional before considering any level of investing in stocks.All material included herein is republished content and details which were previously disseminated by the companies mentioned in this release.FNM is not liable for any investment decisions by its readers or subscribers.Investors are cautioned that they may lose all or a portion of their investment when investing in stocks.For current services performed FNM was compensated twenty five hundred dollars for news coverage of current press release issued by NanoViricides, Inc.by a non-affiliated third party.FNM HOLDS NO SHARES OF ANY COMPANY NAMED IN THIS RELEASE.

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Market Share in Nanotechnology and Nanomedicine for Treatment of Viral Infections Could Reach Tens of Billion Dollars - P&T Community

TLC Presents Clinical and Preclinical Data of TLC590 at ANESTHESIOLOGY Annual Meeting and in International Journal of Nanomedicine TLC590 showed…

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SOUTH SAN FRANCISCO, Calif. and TAIPEI, Taiwan, Oct. 21, 2019 (GLOBE NEWSWIRE) -- TLC (Nasdaq: TLC, TWO: 4152), a clinical-stage specialty pharmaceutical company developing novel nanomedicines to target areas of unmet medical need in pain management, ophthalmology and oncology, recently presented data at the American Society of Anesthesiologists (ASA) ANESTHESIOLOGY annual meeting from a Phase I/II clinical trial which showed TLC590 to yield more immediate and long-lasting pain reduction than ropivacaine. In addition, in vivo findings in which TLC590 showed no dose-related toxicity and other preclinical data were recently published in the International Journal of Nanomedicine. TLC590 is a non-opioid, BioSeizer formulation of ropivacaine with the aim to manage postsurgical pain for four to seven days with a single dose, potentially deterring the use of opioids following surgery.

At ANESTHESIOLOGY 2019, which took place October 19-23 at the Orange County Convention Center in Orlando, FL, principal investigator Todd Bertoch, MD, Chief Medical Officer at JBR Clinical Research, a CenExel Clinical Research Center of Excellence, presented findings from a Phase I/II, randomized, double-blind, comparator-controlled, dose-escalation study of TLC590 following inguinal hernia repair.

Highlights from the e-poster presentation are as follows:

I am delighted to have had the opportunity to present these fantastic results, said Dr. Todd Bertoch. As a clinical researcher specializing in pain, it is so rewarding to be able to share findings that provide hope for a real, substantive weapon in the war against opioids. Clinicians have been waiting patiently for safe, easily administered, very long acting local anesthetics with a rapid onset. These data suggest that we may have found one.

Results of studies evaluating the release profile of TLC590 in vitro and its pharmacokinetics and anesthetic effect in vivo were recently published in the International Journal of Nanomedicine.

Highlights from the publication article are as follows:

The poster presentation and full text article can be accessed under Publications in the Pressroom section of TLCs website at http://www.tlcbio.com.

About TLC590

TLC590 is a non-opioid, BioSeizer sustained release formulation of ropivacaine designed to prolong the retention time of ropivacaine around the injection site as a drug depot, simultaneously extending its therapeutic period and reducing unwanted systemic exposure. A Phase II, randomized, double-blind, comparator- and placebo-controlled clinical trial to evaluate the safety, pharmacokinetics and efficacy of TLC590 following bunionectomy is ongoing.

About TLC

TLC (NASDAQ: TLC, TWO: 4152) is a clinical-stage specialty pharmaceutical company dedicated to the research and development of novel nanomedicines that maximize the potential of its proprietary lipid-assembled drug delivery platform (LipAD). TLC believes that its deep experience with liposome science allows a combination of onset speed and benefit duration, improving active drug concentrations while decreasing unwanted systemic exposures. TLCs BioSeizer technology is designed to enable local sustained release of therapeutic agents at the site of disease or injury; its NanoX active drug loading technology is designed to alter the systemic exposure of a drug, potentially reducing dosing frequency and enhancing distribution of liposome-encapsulated active agents to the desired site. These technologies are versatile in the choice of active pharmaceutical ingredients, and scalable with respect to manufacturing. TLC has a diverse, wholly owned portfolio of therapeutics that target areas of unmet medical need in pain management, ophthalmology, and oncology.

Cautionary Note on Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements contained in this press release include, without limitation, statements regarding TLCs expectations regarding the clinical development of TLC590, the clinical benefits of TLC590 for postsurgical pain management, the timing, scope, progress and outcome of the clinical trials, and the anticipated timelines for the release of clinical data. Words such as may, believe, will, expect, plan, anticipate, estimate, intend and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are not guarantees of future performance and involve a number of risks, assumptions, uncertainties and factors, including risks that the outcome of any clinical trial is inherently uncertain and TLC590 or any of our other product candidates may prove to be unsafe or ineffective, or may not achieve commercial approval. Other risks are described in the Risk Factors section of TLCs annual report on Form 20-F for the year ended December 31, 2018 filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on TLCs expectations and assumptions as of the date of this press release. Actual results may differ materially from these forward-looking statements. Except as required by law, TLC expressly disclaims any responsibility to update any forward-looking statement contained herein, whether as a result of new information, future events or otherwise.

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TLC Presents Clinical and Preclinical Data of TLC590 at ANESTHESIOLOGY Annual Meeting and in International Journal of Nanomedicine TLC590 showed...

Briggs undergrad researcher wins award at international conference – MSUToday

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For senior Hasaan Hayat, a Lyman Briggs student with dual majors in neuroscience and human biology, the opportunity to work in a cutting-edge laboratory as an undergraduate researcher both confirmed his interests in technology and medicine and helped illuminate his career path.

For about a year, Hayat has been contributing to research in the lab of Ping Wang, an affiliate with MSUs Precision Health Program, or PHP. Precision medicine, a component of PHP, is a fairly recent field of biomedicine. This field develops personalized, patient-specific therapies and treatments, often incorporating tools like molecular imaging, nanoparticle technology and artificial intelligence to produce better outcomes for patients.

Through research like that of Wang, tools and technologies can be developed to detect disease sooner and treat it earlier, achieving better outcomes and reducing healthcare costs. PHP at MSU aims to transform the approach to healthcare from reactive to proactive by focusing on disease prediction, prevention and early detection.

Hayat has been interested in technology and human biology for as long as he can remember. After he joined Wangs lab, he became especially intrigued by the use of artificial intelligence, or AI, in the field of precision medicine.

As a child, I only dreamed of working on such technology myself due to its complexity and mass potential, but I also feared it, thanks to dystopian films such asTerminatorandiRobotwhere the sentient machine is always portrayed as the bad guy, he said. However, I find that AI can be a crucial, beneficial tool for analysis and monitoring of patients in a more modern field of medicine, specifically in oncology, radiology and stem-cell transplants.

Researching in Wangs lab has provided Hayat a unique platform to investigate the intersection of technology and biology. One specific study involved the application of deep learning in non-invasive imaging for monitoring tumor response to chemotherapy.

With help from Wang and Moore, Hayat put together an abstract of his work titled, Molecular imaging and analysis of uMUC1 expression levels in response to chemotherapy in an orthotopic murine model of ovarian cancer, and submitted it to the World Molecular Imaging Congress 2019, or WMIC 2019, in Montreal, Canada.

The WMIC 2019 program committee invited Hayat to present this research as an oral presentation, which is a high honor for the attendees. Hayats paper was one of the highest-rated abstracts at the conference and he won the Student Travel Award.

Hayat was grateful and energized by the experience of presenting at an international research conference.

The congress was phenomenal. I was able to hear about some amazing research and innovations in the field of medicine and molecular imaging/biology, he said. Networking with knowledgeable individuals from top institutions all over the world was a highlight of the event, and I am thankful to PHP and MSU for this opportunity.

Hayat was originally drawn to MSU for its many research opportunities, and specifically to Lyman Briggs College, because of its solid foundations in science.

I admire Lyman Briggs for its creative and innovative approach to STEM fields, and its focus on preparing students for success in graduate school, he said. The faculty at Lyman Briggs are very supportive and ensure that students have a clear understanding of core scientific concepts.

As for the future, his work with the Precision Health Program is inspiring him to go to medical school.

I aim to pursue an M.D.-Ph.D. after I graduate, a decision that has been heavily reinforced by the research I am doing at the Precision Health Program, and my mentor and PI, Dr. Wang, who himself is an M.D.-Ph.D. I salute the cutting-edge work that is performed here, he said. In the future, it is a dream and vision of mine to bring novel, innovative therapies and technologies such as AI and nanomedicine to the clinic in order to provide tools for physicians to use and to improve patient outcomes.

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New CBE professor Bardhan to bring image-guided techniques to fight against disease College of Engineering News Iowa State University – Iowa State…

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Rizia Bardhan

With a research specialty in nanomedicine and nanophotonics and designing materials that fight diseases using image-guided techniques Rizia Bardhan will join the faculty of the Department of Chemical and Biological Engineering in January, 2020.

Bardhan, who has been hired as a tenured associate professor, comes to Iowa State from Vanderbilt University, where she has been an assistant professor in the Department of Chemical and Biomolecular Engineering since 2012.

Her research focuses on designing nanomaterials that can be activated by external stimuli and then utilize them for biomedical imaging, and image-guided drug delivery and immunotherapies across many disease models, including cancer, neurodegenerative disease and infection. She also develops point of care diagnostics that she is currently applying for early detection of preterm birth in pregnant women. Click here for more on her current research.

Prior to joining the faculty of Vanderbilt University she was a postdoctoral fellow at The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA.

She received a B.A. in mathematics and chemistry at Westminster College, Fulton, Missouri, in 2005 and a Ph.D. in chemistry at Rice University in 2010 under the guidance of Prof. Naomi Halas, a pioneer in nanophotonics and plasmonics.

In the 2020 spring semester at Iowa State she will teach ChE 381, chemical engineering thermodynamics.

Outside of research and teaching, Bardhan enjoys spending time outdoors with her two sons Elan (3) and Jonah (5), and husband Cary Pint, who is also a new Iowa State University faculty member, joining the Department of Mechanical Engineering in January.

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New CBE professor Bardhan to bring image-guided techniques to fight against disease College of Engineering News Iowa State University - Iowa State...

Global Nanomedicine Market To Witness Steady Growth During The Forecast Period 2019-2028 – The State News – BBState

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New York City, NY: October 23, 2019 Published via (Wired Release) Global Nanomedicine Market Research Reportrepresents the proficient analysis of Nanomedicine industry providing a competitive study of leading market players, market growth, consumption(sales) volume, key drivers and limiting factors, future projections for the new-comer to plan their strategies for business. Further, the report contains the study of Nanomedicine market ups and downs of the past few years and forecasts sales investment data from 2019 to 2028.

The Nanomedicine Report outlining the vitals details which are based on manufacturing region, top players, type, applications and so on will give a transparent view of Industry. The important presence of different regional and local players of Nanomedicine market is tremendously competitive. The Nanomedicine Report is beneficial to recognize the annual revenue of key players, business strategies, key company profiles and their benefaction to the market share.

Download Free Sample Copy of Nanomedicine Market Report:https://marketresearch.biz/report/nanomedicine-market/request-sample

Top Manufacturers Are Covered in This Report:Abbott Laboratories, Ablynx NV, Abraxis BioScience, Inc., Celgene Corporation, Teva Pharmaceutical Industries Limited, GE Healthcare Limited, Merck & Co., Inc., Pfizer Inc., Nanosphere, Inc., Johnson & Johnson Services, Inc.

This research report contains the pictorial representation of important data in the form of graphs, figures, diagrams and tables to make simplified for the users to understand the Nanomedicine market new trends clearly.

Geographically, report on Nanomedicine is based on several regions with respect to Nanomedicine export-import ratio of the region, production and sales volume, share of Nanomedicine market and growth rate of the industry. Major regions included while preparing the report areNorth America, Latin America, Europe, Middle East, Africa, and Asia Pacific.

The leading players in Nanomedicine industry are estimated to ahead on these opportunities to invade the global market. Nanomedicine market size and revenue of key players is assessed using the Bottom-up way.

Reasons for Buying Global Nanomedicine Market Report

* Report provides in-depth study on changing Nanomedicine market dynamics.

* Report offers Pin Point study on distinct factors driving and constraining industry growth.

* Technological innovation in market to study Nanomedicine market growth rate.

* Estimated Nanomedicine market growth depending on the study of historical and the present size of the industry.

Customize Report AndInquiry For The Nanomedicine Market Report:https://marketresearch.biz/report/nanomedicine-market/#inquiry

Report Table of Content Gives Exact Idea about Global Nanomedicine Market Report:

Chapter 1explains Nanomedicine report necessary market surveillance, product price structure, and study, market scope and size forecast from 2019 to 2028. Although, Nanomedicine market activity, factors impacting the growth of business also complete analysis of current market holders.

Chapter 2offers detailing of top manufacturers of Nanomedicine market with their share, sales, and revenue.

Chapters 3, 4, 5studies Nanomedicine report competitive study based on the type of product, their regional sales and import-export study, the annual growth ratio of the market and the coming years study from 2019 to 2028.

Chapter 6offers a detailed analysis of Nanomedicine business channels, Nanomedicine market investors, vendors, Nanomedicine suppliers, dealers, Nanomedicine market opportunities and threats.

This content has been distributed via WiredRelease press release distribution service. For press release service inquiry, please reach us at[emailprotected]

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Nanobiotechnology – Wikipedia

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Nanobiotechnology, bionanotechnology, and nanobiology are terms that refer to the intersection of nanotechnology and biology.[1] Given that the subject is one that has only emerged very recently, bionanotechnology and nanobiotechnology serve as blanket terms for various related technologies.

This discipline helps to indicate the merger of biological research with various fields of nanotechnology. Concepts that are enhanced through nanobiology include: nanodevices (such as biological machines), nanoparticles, and nanoscale phenomena that occurs within the discipline of nanotechnology. This technical approach to biology allows scientists to imagine and create systems that can be used for biological research. Biologically inspired nanotechnology uses biological systems as the inspirations for technologies not yet created.[2] However, as with nanotechnology and biotechnology, bionanotechnology does have many potential ethical issues associated with it.

The most important objectives that are frequently found in nanobiology involve applying nanotools to relevant medical/biological problems and refining these applications. Developing new tools, such as peptoid nanosheets, for medical and biological purposes is another primary objective in nanotechnology. New nanotools are often made by refining the applications of the nanotools that are already being used. The imaging of native biomolecules, biological membranes, and tissues is also a major topic for the nanobiology researchers. Other topics concerning nanobiology include the use of cantilever array sensors and the application of nanophotonics for manipulating molecular processes in living cells.[3]

Recently, the use of microorganisms to synthesize functional nanoparticles has been of great interest. Microorganisms can change the oxidation state of metals. These microbial processes have opened up new opportunities for us to explore novel applications, for example, the biosynthesis of metal nanomaterials. In contrast to chemical and physical methods, microbial processes for synthesizing nanomaterials can be achieved in aqueous phase under gentle and environmentally benign conditions. This approach has become an attractive focus in current green bionanotechnology research towards sustainable development.[4]

The terms are often used interchangeably. When a distinction is intended, though, it is based on whether the focus is on applying biological ideas or on studying biology with nanotechnology. Bionanotechnology generally refers to the study of how the goals of nanotechnology can be guided by studying how biological "machines" work and adapting these biological motifs into improving existing nanotechnologies or creating new ones.[5][6] Nanobiotechnology, on the other hand, refers to the ways that nanotechnology is used to create devices to study biological systems.[7]

In other words, nanobiotechnology is essentially miniaturized biotechnology, whereas bionanotechnology is a specific application of nanotechnology. For example, DNA nanotechnology or cellular engineering would be classified as bionanotechnology because they involve working with biomolecules on the nanoscale. Conversely, many new medical technologies involving nanoparticles as delivery systems or as sensors would be examples of nanobiotechnology since they involve using nanotechnology to advance the goals of biology.

The definitions enumerated above will be utilized whenever a distinction between nanobio and bionano is made in this article. However, given the overlapping usage of the terms in modern parlance, individual technologies may need to be evaluated to determine which term is more fitting. As such, they are best discussed in parallel.

Most of the scientific concepts in bionanotechnology are derived from other fields. Biochemical principles that are used to understand the material properties of biological systems are central in bionanotechnology because those same principles are to be used to create new technologies. Material properties and applications studied in bionanoscience include mechanical properties(e.g. deformation, adhesion, failure), electrical/electronic (e.g. electromechanical stimulation, capacitors, energy storage/batteries), optical (e.g. absorption, luminescence, photochemistry), thermal (e.g. thermomutability, thermal management), biological (e.g. how cells interact with nanomaterials, molecular flaws/defects, biosensing, biological mechanisms s.a. mechanosensing), nanoscience of disease (e.g. genetic disease, cancer, organ/tissue failure), as well as computing (e.g. DNA computing)and agriculture(target delivery of pesticides, hormones and fertilizers.[8] The impact of bionanoscience, achieved through structural and mechanistic analyses of biological processes at nanoscale, is their translation into synthetic and technological applications through nanotechnology.

Nano-biotechnology takes most of its fundamentals from nanotechnology. Most of the devices designed for nano-biotechnological use are directly based on other existing nanotechnologies. Nano-biotechnology is often used to describe the overlapping multidisciplinary activities associated with biosensors, particularly where photonics, chemistry, biology, biophysics, nano-medicine, and engineering converge. Measurement in biology using wave guide techniques, such as dual polarization interferometry, are another example.

Applications of bionanotechnology are extremely widespread. Insofar as the distinction holds, nanobiotechnology is much more commonplace in that it simply provides more tools for the study of biology. Bionanotechnology, on the other hand, promises to recreate biological mechanisms and pathways in a form that is useful in other ways.

Nanomedicine is a field of medical science whose applications are increasing more and more thanks to nanorobots and biological machines, which constitute a very useful tool to develop this area of knowledge. In the past years, researchers have done many improvements in the different devices and systems required to develop nanorobots. This supposes a new way of treating and dealing with diseases such as cancer; thanks to nanorobots, side effects of chemotherapy have been controlled, reduced and even eliminated, so some years from now, cancer patients will be offered an alternative to treat this disease instead of chemotherapy, which causes secondary effects such as hair loss, fatigue or nausea killing not only cancerous cells but also the healthy ones. At a clinical level, cancer treatment with nanomedicine will consist on the supply of nanorobots to the patient through an injection that will seek for cancerous cells leaving untouched the healthy ones. Patients that will be treated through nanomedicine will not notice the presence of this nanomachines inside them; the only thing that is going to be noticeable is the progressive improvement of their health.[9]

Nanobiotechnology (sometimes referred to as nanobiology) is best described as helping modern medicine progress from treating symptoms to generating cures and regenerating biological tissues. Three American patients have received whole cultured bladders with the help of doctors who use nanobiology techniques in their practice. Also, it has been demonstrated in animal studies that a uterus can be grown outside the body and then placed in the body in order to produce a baby. Stem cell treatments have been used to fix diseases that are found in the human heart and are in clinical trials in the United States. There is also funding for research into allowing people to have new limbs without having to resort to prosthesis. Artificial proteins might also become available to manufacture without the need for harsh chemicals and expensive machines. It has even been surmised that by the year 2055, computers may be made out of biochemicals and organic salts.[10]

Another example of current nanobiotechnological research involves nanospheres coated with fluorescent polymers. Researchers are seeking to design polymers whose fluorescence is quenched when they encounter specific molecules. Different polymers would detect different metabolites. The polymer-coated spheres could become part of new biological assays, and the technology might someday lead to particles which could be introduced into the human body to track down metabolites associated with tumors and other health problems. Another example, from a different perspective, would be evaluation and therapy at the nanoscopic level, i.e. the treatment of Nanobacteria (25-200nm sized) as is done by NanoBiotech Pharma.

While nanobiology is in its infancy, there are a lot of promising methods that will rely on nanobiology in the future. Biological systems are inherently nano in scale; nanoscience must merge with biology in order to deliver biomacromolecules and molecular machines that are similar to nature. Controlling and mimicking the devices and processes that are constructed from molecules is a tremendous challenge to face the converging disciplines of nanotechnology.[11] All living things, including humans, can be considered to be nanofoundries. Natural evolution has optimized the "natural" form of nanobiology over millions of years. In the 21st century, humans have developed the technology to artificially tap into nanobiology. This process is best described as "organic merging with synthetic." Colonies of live neurons can live together on a biochip device; according to research from Dr. Gunther Gross at the University of North Texas. Self-assembling nanotubes have the ability to be used as a structural system. They would be composed together with rhodopsins; which would facilitate the optical computing process and help with the storage of biological materials. DNA (as the software for all living things) can be used as a structural proteomic system - a logical component for molecular computing. Ned Seeman - a researcher at New York University - along with other researchers are currently researching concepts that are similar to each other.[12]

DNA nanotechnology is one important example of bionanotechnology.[13] The utilization of the inherent properties of nucleic acids like DNA to create useful materials is a promising area of modern research. Another important area of research involves taking advantage of membrane properties to generate synthetic membranes. Proteins that self-assemble to generate functional materials could be used as a novel approach for the large-scale production of programmable nanomaterials. One example is the development of amyloids found in bacterial biofilms as engineered nanomaterials that can be programmed genetically to have different properties.[14]Protein folding studies provide a third important avenue of research, but one that has been largely inhibited by our inability to predict protein folding with a sufficiently high degree of accuracy. Given the myriad uses that biological systems have for proteins, though, research into understanding protein folding is of high importance and could prove fruitful for bionanotechnology in the future.

Lipid nanotechnology is another major area of research in bionanotechnology, where physico-chemical properties of lipids such as their antifouling and self-assembly is exploited to build nanodevices with applications in medicine and engineering.[15]

Meanwhile, nanotechnology application to biotechnology will also leave no field untouched by its groundbreaking scientific innovations for human wellness; the agricultural industry is no exception. Basically, nanomaterials are distinguished depending on the origin: natural, incidental and engineered nanoparticles. Among these, engineered nanoparticles have received wide attention in all fields of science, including medical, materials and agriculture technology with significant socio-economical growth. In the agriculture industry, engineered nanoparticles have been serving as nano carrier, containing herbicides, chemicals, or genes, which target particular plant parts to release their content.[16] Previously nanocapsules containing herbicides have been reported to effectively penetrate through cuticles and tissues, allowing the slow and constant release of the active substances. Likewise, other literature describes that nano-encapsulated slow release of fertilizers has also become a trend to save fertilizer consumption and to minimize environmental pollution through precision farming. These are only a few examples from numerous research works which might open up exciting opportunities for nanobiotechnology application in agriculture. Also, application of this kind of engineered nanoparticles to plants should be considered the level of amicability before it is employed in agriculture practices. Based on a thorough literature survey, it was understood that there is only limited authentic information available to explain the biological consequence of engineered nanoparticles on treated plants. Certain reports underline the phytotoxicity of various origin of engineered nanoparticles to the plant caused by the subject of concentrations and sizes . At the same time, however, an equal number of studies were reported with a positive outcome of nanoparticles, which facilitate growth promoting nature to treat plant.[17] In particular, compared to other nanoparticles, silver and gold nanoparticles based applications elicited beneficial results on various plant species with less and/or no toxicity.[18][19] Silver nanoparticles (AgNPs) treated leaves of Asparagus showed the increased content of ascorbate and chlorophyll. Similarly, AgNPs-treated common bean and corn has increased shoot and root length, leaf surface area, chlorophyll, carbohydrate and protein contents reported earlier.[20] The gold nanoparticle has been used to induce growth and seed yield in Brassica juncea.[21]

This field relies on a variety of research methods, including experimental tools (e.g. imaging, characterization via AFM/optical tweezers etc.), x-ray diffraction based tools, synthesis via self-assembly, characterization of self-assembly (using e.g. MP-SPR, DPI, recombinant DNA methods, etc.), theory (e.g. statistical mechanics, nanomechanics, etc.), as well as computational approaches (bottom-up multi-scale simulation, supercomputing).

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Nanobiotechnology - Wikipedia

Nanomedicine Market Size Worth $350.8 Billion By 2025 | CAGR … – Press Release Rocket

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Grand View Research, Inc. Market Research And Consulting.

According to new report published by Grand View Research,The global nanomedicine market size was estimated at USD 138.8 billion in 2016.Demand for biodegradable implants with longer lifetimes that enable tissue restoration is anticipated to influence demand.

The global nanomedicine market is anticipated to reach USD 350.8 billion by 2025, according to a new report by Grand View Research, Inc. Development of novel nanotechnology-based drugs and therapies is driven by the need to develop therapies that have fewer side effects and that are more cost-effective than traditional therapies, in particular for cancer.

Application of nanotechnology-based contrast reagents for diagnosis and monitoring of the effects of drugs on an unprecedented short timescale is also attributive drive growth in the coming years. Additionally, demand for biodegradable implants with longer lifetimes that enable tissue restoration is anticipated to influence demand.

As per the WHO factsheet, cancer is found to be one of the major causes of mortality and morbidity worldwide, with approximately 14 million new cases in 2012 and 8.2 million cancer-related deaths. Thus, demand for nanomedicine in order to curb such high incidence rate is expected to boost market progress during the forecast period.

Solutions such as nanoformulations with triggered release for tailor-made pharmacokinetics, nanoparticles for local control of tumor in combination with radiotherapy, and functionalized nanoparticles for targeted in-vivo activation of stem cell production are anticipated to drive R&D, consequently resulting in revenue generation in the coming years.

Biopharmaceutical and medical devices companies are actively engaged in development of novel products as demonstrated by the increasingly growing partnerships between leading enterprises and nanomedicine startups. For instance, in November 2015, Ablynx and Novo Nordisk signed a global collaboration and a licensing agreement for development and discovery of innovative drugs with multi-specific nanobodies. This strategic partnership is anticipated to rise the net annual sales of the products uplifting the market growth.

However, in contrary with the applications of nanotechnology, the entire process of lab to market approval is a tedious and expensive one with stringent regulatory evaluation involved thereby leading investors to remain hesitant for investments.

Full research report on nanomedicine market analysis:http://www.grandviewresearch.com/industry-analysis/nanomedicine-market

U.S. nanomedicine market by products, 2013 2025 (USD Billion)

Further key findings from the report suggest:

Therapeutics accounted for the largest share of market revenue in 2016 owing to presence of nanoemulsions, nanoformulations, or nanodevices

These devices possess the ability to cross biological barriers. Moreover, presence of drugs such as Doxil, Abraxane, and Emend is attributive for higher revenue generation

Presence of substantial number of products manufactured through the use of microbial sources can be attributed for the largest share

In-vitrodiagnostics is expected to witness lucrative progress as a result of R&D carried out in this segment

Introduction of nano-enabled biomarkers, vectors and contrast agents with high-specificity and sensitivity are attributive for projected progress

Clinical cardiology is expected to witness the fastest growth through to 2025 owing to development in nano-functionalization and modification of surfaces for increased biocompatibility of implants in treatment of late thrombosis

Moreover, an abundance of research publications and patent filings from European region with a share of about 25% in nanomedicine-related publications is supportive for revenue generation from European economies

Asia Pacific is estimated to witness the fastest growth over the forecast period

Factors responsible include government and regulatory authorities that have implemented a framework to encourage R&D collaborations and framework extension.

Key players operating in this industry include Pfizer Inc., Ablynx NV, Nanotherapeutics Inc., Nanoviricides Inc., Abraxis Inc., Arrowhead Research Inc., Celgene Corporation, Bio-Gate AG, and Merck

Active expansion strategies are undertaken by a number of the major market entities in order to strengthen their position

North America dominated the industry in 2016, accounting for a 42% of total revenue

Presence of key participants operating in the region are involved in collaborative activities are attributive for the largest share of North America in sector revenue

View more reports of this category by Grand View Research at:http://www.grandviewresearch.com/industry/pharmaceuticals

Grand View Research has segmented the nanomedicine market on the basis of product, application, nanomolecule type, and region:

Nanomedicine Product Outlook (Revenue, USD Billion; 20132025)

Therapeutics

Regenerative medicine

In-vitro diagnostics

In-vivo diagnostics

Vaccines

Nanomedicine Application Outlook (Revenue, USD Billion; 2013 2025)

Clinical Oncology

Infectious diseases

Clinical Cardiology

Orthopedics

Others

Nanomedicine Nanomolecule Type Outlook (Revenue, USD Billion; 2013 2025)

Nanoparticles

Nanoshells

Nanotubes

Nanodevices

Nanomedicine Regional Outlook (Revenue, USD Billion; 2013 2025)

Read Our Blog:Nanomedicine: Nanoparticles-An innovative solution for targeted drug delivery

About Grand View Research

Grand View Research, Inc. is a U.S. based market research and consulting company, registered in the State of California and headquartered in San Francisco. The company provides syndicated research reports, customized research reports, and consulting services. To help clients make informed business decisions, we offer market intelligence studies ensuring relevant and fact-based research across a range of industries, from technology to chemicals, materials and healthcare.

For more information: http://www.grandviewresearch.com

Media Contact Company Name: Grand View Research, Inc. Contact Person: Sherry James, Corporate Sales Specialist U.S.A. Email: Send Email Phone: 1-415-349-0058, Toll Free: 1-888-202-9519 Address:28 2nd Street, Suite 3036 City: San Francisco State: California Country: United States Website: http://www.grandviewresearch.com/industry-analysis/nanomedicine-market

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Nanomedicine Market Size Worth $350.8 Billion By 2025 | CAGR ... - Press Release Rocket

Nanomedicine Market – Global Industry Analysis, Size, Share,Growth, Trends and Forecast, 2013 20 – Video

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