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Find video protocols related to scientific articles indexed in Pubmed.
Carbonization of self-assembled nanoporous hemin with a significantly enhanced activity for the oxygen reduction reaction.
Faraday Discuss.
PUBLISHED: 11-20-2014
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The scarcity and high cost of Pt-based electrocatalysts for the oxygen reduction reaction (ORR) hinder the practical application of proton exchange membrane fuel cells (PEMFCs). It is critical to replace platinum with non-noble metal electrocatalysts (NNMEs). Carbonized metalloporphyrins represent an important class of NNMEs, but most metalloporphyrins are costly and the corresponding NNMEs do not possess a high ORR activity. Herein, we report that the self-assembly of inexpensive hemin leads to porous nanomaterials in water under ambient conditions and subsequent heat-treatment of the unprecedented nanoporous hemin results in a magnetic NNME with a much enhanced ORR activity compared with directly carbonized hemin without self-assembly. The improvement of the ORR activity likely originates from the exposure of more ORR active sites, caused by the surface area increase of the nanoporous hemin after carbonization over that of micro-scale pristine hemin crystals. Moreover, the ORR activity of heat-treated nanoporous hemin is actually comparable to that of commercial Pt/C in alkaline solution. Additionally, the carbonized nanoporous hemin is much better than commercial Pt/C in terms of durability and tolerance to methanol. This study opens up a new avenue to the production of inexpensive metalloporphyrin-based NNMEs with a high ORR performance by using a self-assembly method in combination with traditional pyrolysis.
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PEG-b-PCL Copolymer Micelles with the Ability of pH-Controlled Negative-to-Positive Charge Reversal for Intracellular Delivery of Doxorubicin.
Biomacromolecules
PUBLISHED: 10-29-2014
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The application of PEG-b-PCL micelles was dampened by their inherent low drug-loading capability and relatively poor cell uptake efficiency. In this study, a series of novel PEG-b-PCL copolymers methoxy poly(ethylene glycol)-b-poly(?-caprolactone-co-?-dimethyl maleamidic acid -?-caprolactone) (mPEG-b-P(CL-co-DCL)) bearing different amounts of acid-labile ?-carboxylic amides on the polyester moiety were synthesized. The chain structure and chemical composition of copolymers were characterized by (1)H NMR, Fourier transform infrared spectroscopy (FT-IR), and gel permeation chromatography (GPC). mPEG-b-P(CL-co-DCL) with critical micellar concentrations (CMCs) of 3.2-6.3 ?g/mL could self-assemble into stable micelles in water with diameters of 100 to 150 nm. Doxorubicin (DOX), a cationic hydrophobic drug, was successfully encapsulated into the polymer micelles, achieving a very high loading content due to electrostatic interaction. Then the stability, charge-conversional behavior, loading and release profiles, cellular uptake and in vitro cytotoxicity of free drug and drug-loaded micelles were evaluated. The ?-carboxylic amides functionalized polymer micelles are negatively charged and stable in neutral solution but quickly become positively charged at pH 6.0, due to the hydrolysis of ?-carboxylic amides in acidic conditions. The pH-triggered negative-to-positive charge reversal not only resulted in a very fast drug release in acidic conditions, but also effectively enhanced the cellular uptake by electrostatic absorptive endocytosis. The MTT assay demonstrated that mPEG-b-P(CL-co-DCL) micelles were biocompatible to HepG2 cells while DOX-loaded micelles showed significant cytotoxicity. In sum, the introduction of acid-labile ?-carboxylic amides on the polyester block in mPEG-b-P(CL-co-DCL) exhibited great potentials for the modifications in the stability in blood circulation, drug solubilization, and release properties, as well as cell internalization and intracellular drug release.
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Zwitterionic nanoparticles constructed with well-defined reduction-responsive shell and pH-sensitive core for "spatiotemporally pinpointed" drug delivery.
ACS Appl Mater Interfaces
PUBLISHED: 08-13-2014
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Enabling nanocarriers to complete the sophisticated journey from the initial injection site to the targeted tumor cells and achieve "spatiotemporally pinpointed" drug release intracellularly is a challenging task in anticancer drug delivery. Herein, versatile shell-cross-linked nanoparticles (SCNPs) were prepared by one-step assembly of triblock zwitterionic copolymers, polycarboxybetaine methacrylate-block-poly(N-(2-(2-pyridyl disulde) ethyl methacrylamide-block-poly(2-(diisopropylamino) ethyl methacrylate) (PCB-b-PDS-b-PDPA, termed as PCSSD), which was well-defined via reversible additive fragment transfer (RAFT) polymerization, followed by functionalization with Arg-Gly-Asp (RGD). Thus, the RGD-PCSSD SCNPs cooperatively combine the ultra pH-sensitive PDPA core for efficient drug loading and pH-responsive drug release, the disulfide-cross-linked PDS shell that prevents premature drug release, the zwitterionic PCB corona to stabilize the SCNPs and prolong its systemic circulation, the RGD ligand for active tumor targeting and receptor-mediated endocytosis. Doxorubicin (DOX) was loaded as a model medicine (termed as RGD-PCSSD/DOX SCNPs). The dual-sensitivity studies showed that the pH-sensitivity of PDPA core could be adjusted by the shell-cross-linking density, accompanied by better control over premature drug release. Furthermore, results obtained by flow cytometry and fluorescence microscopy analysis demonstrated that once the RGD-PCSS10D/DOX SCNPs were internalized into tumor cells via receptor-mediated endocytosis, boost drug release was observed with considerable cytotoxicity in vitro. The results of ex vivo imaging studies further confirmed the successful drug delivery from the injection site to the tumor tissue. In summary, the well-constructed RGD-PCSS10D/DOX SCNPs with cooperative multifunctionality showed great potential as novel nanocarriers for tumor targeted anticancer drug delivery.
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Integrin-targeted zwitterionic polymeric nanoparticles with acid-induced disassembly property for enhanced drug accumulation and release in tumor.
Biomacromolecules
PUBLISHED: 07-30-2014
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Reasonably structural design of nanoparticles (NPs) to combine functions of prolonged systemic circulation, enhanced tumor targeting and specific intracellular drug release is crucial for antitumor drug delivery. Combining advantages of Arg-Gly-Asp (RGD) for active tumor targeting, zwitterionic polycarboxybetaine methacrylate (PCB) for prolonged systemic circulation, poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) for acid-triggered intracellular release, novel RGD-PCB-b-PDPA (RGD-PCD) block copolymers were prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization and followed by functionalization with RGD. Doxorubicine (DOX) was encapsulated within the RGD-PCD NPs as model medicine (RGD-PCD/DOX NPs). With ultra pH-sensitivity of PDPA, the drug release was restrained at pH 7.4 for only 24% within 36 h, which was increased to 60% at pH 6.0 within 24 h, and released more rapidly at pH 5.0 for 100% within 5 h, indicating that the RGD-PCD/DOX NPs were able to turn drug release "off" at neutral pH (e.g., systemic circulation) whereas "on" under acidic conditions (e.g., inside endo/lysosomes). Furthermore, the results of fluorescence microscopy and flow cytometry analysis demonstrated improved internalization of RGD-PCD/DOX NPs in HepG2 cells via integrin-mediated endocytosis with rapid DOX release intracellularly. Consequently, the RGD-PCD/DOX NPs showed considerable cytotoxicity against HepG2 and HeLa cells in comparison with free DOX. Importantly, the RGD-PCD/DOX NPs exhibited little protein adsorption property with excellent serum stability, which led to prolonged systemic circulation and enhanced tumor accumulation in tumor-bearing nude mice. Therefore, this multifunctional RGD-PCD NPs, which represented the flexible design approach, showed great potential for the development of novel nanocarriers in tumor-targeted drug delivery.
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Extended-release nifedipine and the risk of intestinal obstruction: a population-based study.
BMJ Open
PUBLISHED: 07-26-2014
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To examine the risk of bowel obstruction in older adults during treatment with extended-release nifedipine compared with patients treated with amlodipine.
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Identification of a novel PHEX mutation in a Chinese family with X-linked hypophosphatemic rickets using exome sequencing.
Biol. Chem.
PUBLISHED: 07-03-2014
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Abstract Familial hypophosphatemic rickets (HR), the most common inherited form of rickets, is a group of inherited renal phosphate wasting disorders characterized by growth retardation, rickets with bone deformities, osteomalacia, poor dental development, and hypophosphatemia. The purpose of this study was to identify the genetic defect responsible for familial HR in a 4-generation Chinese Han pedigree by exome sequencing and Sanger sequencing. Clinical features include skeletal deformities, teeth abnormalities, hearing impairments and variable serum phosphate level in patients of this family. A novel deletion mutation, c.1553delT (p.F518Sfs*4), was identified in the X-linked phosphate regulating endopeptidase homolog gene (PHEX). The mutation is predicted to result in prematurely truncated and loss-of-function PHEX protein. Our data suggest that exome sequencing is a powerful tool to discover mutation(s) in HR, a disorder with genetic and clinical heterogeneity. The findings may also provide new insights into the cause and diagnosis of HR, and have implications for genetic counseling and clinical management.
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Focal Adhesion Kinase Knockdown in Carcinoma-Associated Fibroblasts Inhibits Oral Squamous Cell Carcinoma Metastasis via Downregulating MCP-1/CCL2 Expression.
J. Biochem. Mol. Toxicol.
PUBLISHED: 06-23-2014
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Carcinoma-associated fibroblasts (CAFs) have been demonstrated to play an important role in the occurrence and development of oral squamous cell carcinoma (OSCC). The aim of this study is to investigate the influence of CAFs on OSCC cells and to explore the role of focal adhesion kinase (FAK) in this process. The results showed that oral CAFs expressed a higher level of FAK than normal human gingival fibroblasts (HGFs), and the conditioned medium (CM) of CAFs could induce the invasion and migration of SCC-25, one oral squamous carcinoma cell line. However, knockdown of FAK by small interfering RNA (siRNA) resulted in inhibition of CAF-CM induced cell invasion and migration in SCC-25, probably by reducing the production of monocyte chemoattractant protein-1 (MCP-1/CCL2), one of downstream target chemokines. Therefore, our findings indicated that targeting FAK in CAFs might be a promising strategy for the treatment of OSCC in the future.
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CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection.
J. Virol.
PUBLISHED: 06-18-2014
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A unique aspect of human monocytes, compared to monocytes from many other species, is that they express the CD4 molecule. However, the role of the CD4 molecule in human monocyte development and function is not known. We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. Importantly, we determined that CD4 activation induces intracellular signaling in monocytes and that inhibition of the MAPK and Src family kinase pathways blocked the ability of CD4 ligation to trigger macrophage differentiation. We observed that ligation of CD4 by MHC-II on activated endothelial cells induced CD4-mediated macrophage differentiation of blood monocytes. Finally, CD4 ligation by MHC-II increases the susceptibility of blood-derived monocytes to HIV binding and subsequent infection. Altogether, our studies have identified a novel function for the CD4 molecule on peripheral monocytes and suggest that a unique set of events that lead to innate immune activation differ between humans and mice. Further, these events can have effects on HIV infection and persistence in the macrophage compartment.
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Balancing the stability and drug release of polymer micelles by the coordination of dual-sensitive cleavable bonds in cross-linked core.
Acta Biomater
PUBLISHED: 06-10-2014
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The optimal structure design of nanocarriers to inhibit premature release of anticancer drugs from nanocarriers during blood circulation and improve drug release inside tumor cells is still a significant issue for polymer micelles applied to antitumor drug delivery. Herein, in order to balance the contradiction between polymer micellar stability and drug release, dual-sensitive cleavable cross-linkages of benzoic imine conjugated disulfide bonds were introduced into the core of the amphiphilic copolymer micelles to form core-cross-linked micelles. First, biodegradable poly(ethylene glycol)-b-(polycaprolactone-g-poly(methacrylic acid-p-hydroxy benzaldehyde-cystamine)), i.e. mPEG-b-(PCL-g-P(MAA-Hy-Cys)) (PECMHC) copolymers were synthesized and assembled into PECMHC micelles (PECMHC Ms). Then, simply by introducing H2O2 to the PECMHC Ms dispersions to oxidate the thiol groups of cystamine moieties in the core, core-cross-linked PECMHC micelles (cc-PECMHC Ms) ?100nm in size were readily obtained in water. In vitro studies of doxorubicin (DOX)-loaded cc-PECMHC Ms show that the cross-linked core impeded the drug release in the physical conditions, owing to the high stability of the micelles against both extensive dilution and salt concentration, while it greatly accelerated DOX release in mildly acidic (pH ?5.0-6.0) medium with glutathione, owing to the coordination of the pH-sensitive cleaving of benzoic imine bonds and the reduction-sensitive cleaving of disulfide bonds. The in vivo tissue distribution and tumor accumulation of the DOX-loaded cc-PECMHC Ms were monitored via fluorescence images of DOX. DOX-loaded cc-PECMHC Ms exhibited enhanced tumor accumulation because of their high stability in blood circulation and less DOX premature release. Therefore, the cc-PECMHC Ms with dual-sensitive cleavable bonds in the cross-linked core were of excellent biocompatibility, high extracellular stability and had intelligent intracellular drug release properties, indicating promise as candidates for anticancer drug delivery.
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Preparation and investigation of high solid content PTX-loaded nanoparticles dispersion via nanoprecipitation method.
J Biomater Sci Polym Ed
PUBLISHED: 06-04-2014
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The improvement of the solid content of the hydrophobic drugs (such as paclitaxel (PTX), etc.) loaded nanoparticles (NPs) dispersion is important for enhancing drug-loaded efficiency and reducing the cost in production and application. A diblock copolymer methoxy poly(ethylene glycol)-b-poly(?-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (mPECT) is synthesized via the ring-opening polymerization of ?-caprolactone and 1,4,8-trioxa[4.6]spiro-9-undecanone (TOSUO) with methoxy poly(ethyleneglycol) (mPEG? as the initiator. The chemical structures and thermal properties of mPECT are characterized by (1)HNMR, Fourier transform infrared (FT-IR), gel permeation chromatography, differential scanning calorimetry, etc. PEG45.45-b-P(C28.33-co-T5.38) (mPECT-2) is able to self-assemble into stable NPs in water via nanoprecipitation method at a high solid content (?25?wt%) and their freeze-dried powders can well re-disperse in water. The paclitaxel (PTX) is chosen as a hydrophobic drug model and successfully encapsulate into the mPECT-2 NPs via the same method at a high solid content. The encapsulation efficiency, cytotoxicity and in vitro release of PTX-loaded NPs are investigated. The results suggest that the behavior of the drug-loaded mPECT-2 NPs prepared at a solid content of 25?wt% is similar to that of NPs prepared at a solid content of 1?wt%, which indicate that increasing solid content of polymer has no negative effect on the properties of NPs dispersion in application. In summary, the freeze-dried NPs prepared from the high solid content dispersion (?25?wt%) has a good redispersibility and exhibits great potential in cost control of preparing NPs dispersion used as drug delivery system.
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Differential expression of microRNAs in dorsal root ganglia after sciatic nerve injury.
Neural Regen Res
PUBLISHED: 04-02-2014
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This study investigated the possible involvement of microRNAs in the regulation of genes that participate in peripheral neural regeneration. A microRNA microarray analysis was conducted and 23 microRNAs were identified whose expression was significantly changed in rat dorsal root ganglia after sciatic nerve transection. The expression of one of the downregulated microRNAs, microRNA-214, was validated using quantitative reverse transcriptase-PCR. MicroRNA-214 was predicted to target the 3'-untranslated region of Slit-Robo GTPase-activating protein 3. In situ hybridization verified that microRNA-214 was located in the cytoplasm of dorsal root ganglia primary neurons and was downregulated following sciatic nerve transection. Moreover, a combination of in situ hybridization and immunohistochemistry revealed that microRNA-214 and Slit-Robo GTPase-activating protein 3 were co-localized in dorsal root ganglion primary neurons. Western blot analysis suggested that Slit-Robo GTPase-activating protein 3 was upregulated in dorsal root ganglion neurons after sciatic nerve transection. These data demonstrate that microRNA-214 is located and differentially expressed in dorsal root ganglion primary neurons and may participate in regulating the gene expression of Slit-Robo GTPase-activating protein 3 after sciatic nerve transection.
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A novel transdermal drug delivery system based on self-adhesive Janus nanofibrous film with high breathability and monodirectional water-penetration.
J Biomater Sci Polym Ed
PUBLISHED: 03-18-2014
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Transdermal drug delivery systems (TDDS) had achieved significant success in medical practice, but still suffered from adhesion failure and skin reaction due to the occlusive properties of hydrophobic pressure sensitive adhesives (PSAs). In order to solve these problems, a novel TDDS patch based on self-adhesive Janus nanofibrous film was prepared by a multilayered electrospinning. This multifunctional patch was a bilayer structure. The subjacent layer was a hydrophobic and adhesive fibrous layer electrospun from polyacrylate PSA (HPSA), and the upper backing layer was a hydrophilic cross-linked poly (vinyl alcohol) (c-PVA) nanofibrous film. The structures of the HPSA/c-PVA composite fibrous films were characterized and their application properties, including adherence performance, water vapor permeability, water-penetration, release characteristics, and skin irritation were evaluated. The results indicated that the HPSA/c-PVA composite fibrous films could provide suitable adhesive properties for TDDS application, excellent capacity for drug loading and release, aesthetical appearance and high safety for use on the skin. Especially, due to the nanofibrous network structures and the hydrophobic-hydrophilic wettability gradient from hydrophobic HPSA layer to the hydrophilic c-PVA layer, the Janus films possessed high breathability and monodirectional water-penetration. Water could penetrate from the hydrophobic to the hydrophilic side, but could not permeate through in the opposite direction. This may provide a feasible solution to the problems caused by the water, sweat, or wound exudate on the skin, when the hydrophobic PSAs were used as matrix for TDDS and wound dressing patches.
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Sustained release of PTX-incorporated nanoparticles synergized by burst release of DOX?HCl from thermosensitive modified PEG/PCL hydrogel to improve anti-tumor efficiency.
Eur J Pharm Sci
PUBLISHED: 03-11-2014
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As drug therapies become increasingly sophisticated, the synergistic benefits of two or more drugs are often required. In this study, we aimed at improving anti-tumor efficiency of paclitaxel (PTX)-incorporated thermo-sensitive injectable hydrogel by the synergy of burst release of doxorubicin hydrochloride (DOX?HCl). Thermosensitive injectable hydrogel composed of nanoparticles assembled from amphiphilic copolymer poly(?-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(?-caprolaone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) was fabricated. Hydrophobic PTX and hydrophilic DOX?HCl were loaded simultaneously in the thermo-sensitive injectable hydrogel by a two-stage entrapment. Thermosensitive gelling behaviors of drug-loading PECT nanoparticle aqueous dispersions were studied. In vitro release profiles of PTX and DOX?HCl and in vivo anti-tumor effect by dual drugs from PECT hydrogel were investigated. The results showed that hydrophilic and hydrophobic drugs could be successfully entrapped in PECT hydrogel simultaneously without affecting its thermo-sensitive behavior. In vitro release profiles demonstrated the burst release of DOX?HCl and the sustained release of PTX. Anti-tumor effect was improved by a fast and tense attack caused by the burst release of hydrophilic DOX?HCl from hydrogel, which was continued by the sequent sustained release of PTX-incorporated nanoparticles and remnant DOX?HCl. Unintentionally, entrapped in PECT hydrogel, hydrophilic DOX?HCl was observed to have a sustained releasing pattern in vitro and in vivo.
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Thermosensitive in situ hydrogel based on the hybrid of hyaluronic acid and modified PCL/PEG triblock copolymer.
Carbohydr Polym
PUBLISHED: 02-20-2014
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In this work, a new hydrogel was constructed using poly(?-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(?-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) tri-block copolymers (PECT) with hyaluronic acid (HA) in order to expand application scopes of PECT hydrogel. The rheological and sol-gel phase transition behaviors were investigated by rheometer and test tube inversion method, and the interior morphologies of hydrogel systems were observed by scanning electron microscope (SEM). With the introduction of HA, certain properties of PECT hydrogel, such as viscosity and morphology, have present trends with regularity. Furthermore, with the participation of HA, the degradation and release of acetylsalicylic acid was slightly affected, however, the drug release mechanism of hydrogel has not been changed. PECT/HA hydrogel is confirmed to be non-toxic through a test to NIH3T3 cells. In conclusion, blending with HA is a feasible and safe method to tune properties of PECT hydrogel.
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Risk of serious gastrointestinal bleeding in living kidney donors.
Clin Transplant
PUBLISHED: 02-18-2014
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Individuals with moderate-to-severe reduced renal function have greater risk of gastrointestinal bleeding than those with normal renal function. We conducted a retrospective matched cohort study to assess whether living kidney donors share a similar risk. We reviewed pre-donation charts for living kidney donations from 1992 to 2009 in Ontario, Canada, and linked this information to healthcare databases. We selected healthy non-donors from the general population and matched ten non-donors to every donor. Of the 2009 donors and 20,090 matched non-donors, none had evidence of gastrointestinal bleeding prior to cohort entry. The cohort was followed for a median of 8.4 yr (maximum 19.7 yr; loss to follow-up <7%). There was no significant difference in the rate of hospitalization with gastrointestinal bleeding in donors compared to non-donors (18.5 vs. 14.9 events per 10,000 person-years; rate ratio 1.24; 95% confidence interval [CI] 0.85-1.81). Similar results were obtained when we assessed the time to first hospitalization with gastrointestinal bleeding (hazard ratio 1.25, 95% CI 0.87-1.79). In conclusion, we found living kidney donation was not associated with a higher risk of hospitalization with gastrointestinal bleeding. These results are reassuring for the safety of the practice.
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Thermosensitive injectable hydrogel enhances the antitumor effect of embelin in mouse hepatocellular carcinoma.
J Pharm Sci
PUBLISHED: 01-14-2014
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Embelin, an active ingredient of traditional herbal medicine, is used to treat many diseases such as cancer. However, embelin is hydrophobic and insoluble in water, which makes it unsuitable for in vivo applications. In this study, we constructed an embelin-loaded thermosensitive injectable hydrogel system that we named Embelin/PECT(gel) based on the amphiphilic triblock copolymer of poly (?-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly (ethylene glycol)-poly (?-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT). The cytotoxicity and the antitumor effects of Embelin/PECT(gel) on mouse hepatic cancers were investigated in vitro and in vivo. Results indicated that embelin was formulated in PECT hydrogel and could be continuously released from Embelin/PECT(gel) , showing a higher cytotoxicity for H22 cells in vitro compared with free embelin. The aqueous solution of Embelin/PECT(gel) transformed into gel at the injection site within seconds, which later eroded and degraded over time in vivo. A single local peritumoral injection of Embelin/PECT(gel) in liver at a low dosage of 0.5 mg per mouse exhibited a significant antitumor effect, which was comparable to the antitumor effect of the embelin solution treatment at a total dose of 6 mg per mouse in mouse hepatic cancer. Embelin/PECT(gel) , as a drug delivery system in liver, represents a novel therapeutic drug candidate for the clinical treatment of advanced hepatocellular carcinoma.
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Facile access to cytocompatible multicompartment micelles with adjustable Janus-cores from A-block-B-graft-C terpolymers prepared by combination of ROP and ATRP.
Colloids Surf B Biointerfaces
PUBLISHED: 01-07-2014
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The architecture of hydrophobic segments can determine the specific morphology of multicompartment micelles (MCMs) that are generated from aqueous assembly of amphiphilic terpolymers. In this study, we aimed to design and generate poly(?-caprolactone)-based multicompartment micelles with adjustable Janus-cores. Well-defined terpolymers with a novel A-block-B-graft-C architecture composed of biologically compatible polymers, methoxy poly(ethylene glycol) (PEG), poly(?-caprolactone) (PCL) and poly(2-(perfluorobutyl)ethyl methacrylate) (PPFEMA), were prepared by the stepwise use of ring-opening polymerization and atom transfer radical polymerization. Characterization of the obtained terpolymers was carried out by (1)H NMR and gel permeation chromatography. Results from differential scanning calorimetry and X-ray diffraction studies indicated that within the terpolymer structure, the PCL segments are in the crystalline state, while fluorocarbon segments belong to the amorphous domains. Due to the thermodynamic incompatibility of PCL and PPFEMA, MCMs could be obtained upon aqueous self-assembly of the terpolymer. The well-segregated Janus-cores with adjustable compartment balance were revealed by transmission electron microscopy. In vitro cell viability assays further demonstrated an excellent cytocompatibility of the MCMs both in mouse embryonic fibroblasts (3T3) and human acute monocytic leukemia (THP-1) cells.
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Graft Copolymer Nanoparticles with pH and Reduction Dual-Induced Disassemblable Property for Enhanced Intracellular Curcumin Release.
ACS Appl Mater Interfaces
PUBLISHED: 12-13-2013
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Nanoparticle (NP)-assisted drug delivery systems with disassemblable behaviors in response to intracellular microenvironment are urgently demanded in systemic cancer chemotherapy for enhanced intracellular drug release. Curcumin (CUR), an effective and safe anticancer agent, was limited by its water insolubility and poor bioavailability. Herein, pH and reduction dual-induced disassemblable NPs for high loading efficiency and improved intracellular release of CUR were developed based on an acid degradable cyclic benzylidene acetal groups (CBAs)-functionalized poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate)-g-SS-poly(ethylene glycol) (PTTMA-g-SS-PEG) graft copolymer, which was readily prepared via RAFT copolymerization and coupling reaction. The NPs self-assembled from PTTMA-g-SS-PEG copolymers were stable at physiological pH, and quickly disassembled in mildly acidic and reductive environments because of the hydrolysis of CBAs in hydrophobic PTTMA core and the cleavage of disulfide-linked detachable PEG shell. PTTMA-g-SS-PEG NPs exhibited excellent CUR loading capacity with drug loading content up to 19.2% and entrapment efficiency of 96.0%. Within 20 h in vitro, less than 15.0% of CUR was released from the CUR-loaded NPs in normal physiological conditions, whereas 94.3% was released in the presence of reductive agent and mildly acidic conditions analogous to the microenvironment in endosome/lysosome and cytoplasm. Confocal fluorescence microscopies revealed that the CUR-loaded PTTMA-g-SS-PEG NPs exhibited more efficiently intracellular CUR release for EC-109 cells than that of CUR-loaded reduction-unresponsive PTTMA-g-PEG NPs and free CUR. In vitro cytotoxicity studies displayed blank PTTMA-g-SS-PEG NPs showed low toxicity at concentrations up to 1.0 mg/mL, whereas CUR-loaded PTTMA-g-SS-PEG NPs demonstrated more efficient growth inhibition toward EC-109 and HepG-2 cells than reduction-unresponsive controls and free CUR. Therefore, the above results indicated that pH and reduction dual-induced disassemblable PTTMA-g-SS-PEG NPs may have emerged as superior nanocarriers for active loading and promoted intracellular drug delivery in systemic cancer chemotherapy.
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Stem-Cell-Based Gene Therapy for HIV Infection.
Viruses
PUBLISHED: 11-01-2013
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Despite the enormous success of combined anti-retroviral therapy, HIV infection is still a lifelong disease and continues to spread rapidly worldwide. There is a pressing need to develop a treatment that will cure HIV infection. Recent progress in stem cell manipulation and advancements in humanized mouse models have allowed rapid developments of gene therapy for HIV treatment. In this review, we will discuss two aspects of HIV gene therapy using human hematopoietic stem cells. The first is to generate immune systems resistant to HIV infection while the second strategy involves enhancing anti-HIV immunity to eliminate HIV infected cells.
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Comb-like amphiphilic copolymers bearing acetal-functionalized backbones with the ability of acid-triggered hydrophobic-to-hydrophilic transition as effective nanocarriers for intracellular release of curcumin.
Biomacromolecules
PUBLISHED: 10-29-2013
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The pH-responsive micelles have enormous potential as nanosized drug carriers for cancer therapy due to their physicochemical changes in response to the tumor intracellular acidic microenvironment. Herein, a series of comb-like amphiphilic copolymers bearing acetal-functionalized backbone were developed based on poly[(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate-co-poly(ethylene glycol) methyl ether methacrylate] [P(TTMA-co-mPEGMA)] as effective nanocarriers for intracellular curcumin (CUR) release. P(TTMA-co-mPEGMA) copolymers with different hydrophobic-hydrophilic ratios were prepared by one-step reversible addition fragmentation chain transfer (RAFT) copolymerization of TTMA and mPEGMA. Their molecular structures and chemical compositions were confirmed by (1)H NMR, Fourier transform infrared spectroscopy (FT-IR) and gel permeation chromatography (GPC). P(TTMA-co-mPEGMA) copolymers could self-assemble into nanosized micelles in aqueous solution and displayed low critical micelle concentration (CMC). All P(TTMA-co-mPEGMA) micelles displayed excellent drug loading capacity, due to the strong ?-? conjugate action and hydrophobic interaction between the PTTMA and CUR. Moreover, the hydrophobic PTTMA chain could be selectively hydrolyzed into a hydrophilic backbone in the mildly acidic environment, leading to significant swelling and final disassembly of the micelles. These morphological changes of P(TTMA-co-mPEGMA) micelles with time at pH 5.0 were determined by DLS and TEM. The in vitro CUR release from the micelles exhibited a pH-dependent behavior. The release rate of CUR was significantly accelerated at mildly acidic pH of 4.0 and 5.0 compared to that at pH 7.4. Toxicity test revealed that the P(TTMA-co-mPEGMA) copolymers exhibited low cytotoxicity, whereas the CUR-loaded micelles maintained high cytotoxicity for HepG-2 and EC-109 cells. The results indicated that the novel P(TTMA-co-mPEGMA) micelles with low CMC, small and tunable sizes, high drug loading, pH-responsive drug release behavior, and good biocompatibility may have potential as hydrophobic drug delivery nanocarriers for cancer therapy with intelligent delivery.
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Living kidney donor estimated glomerular filtration rate and recipient graft survival.
Nephrol. Dial. Transplant.
PUBLISHED: 10-21-2013
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Kidney transplants from living donors with an estimated glomerular filtration rate (eGFR) < 80 mL/min per 1.73 m(2) may be at risk for increased graft loss compared with a recipient who receives a kidney from a living donor with a higher eGFR.
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Smoke-free or not: a pilot evaluation in selected Beijing Hospitals.
BMC Public Health
PUBLISHED: 10-11-2013
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China enacted a policy to ban smoking in hospitals. The Chinese Association for Tobacco Control (CATC) developed a program to help hospitals implement this policy. They conducted a program and an assessment in 3 Chinese cities (Beijing, Shanghai and Guangdong). A more in-depth evaluation was implemented with a sub-sample of hospitals in Beijing (N = 7) to provide an independent assessment. This independent assessment focused on evaluating policy development and an assessment of secondhand smoke (SHS) to determine compliance with the smoke-free policy initiative.
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Electrospinning of ibuprofen-loaded composite nanofibers for improving the performances of transdermal patches.
J Nanosci Nanotechnol
PUBLISHED: 07-19-2013
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The main aim of the present study was to electrospin ibuprofen (IBU)-loaded composite nanofibers to improve the performances of transdermal patches. Cellulose acetate/poly(vinyl pyrrolidone) (CA/PVP) blends were used to fabricate uniform nanofibers. Investigations on the physicochemical properties of CA/PVP solutions indicated that the addition of appropriate PVP improved the electrospinnability of original CA solutions. Detections on the physical states of IBU in medicated CA/PVP nanofibers suggested that IBU was uniformly distributed in nanofibers in an amorphous state. Comparing to IBU-loaded casting membrane, the medicated CA/PVP nanofibers provided a faster IBU diffusion manner and a better ex vitro skin permeation profile due to their high superficial areas and the amorphous IBU. Furthermore, CA/PVP nanofibers exhibited a high water vapor permeability, which could render an improved breathability to transdermal patches. In sum, the electrospun drug-loaded CA/PVP nanofibers exhibited great potentials to improve the thermodynamic stability and breathability of transdermal patches, which could be used to develop new types of transdermal drug delivery system (TDDS).
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Hypertension in pregnancy after Escherichia coli O157:H7 gastroenteritis: a cohort study.
Hypertens Pregnancy
PUBLISHED: 07-11-2013
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Escherichia coli O157:H7 is a common cause of bacterial gastroenteritis and may increase the risk of hypertension. We studied the risk of hypertension in pregnancy following a large E. coli O157:H7 outbreak that occurred in Walkerton, Canada, in the year 2000.
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Compact solar autoclave based on steam generation using broadband light-harvesting nanoparticles.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-08-2013
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The lack of readily available sterilization processes for medicine and dentistry practices in the developing world is a major risk factor for the propagation of disease. Modern medical facilities in the developed world often use autoclave systems to sterilize medical instruments and equipment and process waste that could contain harmful contagions. Here, we show the use of broadband light-absorbing nanoparticles as solar photothermal heaters, which generate high-temperature steam for a standalone, efficient solar autoclave useful for sanitation of instruments or materials in resource-limited, remote locations. Sterilization was verified using a standard Geobacillus stearothermophilus-based biological indicator.
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Photo-crosslinked poly(ethylene glycol)-b-poly(?-caprolactone) nanoparticles for controllable paclitaxel release.
J Biomater Sci Polym Ed
PUBLISHED: 06-27-2013
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Novel biodegradable core-crosslinked nanoparticles (CNPs) consisting of methoxy poly(ethylene glycol)-block-poly(?-caprolactone-co-?-cinnamoyloxy-?-caprolactone) (mPEG-b-P(CL-co-CCL)) were prepared and evaluated for paclitaxel (PTX) delivery. mPEG113-b-P(CL65.2-co-CCL10.1) had a higher drug loading efficiency (95%) compared to mPEG113-b-PCL93.1 (43%). The stability of NPs has been largely improved and PTX release was significantly inhibited by crosslinking via UV irradiation at ??=?254?nm. MTT assays demonstrated that both blank non-crosslinked and crosslinked NPs showed low cytotoxicity to NCL-H460 cells while PTX-loaded non-crosslinked and crosslinked NPs exhibited obvious cytotoxicity against NCL-H460 cells, and the cytotoxicity was both dose-dependent and time-dependent. Furthermore, after 48?h incubation the cell viability of PTX-loaded crosslinked NPs was lower compared to that of PTX-loaded non-crosslinked NPs or free PTX. These properties indicated that CNPs prepared from mPEG-b-P(CL-co-CCL) have great potentials as carriers for drug delivery.
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Contribution of hydrophobic/hydrophilic modification on cationic chains of poly(?-caprolactone)-graft-poly(dimethylamino ethylmethacrylate) amphiphilic co-polymer in gene delivery.
Acta Biomater
PUBLISHED: 05-26-2013
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Nanoparticles (NPs) assembled from amphiphilic polycations have been certified as potential carriers for gene delivery. Structural modification of polycation moieties may be an efficient route to further enhance gene delivery efficiency. In this study two electroneutral monomers with different hydrophobicities, 2-hydroxyethyl methacrylate (HEMA) and 2-hydroxyethyl acrylate (HEA), were incorporated into the cationic poly(dimethylamino ethyl methacrylate) (PDMAEMA) side-chains of amphiphilic poly(?-caprolactone)-graft-poly(dimethylamino ethylmethacrylate) (PCD) by random co-polymerization, to obtain poly(?-caprolactone)-graft-poly(dimethylamino ethyl methacrylate-co-2-hydroxyethyl methacrylate) (PCD-HEMA) and poly(?-caprolactone)-graft-poly(dimethylamino ethyl methacrylate-co-2-hydroxyethyl acrylate) (PCD-HEA). Minimal HEA or HEMA moieties in PDMAEMA do not lead to statistically significant changes in particle size, zeta potential, DNA condensation properties and buffering capacity of the naked NPs. However, the incorporation of HEMA and HEA lead to reductions and increases, respectively, in the surface hydrophilicity of the naked NPs and NPs/DNA complexes, which was confirmed by water contact angle assay. These simple modifications of PDMAEMA with HEA and HEMA moieties significantly affect the gene transfection efficiency on HeLa cells in vitro: PCD-HEMA NP/DNA complexes show a much higher transfection efficiency than PCD NPs/DNA complexes, while PCD-HEA NPs/DNA complexes show a lower transfection efficiency than PCD NP/DNA complexes. Fluorescence activated cell sorter and confocal laser scanning microscope results indicate that the incorporation of hydrophobic HEMA moieties facilitates an enhancement in both cellular uptake and endosomal/lysosomal escape, leading to a higher transfection efficiency. Moreover, the process of endosomal/lysosomal escape confirmed in our research that PCD and its derivatives do not just rely on the proton sponge mechanism, but also on membrane damage due to the polycation chains, especially hydrophobic modified ones. Hence, it is proved that hydrophobic modification of cationic side-chains is a crucial route to improve gene transfection mediated by polycation NPs.
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Genetic regulation and potentially therapeutic application of cancer-associated fibroblasts in oral cancer.
J. Oral Pathol. Med.
PUBLISHED: 05-16-2013
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Carcinoma-associated fibroblast (CAF) is the most important host cell type in tumor microenvironment, which greatly contributes to tumor initiation, progression, and metastasis. Therefore, a large amount of data has emerged, showing the cancer-promoting function of these cells via paracrine effects that escort tumor cells through all the steps of cancer development. CAF is a heterogeneous cell population that can arise from the differentiation of resting fibroblasts, epithelial cells, endothelial cells, and mesenchymal stem cells. This review summarizes the current knowledge of the role of CAFs in tumor progression, with a particular focus on the cellular and molecular features and recent advances in researches on the genetic status and microRNA regulation, and addresses the potential prognostic and therapeutic values for patients with oral cancer by targeting CAFs.
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Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous silica nanoparticles for efficient siRNA delivery in vitro and in vivo.
Nanoscale
PUBLISHED: 04-05-2013
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A low cytotoxicity and high efficiency delivery system with the advantages of low cost and facile fabrication is needed for the application of small interfering RNA (siRNA) delivery both in vitro and in vivo. For these prerequisites, cationic polymer-mesoporous silica nanoparticles (ssCP-MSNs) were prepared by surface functionalized mesoporous silica nanoparticles with disulfide bond cross-linked poly(2-dimethylaminoethyl methacrylate) (PDMAEMA). In vitro and in vivo evaluations were performed. The synthesized ssCP-MSNs are 100-150 nm in diameter with a pore size of 10 nm and a positively charged surface with a high zeta potential of 27 mV. Consequently, the ssCP-MSNs showed an excellent binding capacity for siRNA, and an enhancement in the cell uptake and cytosolic availability of siRNA. Furthermore, the intracellular reducing cleavage of the disulfide bonds cross-linking the PDMAEMA segments led to intracellular cleavage of PDMAEMA from ssCP-MSNs, which facilitated the intracellular triggered release of siRNA. Therefore, promoted RNA interference was observed in HeLa-Luc cells, which was equal to that of Lipofectamine 2000. Significantly, compared to Lipofectamine 2000, the ssCP-MSNs were more biocompatible, with low cytotoxicity (even non-cytotoxicity) and promotion of cell proliferation to HeLa-Luc cells. The in vivo systemic distribution studies certified that ssCP-MSNs/siRNA could prolong the duration of siRNA in vivo, and that they accumulated in the adrenal gland, liver, lung, spleen, kidney, heart and thymus after intravenous injection. Encouragingly, with the ability to deliver siRNA to a tumor, ssCP-MSNs/siRNA showed a tumor suppression effect in the HeLa-Luc xenograft murine model after intravenous injection. Therefore, the ssCP-MSNs cationic polymer-mesoporous silica nanoparticles with low cytotoxicity are promising for siRNA delivery.
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Bioinspired superhydrophobic carbonaceous hairy microstructures with strong water adhesion and high gas retaining capability.
Adv. Mater. Weinheim
PUBLISHED: 02-23-2013
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Various hydrophobic hairy carbonaceous fibers are obtained by a low-temperature CVD process on catalyst-patterned surface patches which are selectively coated with silica to make the surface superhydrophobic and yet allow strong water adhesion for the "Salvinia effect". The versatility of the functional hairy fiber surfaces is demonstrated with a liquid barrier grid for cell microarray, a gas retaining capability under water/liquid for a membrane-free microfluidic chemical process, and functionalized papillae for cell immobilization with green algae.
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Toxicity and in vivo biological effect of the nanoparticular self-supported hydrogel of a thermosensitive copolymer for noninvasive drug delivery.
J Biomed Mater Res A
PUBLISHED: 02-19-2013
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Injectable thermosensitive hydrogels provide local non-invasive platforms for sustained drug release, tissue engineering and cellular immunity. As a long-term implant, the toxicity and in vivo biological effect should be concerned. Previously, we developed a novel type of injectable nanoparticular self-supported hydrogel (PECT NPs(Gel) ) of poly(ethylene glycol) and pendent cycle ethers modified poly(?-caprolactone) triblock copolymer (PECT), which could sustainedly release PECT or drug-loaded PECT nanoparticles with the hydrogel disassembly and provided efficient antitumor activity and significant decrease of side effects. Herein, the aim of this work was to reveal the toxicity and in vivo biological effect of PECT nanoparticles and PECT NPs(Gel) . In vitro cytotoxicity indicated no cell cytotoxicity was observed when the concentration of PECT nanoparticle was up to 500 µg/mL, and also no mutagenic effect and no genotoxicity were observed. In vivo intravenous injection of PECT nanoparticles demonstrated that the median lethal dose was approximate high to 2.564 g/kg, and compared with the control mice, the mice treated with daily administration of PECT nanoparticles showed no difference in the physical or behavioral alterations, body weight changes, biochemical and hematological parameters as well as organ coefficients. The in vivo chronic effect of PECT NPs(Gel) confirmed no toxic lesions to animals in a whole period of 3 months even the dosage was high to 20 g/kg. These findings indicated PECT nanoparticles and PECT NPs(Gel) were of well biocompatibility and did not provoke any side effect to body, which represented a new class of injectable and noninvasive systemic or site-specific delivery carrier. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
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Gene transfection efficacy and biocompatibility of polycation/DNA complexes coated with enzyme degradable PEGylated hyaluronic acid.
Biomaterials
PUBLISHED: 02-14-2013
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Coating the polycation/DNA binary complexes with PEGylated polyanions can improve long-circulation and biocompatibility in vivo. However, it has been certificated PEG dilemma can reduces gene transfection efficiency because of inhibition in cellular uptake and endosomal escape. Herein, two PEGylated anionic polymers, PEGylated hyaluronic acid (HgP) and PEGylated polyglutamic acid (PGgP) were synthesized to coat the binary complexes of core-shell cationic polycaprolactone-graft-poly (N, N-dimethylaminoethyl methacrylate) nanoparticles/DNA (NP-D). The effects of polyanion structure were evaluated in terms of particle size, zeta potential, cytotoxicity, cellular uptake and transfect efficiency in vitro and in vivo. In vitro study illustrated that HgP coated complexes showed better efficiencies in both cell uptake and transfection than PGgP coated complexes. The coating of HgP on NP-D improved the biocompatibility without reduction in cell uptake and transfection efficacy, and resulted in higher accumulation and gene expression in tumor after IV injection. The success of HgP coating in overcoming PEG dilemma is attributed to the hyaluronic acid (HA)-receptor-mediated endocytosis and outer shell-detachment through the hyaluronidases catalyzed degradation of HA. These results demonstrated that HgP was a promising anionic polymer for coating the polycation/DNA complexes and ternary complexes (HgP coated NP-D) hold promising potential for cancer therapy.
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Variation in the days supply field for osteoporosis medications in Ontario.
Arch Osteoporos
PUBLISHED: 02-12-2013
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We examined pharmacy claims for osteoporosis medications dispensed in the community (78 %) and long-term care (LTC) to determine if days supply values matched expected dosing intervals. Results identify potential reporting errors that can have implications for drug exposure misclassification, particularly in LTC where only 59 % of reported values matched expected values.
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Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and in vivo siRNA delivery.
Acta Biomater
PUBLISHED: 01-07-2013
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Long circulation, cell internalization, endosomal escape and small interfering RNA (siRNA) release to the cytoplasm are the prerequisite considerations for siRNA delivery vectors. Herein, a kind of sheddable nanoparticles (NPs) with micelle architecture for siRNA delivery were fabricated by using an intracellular-activated polycation-detachable copolymer (PECssD), which was prepared by introducing highly reducing environment-responsive disulfide linkages between PEGylated polycaprolactone (PCL) and the grafted polycation, poly(2-dimethylaminoethyl methacrylate) (PDMAEMA). The architecture of PECssD self-assembled NPs includes a biodegradable hydrophobic PCL core, a PEG shield and a detachable comb-like polycation surface. The stable nanosized complexes of PECssD NPs with siRNA, termed PECssD/siRNA micelleplexes, were formed, which could prolong circulation, improve accumulation and retention in tumor tissue, and be favorable for internalization. In particular, the cleavage of the disulfide linkages in the intracellular microenvironment and the subsequent dissociation of the PDMAEMA/siRNA polyplexes from the PEGylated PCL cores of PECssD/siRNA micelleplexes were also confirmed, which facilitated the endosomal escape and the efficient release of siRNA. As a result, the distribution of siRNA in cytoplasm was enhanced and subsequently promoted the efficiency of siRNA in gene silencing. Furthermore, systemic administration of the NPs carrying siPlk1 (polo-like kinase 1 specific siRNA) induced a tumor-suppressing effect in the HeLa-Luc xenograft murine model. Therefore, the devised strategy of the polycation-detachable copolymer PECssD NPs could address the requirements of the multistep systemic delivery process of siRNA. The hydrophobic core of the PECssD/siRNA micelleplexes is expected to entrap antitumor drugs or other therapeutic agents for combined therapies.
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Proton Pump Inhibitors and the Risk of Adverse Cardiac Events.
PLoS ONE
PUBLISHED: 01-01-2013
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Recent evidence suggests that proton pump inhibitors (PPIs) might be linked with adverse cardiac events, but a causal relationship is unproven.
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Statins and intracerebral hemorrhage: a retrospective cohort study.
Arch. Neurol.
PUBLISHED: 09-12-2011
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A recent post hoc analysis of a large randomized trial in patients with cerebrovascular disease suggested that statins may increase the risk of intracerebral hemorrhage (ICH).
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Structural contributions of blocked or grafted poly(2-dimethylaminoethyl methacrylate) on PEGylated polycaprolactone nanoparticles in siRNA delivery.
Biomaterials
PUBLISHED: 07-19-2011
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The multiformity in polymer structure and conformation design provides a great potential in improving the gene silencing efficiency of siRNA by polymer vectors. In order to provide information on the polymer design for siRNA delivery, the structural contributions of blocked or grafted poly(2-dimethylaminoethyl methacrylate) on PEGylated polycaprolactone nanoparticles (NPs) in siRNA delivery were studied. Herein, two kinds of self-assembly nanoparticles (NPs) formed by amphiphilic cationic polymers, methoxy poly(ethylene glycol)-block-polycaprolactone-block-poly(2-dimethylaminoethyl methacrylate) (mPEG-PCL-b-PDMAEMA, PECbD) and methoxy poly(ethylene glycol)-block-(polycaprolactone-graft-poly(2-dimethylaminoethyl methacrylate)) (mPEG-PCL-g-PDMAEMA, PECgD), were used to deliver siRNA for in vitro and in vivo studies. The physiochemical properties including size and zeta potential of PECbD NPs/siRNA and PECgD NPs/siRNA complexes were characterized. In vitro cytotoxicity, cellular uptake and siRNA knockdown efficiency were evaluated in HeLa-Luc cells. The endosome escape and intracellular distribution of PECbD NPs/siRNA and PECgD NPs/siRNA in HeLa-Luc cells were also observed. In vivo polymer mediated siRNA delivery and the complexes distribution in isolated organs were studied using mice and tumor-bearing mice. At the same total degree of polymerization (DP) of DMAEMA, PECgD NPs/siRNA complexes possessed higher zeta potentials than PECbD NPs/siRNA complexes (at the same N/P ratio), which may be the reason that PECgD NPs/siRNA complexes can deliver more siRNA into the cytoplasm and lead to higher in vitro luciferase and lamin A/C silencing efficiency than PECbD NPs/siRNA complexes. The in vivo imaging measurement and histochemical analysis also confirmed that siRNA could be delivered to lungs, livers, pancreas and HeLa-Luc tumors more efficiently by PECgD NPs than PECbD NPs. Meanwhile, the PDMAEMA chains of PECgD could be shortened which provides benefits for clearing. Therefore, PECgD NPs have great potential to be used as efficient non-viral carriers for in vivo siRNA delivery.
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Bioadhesive film formed from a novel organic-inorganic hybrid gel for transdermal drug delivery system.
Eur J Pharm Biopharm
PUBLISHED: 03-30-2011
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A novel organic-inorganic hybrid film-forming agent for TDDS was developed by a modified poly(vinyl alcohol) (PVA) gel using ?-(glycidyloxypropyl)trimethoxysilane (GPTMS) as an inorganic-modifying agent, poly(N-vinyl pyrrolidone) (PVP) as a tackifier and glycerol (GLY) as a plasticizer. The prepared gels can be applied to the skin by a coating method and in situ form very thin and transparent films with good performance, comfortable feel and cosmetic attractiveness. The key properties of the bioadhesive films produced from the hybrid gels were investigated and the results showed that the incorporation of appropriate GPTMS (GPTMS/(PVA+GPTMS) in the range of 20-30%) into the PVA matrix not only can significantly enhance mechanical strength and skin adhesion properties of the resultant film, but also can decrease the crystalline regions of PVA and hence facilitate the diffusion of water vapor and drug. Furthermore, the investigations into in vivo skin irritation suggested the films caused non-irritation to skin after topical application for 120 h. In conclusion, the bioadhesive films formed from organic-inorganic hybrid gels possessed very good qualities for application on the skin and may provide a promising formulation for TDDS, especially when the patient acceptability from an aesthetic perspective of the dosage form is a prime consideration.
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Investigation on injectable, thermally and physically gelable poly(ethylene glycol)/poly(octadecanedioic anhydride) amphiphilic triblock co-polymer nanoparticles.
J Biomater Sci Polym Ed
PUBLISHED: 01-28-2011
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A family of injectable, biodegradable and thermosensitive co-polymer nanoparticle (NP) hydrogels based on mPEG-b-POA-b-mPEG, which was synthesized from mono-methoxy poly(ethylene glycol) (mPEG) and poly(octadecanedioic anhydride) (POA), was investigated in this paper. It was found that the aqueous dispersions of these NPs underwent a reversible gel-sol transition upon temperature change. By using paclitaxel and Bovine serum albumin (BSA) as model drugs, we noticed that the in vitro releases of both in situ gel-forming formulations were sustained and no initial burst releases were observed for 7 days. In vitro cytotoxicity tests via MTT assay indicate that mPEG-b-POA-b-mPEG NPs are non-toxic to normal mouse lung fibroblast cells (L929). The in vivo hydrogel formation and in vivo biocompatibility of co-polymer NP hydrogel were also investigated and the results further validate the biocompatible nature of co-polymer NP hydrogel. In conclusion, our mPEG-b-POA-b-mPEG NP hydrogel is able to control the release of incorporated drug for longer duration.
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Ternary complexes of amphiphilic polycaprolactone-graft-poly (N,N-dimethylaminoethyl methacrylate), DNA and polyglutamic acid-graft-poly(ethylene glycol) for gene delivery.
Biomaterials
PUBLISHED: 01-13-2011
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Binary complexes of cationic polymers and DNA were used commonly for DNA delivery, whereas, the excess cationic charge of the binary complexes mainly leads to high toxicity and unstability in vivo. In this paper, ternary complexes by coating polyglutamic acid-graft-poly(ethylene glycol)(PGA-g-mPEG) onto binary complexes of polycaprolactone-graft-poly(N,N-dimethylaminoethyl methacrylate) (PCL-g-PDMAEMA) nanoparticles (NPs)/DNA were firstly developed for effective and targeted gene delivery. The coating of PGA-g-mPEG was able to decrease the zeta potential of the nano-sized DNA complexes nearly to electroneutrality without interferring with DNA condensation ability. As a result, the stability, the escape ability from endosomes and the transfection efficiency of the complexes were enhanced. The ternary complexes of PCL-g-PDMAEMA NPs/DNA/PGA-g-mPEG demonstrated lower cytotoxicity in CCK-8 measurements and higher gene transfection efficiency than the binary complexes in vitro. In addition, Lactate dehydrogenase (LDH) assay was performed to quantify the membrane-damaging effects of the complexes, which is consistent with the conclusion of CCK-8 measurement for cytotoxicity assay. The in vivo imaging measurement and histochemical analysis of tumor sessions confirmed that the intravenous administration of the ternary complexes with red fluorescent protein (RFP) as payload led to protein expression in tumor, which was further enhanced by the targeted coating of PGA-g-PEG-folate.
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[The application of operating room quality backward system in instrument place management].
Zhongguo Yi Liao Qi Xie Za Zhi
PUBLISHED: 12-25-2010
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Improvement of the surgery instruments clean quality, the optimized preparation way, reasonable arrangement in groups, raising the working efficiency.
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Practical approach for macroporous structure embedded microfluidic system and the catalytic microchemical application.
Lab Chip
PUBLISHED: 11-17-2010
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We present a low cost and practical approach to integrate 3D ordered macroporous polyfluoropolyether (PFPE) patterns into a microchannel by a series of porous pattern fabrication processes and subsequent photolithography in a site- and shape-selective manner. The 3D ordered macroporous patterns with high-resolution edges were firstly fabricated by microtransfer molding (?-TM) of the sacrificial polystyrene (PS) template infiltrated with PFPE as a non-adhesive and solvent-resistant skeletal material. The resulting robust PFPE porous structures with high solvent resistance on a silicon wafer can easily be embedded into the microchannel with the aid of conventional photolithography, leading to a microfluidic system with a built-in microstructure. Moreover, catalytic Pd nanoparticles implanted on the surface of the porous structure were obtained by use of Pd nanoparticle deposited PS spheres, the porous structure embedded channel was utilized to perform a Suzuki coupling reaction.
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Enhanced gene delivery and siRNA silencing by gold nanoparticles coated with charge-reversal polyelectrolyte.
ACS Nano
PUBLISHED: 08-17-2010
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Charge-reversal functional gold nanoparticles first prepared by layer-by-layer technique were employed to deliver small interfering RNA (siRNA) and plasmid DNA into cancer cells. Polyacrylamide gel electrophoresis measurements of siRNA confirmed the occurrence of the charge-reversal property of functional gold nanoparticles. The expression efficiency of enhanced green fluorescent protein (EGFP) was improved by adjuvant transfection with charge-reversal functional gold nanoparticles, which also had much lower toxicity to cell proliferation. Lamin A/C, an important nuclear envelope protein, was effectively silenced by lamin A/C-siRNA delivered by charge-reversal functional gold nanoparticles, whose knockdown efficiency was better than that of commercial Lipofectamine 2000. Confocal laser scanning microscopic images indicated that there was more cy5-siRNA distributed throughout the cytoplasm for cyanine 5-siRNA/polyethyleneimine/cis-aconitic anhydride-functionalized poly(allylamine)/ polyethyleneimine/11-mercaptoundecanoic acid-gold nanoparticle (cy5-siRNA/PEI/PAH-Cit/PEI/MUA-AuNP) complexes. These results demonstrate the feasibility of using charge-reversal functional gold nanoparticles as a means of improving the nucleic acid delivery efficiency.
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Amphiphilic methoxy poly(ethylene glycol)-b-poly(?-caprolactone)-b-poly(2-dimethylaminoethyl methacrylate) cationic copolymer nanoparticles as a vector for gene and drug delivery.
Biomacromolecules
PUBLISHED: 07-30-2010
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We studied methoxy poly(ethylene glycol)-b-poly(?-caprolactone)-b-poly(2-dimethylaminoethyl methacrylate) (mPEG-b-PCL-b-PDMAEMA) nanoparticles as the codelivery vector of hydrophobic drug and pDNA by employing dynamic light scattering (DLS), ? potential, transmission electron microscopy (TEM), gel retardation assay, and confocal microscopy, and subsequently its in vitro cytotoxicity and transfection efficiency were tested. mPEG-b-PCL-b-PDMAEMA nanoparticles (NPs) with or without paclitaxel are both able to complex with pDNA completely when N/P ratio is equal to or above 3, and the combinatorial deliveries of paclitaxel and pDNA have equivalent transfection efficiency compared to blank NPs/pDNA complexes when N/P ratio is equal to or above 15, which indicates that the payload of hydrophobic drug does not influence pDNA condensation and transfection efficiency. Importantly, the in vitro cell experiment results confirm that the introduction of hydrophobic segment between mPEG and PDMAEMA segments can largely improve the gene transfection efficiency, which is about 15 times that of mPEG-b-PDMAEMA. NPs/pDNA complexes can be efficiently internalized into 293T cells after transfection for 2 h. The drug release rate of paclitaxel-loaded NPs in pH 5.0 release medium is higher than that in pH 7.2 release medium. These results suggest that mPEG-b-PCL-b-PDMAEMA NPs may be a promising vector to deliver anticancer drugs and pDNA simultaneously for achieving the synergistic/combined effect on cancer therapies.
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Prevention of rotavirus gastroenteritis in infants and children: rotavirus vaccine safety, efficacy, and potential impact of vaccines.
Biologics
PUBLISHED: 07-29-2010
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Rotavirus infection is the most common cause of severe gastroenteritis globally, with greater than 86% of deaths occurring in low-income and middle-income countries. There are two rotavirus vaccines currently licensed in the United States and prequalified by the World Health Organization. RV1 is a monovalent attenuated human rotavirus strain, given orally in two doses. RV5 is a pentavalent human-bovine reassortant rotavirus vaccine, given orally in three doses. A third rotavirus vaccine, LLV, is a lamb rotavirus strain given orally as a single dose, which is currently available only in China. RV1 and RV5 have been shown to be highly efficacious in developed countries, and initial results from trials in Africa and Asia are promising as well. At least three other vaccines are in development, which are being developed by manufacturers of developing countries. Further studies are needed to clarify issues including administration of oral rotavirus vaccines with breastfeeding and other oral vaccines, and alterations in dosing schedule. Using new data on global diarrheal burden, rotavirus is estimated to cause 390,000 deaths in children younger than 5 years. Should rotavirus vaccines be introduced in the routine immunization programs of all countries, a potential of 170,000 deaths could be prevented annually. The largest impact on mortality would be seen in low-income and middle-income countries, despite poor immunization coverage and lower efficacy. Therefore, international efforts are needed to ensure that rotavirus vaccines reach the populations with highest burden of rotavirus disease.
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Amphiphilic and biodegradable methoxy polyethylene glycol-block-(polycaprolactone-graft-poly(2-(dimethylamino)ethyl methacrylate)) as an effective gene carrier.
Biomaterials
PUBLISHED: 07-25-2010
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A group of amphiphilic cationic polymers, methoxy polyethylene glycol-block-(polycaprolactone-graft-poly(2-(dimethylamino)ethyl methacrylate)) (PECD), were synthesized by combining ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP) methods to form nanoparticles (NPs). The structures of these amphiphilic cationic polymers were characterized by (1)H NMR measurement. The PECD NPs have hydrophobic cores covered with hydrophilic PEG and cationic PDMAEMA chains. These self-assembly nanoparticles were characterized by dynamic light scattering (DLS) technique. PECD NPs can effectively condense DNA to form compact complexes of the size 65-160 nm suitable for gene delivery. The in vitro gene transfection studies of HeLa and HepG2 cells show that PECD NPs have better transfection efficiency compared to polyethylenimine (PEI) and Lipofectamine 2000 at low dose (N/P = 5). The cytotoxicity result shows that PECD NPs/DNA complexes at the optimal N/P ratio for transfection have comparable toxicity with PEI and Lipofectamine. These results indicate that PECD NPs have a great potential to be used as efficient polymeric carriers for gene transfection.
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Poly(ester anhydride)/mPEG amphiphilic block co-polymer nanoparticles as delivery devices for paclitaxel.
J Biomater Sci Polym Ed
PUBLISHED: 06-21-2010
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This work focused on the preparation and characterization of a novel amphiphilic block co-polymer and paclitaxel-loaded co-polymer nanoparticles (NPs) and in vitro evaluation of the release of paclitaxel and cytotoxicity of NPs. mPEG-b-P(OA-DLLA)-b-mPEG was prepared via melt polycondensation of methoxy poly(ethylene glycol) (mPEG), octadecanedioic acid (OA) and D,L-lactic acid (DLLA) and characterized by FT-IR, (1)H-NMR, (13)C-NMR, GPC, DSC and XRD. The paclitaxel-loaded mPEG-b-P(OA-DLLA)-b-mPEG NPs were prepared by nanoprecipitation and then characterized by LPSA, TEM and (1)H-NMR. In vitro release behaviors of the paclitaxel-loaded NPs were investigated by HPLC. In vitro cytotoxicity of NPs was evaluated by MTT assay with normal mouse lung fibroblast cells (L929) as model cells. The composition of mPEG-b-P(OA-DLLA)-b-mPEG is consistent with that of the designed co-polymer. The paclitaxel-loaded NPs are of spherical shape with core/shell structure and size smaller than 300 nm. Paclitaxel can be continuously released from the paclitaxel-loaded NPs and the in vitro release rate of paclitaxel decreases with increasing the content of the P(OA-DLLA) segments in the co-polymer. The mPEG-b-P(OA-DLLA)-b-mPEG NPs are non-toxic to L929. The results suggest that mPEG-b-P(OA-DLLA)-b-mPEG NPs are a potential candidate carrier material for the controlled delivery of paclitaxel and other hydrophobic compounds.
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In vitro enhancement of lactate esters on the percutaneous penetration of drugs with different lipophilicity.
AAPS PharmSciTech
PUBLISHED: 04-30-2010
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Lactate esters are widely used as food additives, perfume materials, medicine additives, and personal care products. The objective of this work was to investigate the effect of a series of lactate esters as penetration enhancers on the in vitro skin permeation of four drugs with different physicochemical properties, including ibuprofen, salicylic acid, dexamethasone and 5-fluorouracil. The saturated donor solutions of the evaluated drugs in propylene glycol were used in order to keep a constant driving force with maximum thermodynamic activity. The permeability coefficient (K(p)), skin concentration of drugs (SC), and lag time (T), as well as the enhancement ratios for K(p) and SC were recorded. All results indicated that lactate esters can exert a significant influence on the transdermal delivery of the model drugs and there is a structure-activity relationship between the tested lactate esters and their enhancement effects. The results also suggested that the lactate esters with the chain length of fatty alcohol moieties of 10-12 are more effective enhancers. Furthermore, the enhancement effect of lactate esters increases with a decrease of the drug lipophilicity, which suggests that they may be more efficient at enhancing the penetration of hydrophilic drugs than lipophilic drugs. The influence of the concentration of lactate esters was evaluated and the optimal concentration is in the range of 5-10 wt.%. In sum, lactate esters as a penetration enhancer for some drugs are of interest for transdermal administration when the safety of penetration enhancers is a prime consideration.
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Polycationic nanoparticles as nonviral vectors employed for gene therapy in vivo.
Mini Rev Med Chem
PUBLISHED: 04-23-2010
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Currently, polycationic nanoparticles (polycation) as nonviral vectors are promising to overcome the defects of traditional viral vectors. This review focuses on the recent progress and challenges to improve the transfection efficacy and circulation time of polyplexes (complexes between polycation and pDNA or oligonucleotides such as siRNA) in vivo.
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Hydrothermal synthesis of ionic liquid [Bmim]OH-modified TiO2 nanoparticles with enhanced photocatalytic activity under visible light.
Chem Asian J
PUBLISHED: 04-10-2010
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TiO(2) nanocomposites modified with the ionic liquid [Bmim]OH are synthesized by a hydrothermal procedure. X-ray diffraction, Zeta-potential measurement, TEM, thermogravimetric analysis, photoluminescence, UV/Vis, FTIR, and X-ray photoelectron spectroscopy are used to characterize the TiO(2) nanocomposites. The TiO(2) nanocomposites consist of pure anatase particles of about 10 nm. The modification of [Bmim]OH on the surface of the TiO(2) particles extends the TiO(2) absorption edge to the visible-light region. The electrochemical redox potentials indicated that the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of [Bmim]OH match well with the valence band (VB) and conduction band (CB) of the TiO(2) semiconductor. [Bmim]OH-modified TiO(2) is much more active than pristine TiO(2) under visible-light irradiation in the photocatalytic degradation of methylene blue in aqueous solution. [Bmim]OH is chemically bonded to the surface Ti-OH of TiO(2) particles rather than adsorbed on the surface. A possible mechanism for the photocatalysis is proposed.
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Study on the adsorption feature of rutin aqueous solution on macroporous adsorption resins.
J Phys Chem B
PUBLISHED: 03-26-2010
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The adsorption feature of different kinds of polystyrene-based macroporous adsorption resins (MARs) was investigated systemically at constant temperature employing Rutin as the adsorbate. Different from traditional adsorption patterns, Langmuir and Freundlich adsorption, and the results showed interesting aspects: (1) With the increase of the volume of the initial solution, the adsorption capacity increased to the maximum, and then decreased gradually. (2) Experimental results clearly verified the opinion that the adsorption process of MARs could be divided into three stages-macropores, mesopores, and micropores-by the capillary effects occurring at the two intersections, and the adsorption feature for every stage could be described well by the fourth type of Brunauer model. (3) The model that the inductive effect transmitted to the first layer could not interpret our experimental results reasonably. Thus, the model that the inductive effect passed on to a higher layer was proposed by investigating regression of the experimental results and the conclusion that the inductive effect transmitted to the third layer was drawn.
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A single amino acid difference in human APOBEC3H variants determines HIV-1 Vif sensitivity.
J. Virol.
PUBLISHED: 11-25-2009
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Several variants of APOBEC3H (A3H) have been identified in different human populations. Certain variants of this protein are particularly potent inhibitors of retrotransposons and retroviruses, including HIV-1. However, it is not clear whether HIV-1 Vif can recognize and suppress the antiviral activity of A3H variants, as it does with other APOBEC3 proteins. We now report that A3H_Haplotype II (HapII), a potent inhibitor of HIV-1 in the absence of Vif, can indeed be degraded by HIV-1 Vif. Vif-induced degradation of A3H_HapII was blocked by the proteasome inhibitor MG132 and a Cullin5 (Cul5) dominant negative mutant. In addition, Vif mutants that were incapable of assembly with the host E3 ligase complex factors Cul5, ElonginB, and ElonginC were also defective for A3H_HapII suppression. Although we found that Vif hijacks the same E3 ligase to degrade A3H_HapII as it does to inactivate APOBEC3G (A3G) and APOBEC3F (A3F), more Vif motifs were involved in A3H_HapII inactivation than in either A3G or A3F suppression. In contrast to A3H_HapII, A3H_Haplotype I (HapI), which differs in only three amino acids from A3H_HapII, was resistant to HIV-1 Vif-mediated degradation. We also found that residue 121 was critical for determining A3H sensitivity and binding to HIV-1 Vif.
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Amphiphilic poly{[alpha-maleic anhydride-omega-methoxy-poly(ethylene glycol)]-co-(ethyl cyanoacrylate)} graft copolymer nanoparticles as carriers for transdermal drug delivery.
Int J Nanomedicine
PUBLISHED: 10-16-2009
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In this study, the transdermal drug delivery properties of D,L-tetrahydropalmatine (THP)-loaded amphiphilic poly{[alpha-maleic anhydride-omega-methoxy-poly(ethylene glycol)]-co-(ethyl cyanoacrylate)} (PEGECA) graft copolymer nanoparticles (PEGECAT NPs) were evaluated by skin penetration experiments in vitro. The transdermal permeation experiments in vitro were carried out in Franz diffusion cells using THP-loaded PEGECAT NPs as the donor system. Transmission electron microscopy and Fourier transform infrared spectroscopy were used to characterize the receptor fluid. The results indicate that the THP-loaded PEGECAT NPs are able to penetrate the rat skin. Fluorescent microscopy measurements demonstrate that THP-loaded PEGECAT NPs can penetrate the skin not only via appendage routes but also via epidermal routes. This nanotechnology has potential application in transdermal drug delivery.
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NanoPCR observation: different levels of DNA replication fidelity in nanoparticle-enhanced polymerase chain reactions.
Nanotechnology
PUBLISHED: 10-13-2009
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Nanoparticle-assisted PCR (polymerase chain reaction) technology is getting more and more attention recently. It is believed that some of the DNA recombinant technologies will be upgraded by nanotechnology in the near future, among which DNA replication is one of the core manipulation techniques. So whether or not the DNA replication fidelity is compromised in nanoparticle-assisted PCR is a question. In this study, a total of 16 different metallic and non-metallic nanoparticles (NPs) were tested for their effects on DNA replication fidelity in vitro and in vivo. Sixteen types of nanomaterials were distinctly different in enhancing the PCR efficiency, and their relative capacity to retain DNA replication fidelity was largely different from each other based on rpsL gene mutation assay. Generally speaking, metallic nanoparticles induced larger error rates in DNA replication fidelity than non-metallic nanoparticles, and non-metallic nanomaterials such as carbon nanopowder or nanotubes were still safe as PCR enhancers because they did not compromise the DNA replication fidelity in the Taq DNA polymerase-based PCR system.
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The use of PEGylated poly [2-(N,N-dimethylamino) ethyl methacrylate] as a mucosal DNA delivery vector and the activation of innate immunity and improvement of HIV-1-specific immune responses.
Biomaterials
PUBLISHED: 07-23-2009
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To minimize the cytotoxicity of poly (2-(dimethylamino) ethyl methacrylate) (PDMAEMA) as a gene delivery vector, we synthesized PEGylated PDMAEMA by atom transfer radical polymerization (ATRP). Here we report its effects on transfection efficiency in vitro delivered with a GFP expression plasmid and immunogenicity in vivo after complexed with a HIV gag gene DNA vaccine. mPEG(113)-b-PDMAEMA(94) was efficient in condensing DNA and formed polyplexes with an average diameter of about 150 nm. The in vitro transfection experiments demonstrated that PEGylation dramatically decreased the cytotoxicity at the N/P ratios above 30, although the transfection efficiency in vitro was reduced. Interestingly, mice in vivo vaccination study clearly showed that PEGylated PDMAEMA used as DNA delivery vector significantly improved the prime effect of DNA vaccine through intranasal administration. Importantly, PEGylated PDMAEMA was further proved its ability to induce cytokines production by murine macrophages. Overall, mPEG-b-PDMAEMA can be used as an efficient DNA vaccine vector which enhances adaptive immune responses by activating innate immunity.
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A new injectable thermogelling material: methoxy poly(ethylene glycol)-poly(sebacic acid-D,L-lactic acid)-methoxy poly(ethylene glycol) triblock co-polymer.
J Biomater Sci Polym Ed
PUBLISHED: 05-21-2009
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A novel injectable thermogelling poly(ester-anhydride) co-polymer, methoxy poly(ethylene glycol)-poly(sebacic acid-D,L-lactic acid)-methoxy poly(ethylene glycol) (mPEG-poly(SA-LA)-mPEG) triblock co-polymer, was prepared by melt-condensation polymerization. The synthesized triblock co-polymer was characterized by FT-IR and (1)H-NMR. The aqueous solutions of mPEG-poly(SA-LA)-mPEG underwent sol-gel precipitation transition when the temperature was increased from 20 to 70 degrees C, depending on the concentration of the polymer. 5-FU, as the model drug, was mixed into the gel in a low-viscous sol state at room temperature. About 63 wt% of the loaded 5-FU could be released in vitro from the gel over 72 h at 37 degrees C. Subcutaneous injection of 25 wt% mPEG-poly(SA-LA)-mPEG aqueous solution resulted in the formation of a in situ gel depot in a rat model, which sustained for longer time than that of Pluronic F-127 aqueous solution. The biodegradable thermogelling mPEG-poly(SA-LA)-mPEG triblock co-polymer is believed to be a promising candidate for drug-delivery applications.
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Controlled release of Paclitaxel from amphiphilic copolymer hybrid assembly nanoparticles.
J Nanosci Nanotechnol
PUBLISHED: 05-14-2009
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A convenient pathway to control drug release from hybrid assembly nanoparticles of several kinds of copolymers was investigated in this paper. Three kinds of biodegradable amphiphilic copolymers, poly(ethylene glycol)-block-poly(L-lactic acid), poly(ethylene glycol)-block-poly(D,L-lactic acid) and poly(ethylene glycol)-block-polycaprolactone-poly(ethylene glycol) were used to assemble into hybrid assembly nanoparticles as carriers of paclitaxel. The results show that small spherical hybrid assembly nanoparticles (diameter < 100 nm) with good paclitaxel loading ability and entrapping efficiency were obtained simply through hybrid assembling of different copolymers. The in vitro release studies indicate that paclitaxel release rate can be controlled easily by varying the ratio of the hybrid copolymers. The release control mechanism is assigned to the crystallization adjustment of the cores of hybrid assembly nanoparticles which provide a convenient approach to control drug release for drug-loaded nanoparticles.
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[Preparation of V(E) acetate-loaded amphiphilic block copolymer nano-dispersions].
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi
PUBLISHED: 04-02-2009
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V(E) acetate-loaded methoxy poly(ethylene glycol)-b-poly(lactic acid) amphiphilic diblock copolymer nano-dispersion (PMV) was prepared by self-emulsification/solvent evaporation method. The drug-loaded amount, size distribution of PMV nanoparticles, and entrapment efficiency of V(E) acetate (V(E)A) were determined by UV and laser particle analyzer. Drug release in vitro was primarily investigated by UV. The results indicate that the size of PMV nanoparticles is less than 300 nm and PMV is largely influenced by preparation methods, property of solvents, V(E)A-fed amount, and the concentration of dispersion. The initial burst release is not observed and the accumulated release is more than 79% after 14 h. This study develops a new formulation for V(E)A and provides an experimental basis for the novel drug delivery systems of V(E)A.
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A novel hydrophilic adhesive matrix with self-enhancement for drug percutaneous permeation through rat skin.
Pharm. Res.
PUBLISHED: 02-06-2009
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In transdermal drug delivery system (TDDS), chemical enhancers and crystallization inhibitors added into the adhesive matrixes to improve drug permeation and formulation stability often result in some negative effect on adhesive properties and dressing performance. The aim of this paper is to develop a hydrophilic pressure sensitive adhesive (PSA) for TDDS without using additional chemical enhancers and crystallization inhibitors.
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Electrospinning of artemisinin-loaded core-shell fibers for inhibiting drug re-crystallization.
J Biomater Sci Polym Ed
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The main aim of this study was to inhibit the re-crystallization of a potent antimalarial drug, artemisinin (ART), by encapsulating it in core-shell fibers via a coaxially electrospun method. The ART-infiltrated cellulose acetate (CA) solution as the core material and poly(vinyl pyrrolidone) (PVP) solution as the shell material were used to prepared ART-loaded core-shell fibers ([ART/CA]/PVP). Transmission electron microscopy images confirmed the core-shell structures of the coaxially electrospun fibers. The scanning electron microscope (SEM), X-ray diffraction, and differential scanning calorimetry were performed to characterize the physical states of ART in the fibers. It was observed that ART crystals were formed in the ART-loaded CA/PVP composite fibers (ART/CA/PVP) during the electrospinning process and increased during storage duration. While ART crystals hardly were observed in the fresh core-shell [ART/CA]/PVP fibers with high ART entrapped amount (20 wt.%) and a little was detected after 6-month storage. Fourier transform infrared spectroscopy (FTIR) results illustrated the hydrogen bonding interaction between ART and CA in the core-shell [ART/CA]/PVP fibers mainly contributed to the amorphous state of ART. Importantly, combination of the hydrophilic PVP shell and the amorphous ART in CA core, the core-shell [ART/CA]/PVP fibers provided a continued and stable ART release manner. Ex vivo permeation studies suggested the amorphous ART in the medicated core-shell fibers could permeate through the stratum corneum smoothly. Hence, the core-shell [ART/CA]/PVP fiber matrix could provide a potential application in transdermal patches.
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Design and in vitro evaluation of transdermal patches based on ibuprofen-loaded electrospun fiber mats.
J Mater Sci Mater Med
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To improve the poor compatibility among different components of Drug-in-adhesive type patch, two novel plasters (Drug-in-fiber and Drug-in-adhesive/fiber) were developed based on ibuprofen (IBU)-loaded fiber mats. These fibrous mats were fabricated via electrospinning of cellulose acetate/poly(vinylpyrrolidone) composites in a binary solvent of N,N-dimethyl acetamide/acetone. Physical status studies suggested that Drug-in-fiber could inhibit IBU re-crystallization, but the active ingredients were released at a relatively slow rate due to the dual-resistance of fiber mat and adhesive matrix. To overcome this shortcoming, Drug-in-adhesive/fiber was designed by coupling medicated hydrophilic pressure sensitive adhesive and IBU-loaded fiber mat. This method endowed Drug-in-adhesive/fiber a fast IBU release rate and high permeated drug amount though simulative skins. This design separated enhancer from adhesive matrix, which guaranteed Drug-in-adhesive/fiber excellent adhesion forces. Hence, the plasters based on medicated fiber mats improved the compatibility among patch components.
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Performance optimization of injectable chitosan hydrogel by combining physical and chemical triple crosslinking structure.
J Biomed Mater Res A
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To improve the biocompatibility and application properties of injectable chitosan hydrogel, an injectable triple crosslinking network hydrogel (CTGP) is prepared by physical interaction, Michael addition and disulfide bond formation based on thiolated chitosan (CS-TGA), ?-glycerophosphate (?-GP) and poly(ethylene glycol) diacrylate (PEGDA) without the addition of cytotoxic crosslinkers and catalysts. Compared with the short gelation time of 2 min of CTG hydrogel (without PEGDA) at 37°C, CTGP hydrogel containing different molecular weight of PEGDA exhibits controllable gelation times from 1 to 22 min, which could meet the different demands in clinical application. Further, the compressive modulus is improved differently by introducing PEGDA into the system. The presence of PEGDA in CTGP hydrogel imparts better swelling property, and there is a sustained protein release from the hydrogel without any initial burst. In vitro cytotoxicity and hemolysis reveal that the gel is biocompatible. In vivo subdermal injection into mice models further confirms the non-cytotoxicity of the hydrogel and the hydrogel is highly resistant to degradation.
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Poly(ethyleneglycol)-b-poly(?-caprolactone-co-?-hydroxyl-?- caprolactone) bearing pendant hydroxyl groups as nanocarriers for doxorubicin delivery.
Biomacromolecules
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A novel biodegradable amphiphilic diblock copolymer methoxy poly(ethylene glycol)-b-poly(?-caprolactone-co-?-hydroxyl-?-caprolactone) (mPEG-b-P(CL-co-HCL)) bearing pendant hydroxyl groups on the PCL block was prepared. The hydroxyl groups were formed through the reduction of ketones by sodium borohydride without protection and deprotection. The obtained polymers were well characterized by (1)H NMR, Fourier transform infrared (FT-IR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and contact angle measurement. mPEG-b-P(CL-co-HCL) could self-assemble into stable nanoparticles (NPs) with critical micellar concentrations (CMC) of 6.3 × 10(-4) ? 8.1 × 10(-4) mg/mL. The NPs prepared from mPEG-b-P(CL-co-HCL) were spherical in shape with diameters about 100 to 140 nm. The hydrophobic doxorubicin (DOX) was chosen as a drug model and successfully encapsulated into the NPs. The encapsulation efficiency and release kinetics of DOX were investigated. The results indicated that the introduction of hydroxyl groups onto the core-forming block could decrease the hydrophobicity of copolymers, thus improving the storage stability of NPs in aqueous solution. Moreover, higher loading capacity and slower in vitro release of DOX were observed, which was due to the hydrogen-bonding formation between DOX and hydroxyl groups. Meanwhile, the MTT assay demonstrated that the blank NPs were biocompatible to HepG2 cell,s while free DOX and DOX-loaded NPs showed significant cytotoxicity against the cells. Moreover, Compared to the free DOX, the DOX-loaded NPs were more efficiently internalized by HepG2 cells. In sum, the introduction of hydroxyl groups on the polyester block in mPEG-b-P(CL-co-HCL) exhibited great potentials for modifications in the stability, drug solubilization, and release properties of NPs.
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Reduced APOBEC3H variant anti-viral activities are associated with altered RNA binding activities.
PLoS ONE
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APOBEC3H (A3H) is a member of the APOBEC3 family of proteins with varying activities against retroviruses and retrotransposons. The A3H gene contains several single nucleotide polymorphisms and up to seven haplotypes have been detected in humans. Although variations in anti-viral function among A3H haplotypes are not fully understood, only 15N105R-containing A3H variants are known to have potent activities against Vif-deficient HIV-1. Unique motif RLYY(F/Y)W of APOBEC3G (A3G) and APOBEC3F (A3F) required for 7SL RNA binding and HIV-1 incorporation is also conserved in all A3H variants. Like A3G, A3H HapII also demonstrated high binding affinity to host small RNAs such as 7SL and Y RNAs. Mutation of a critical amino acid, W115A resulted in reduced expression level, decreased affinity for 7SL RNA, impairment of virion packaging and reduced anti-viral activity. By comparison, A3H HapI had lower binding affinities to host small RNAs and reduced efficiency of virion incorporation, resulting in significantly reduced anti-viral activity. The SNP ?N15 commonly found in A3H HapIII and HapIV abolished their abilities to associate with RNAs, and A3H HapII?15N failed to package into HIV-1 virions or exhibited any anti-viral activity. Finally, we showed that A3H variants had distinct cellular localization patterns, which correlated with their different RNA binding affinities. Thus, Pol-III RNA such as 7SL RNA binding is a conserved feature of potent anti-HIV human APOBEC3 cytidine deaminases.
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Adjustable degradation and drug release of a thermosensitive hydrogel based on a pendant cyclic ether modified poly(?-caprolactone) and poly(ethylene glycol)co-polymer.
Acta Biomater
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The convenient and precise fabrication of drug-hydrogel formulations with satisfactory degradability and a well-controlled drug release profile are crucial factors for injectable hydrogel formulations in clinical applications. Here a new injectable thermosensitive hydrogel formed from poly(?-caprolactone) (PCL)-poly(ethylene glycol)-poly(?-caprolactone) amphiphilicco-polymers with 1,4,8-trioxa[4.6]spiro-9-undecanone (TOSUO) moieties incorporated in the poly(?-caprolactone) (PCL)block (PECT) was constructed to provide a route to tailor the degradation and drug release behavior. The effect of hydrophilic cyclic ether moieties on the degradation of and drug release by PECT hydrogels were evaluated in vitro and in vivo. The results indicated that a freeze-dried powder of paclitaxel-loaded PECT nanoparticles rapidly dissolved in water at ambient temperature with slightly shaking and formed a stable injectable in situ drug-hydrogel formulation at body temperature, which is convenient for clinical operations because it avoids the need for pre-quenching or long-term incubation. The paclitaxel distribution was also more quantitative and homogeneous on entrapping paclitaxel in PECT nanoparticles. Further, the small number of pendant cyclic ether groups in PCL could decrease the cystallinity and hydrophobicity and, as a result, the in vitro and in vivo retention time of PECT hydrogels and the release of entrapped paclitaxel could be tuned from a few weeks to months by varying the amount of PTOSUO in the hydrophobic block. Significantly, paclitaxel-loaded PECT nanoparticles and free paclitaxel could be simultaneously released during the in vitro paclitaxel release from PECT hydrogels. A histopathological evaluation indicated that in vivo injected PECT hydrogels produced only a modest inflammatory response. Thus pendant cyclic ether modification of PCL could be an effective way to achieve the desired degradation and drug release profiles of amphiphilicco-polymer thermosensitive hydrogels and PECT hydrogels may be suitable for local drug delivery.
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In vitro sustained release of recombinant human bone morphogenetic protein-2 microspheres embedded in thermosensitive hydrogels.
Pharmazie
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Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a critical regulator of osteogenic capacity that is commonly used in bone grafts. The effectiveness of rhBMP-2 may be reduced as it can become unstable and degraded after injection into the body. Microspheres are considered appropriate vehicles for the sustained release of proteins in vivo. In this study, rhBMP-2 microspheres were manufactured using the water-in-oil-in-water (W/O/W) double-emulsion solvent-extraction technique by encapsulation in poly(lactic-co-glycolic) acid (PLGA). The microspheres were then embedded in two hydrogels made of either poloxamer 407 hydrogel or chitosan thioglycolic acid (CS-TA). The encapsulation efficiency and in vitro release of rhBMP-2 were examined and compared with the control release system (rhBMP-2 microspheres alone). The rhBMP-2 microspheres in the CS-TA hydrogel showed the lowest burst release (about 40% in the first 8h) among the three groups. The mechanisms may be the high viscosity of CS-TA hydrogel and the sustained release characteristics of CS-TA itself. The CS-TA hydrogel combined with PLGA microspheres can efficiently encapsulate rhBMP-2, control the burst release at early time points, and provide sustained release in vitro. It may be an appropriate rhBMP-2 vehicle for bone regeneration.
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Thermosensitive hydrogel of hydrophobically-modified methylcellulose for intravaginal drug delivery.
J Mater Sci Mater Med
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Hydrogels with the advantages of prolonging drug release and administration convenience are necessary for intravaginal drug delivery to prevent sexual transmission of human immunodeficiency virus and other vaginal infections. In this study, the thermosensitive hydrogel of methylcellulose modified by stearic acid (MCS) were evaluated in the presence of NaCl and phosphates, which exhibited sol-to-gel transition performance at body temperature or even lower. The in vitro cytotoxicity and in vivo mucosal irritation were investigated and the results showed that MCS hydrogel possessed good biocompatibility similar with hydroxyethyl cellulose (HEC) gel. Significantly, the release studies revealed that MCS hydrogel could control tenofovir sustained release for 10 h without burst release, longer than that from HEC gel or poloxamer 407 hydrogel. Therefore, MCS thermosensitive hydrogel would be a promising carrier for intravaginal delivery of antiviral drugs for long time controlled release.
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Thermosensitive hydrogel based on poly(ether-ester anhydride) nanoparticle as drug delivery system: preparation, characterization and biocompatibility.
Colloids Surf B Biointerfaces
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A novel temperature-response hydrogel was developed for drug-delivery applications. The hydrogel matrix (PES) was synthesized by melt polycondensation of poly(ether-ester) diacid based on PEG with low molecular weight and sebacic acid. The sol-gel-sol phase transitions of PES nanoparticle (NP) hydrogel were investigated. In vitro erosion of hydrogel was characterized by Fourier transform infrared spectroscopy, environmental scanning electron microscopy and dynamic light scattering. In vitro release behaviors of hydrophilic and hydrophobic drugs and in vivo histopathological evaluation were studied in detail. The study results revealed that an aqueous dispersion of PES nanoparticle freeze-dried powder exhibited reversible sol-gel transition behavior with increasing temperature. The hydrogel could maintain steadily at least a month during in vitro erosion process. There were sustained release behaviors of hydrophilic and hydrophobic drugs from PES NP hydrogel and histopathological studies confirmed that the PES NP hydrogel only provoked an acceptable modest inflammatory response. Thus, PES NP hydrogel is biodegradable, biocompatible and promising in controlling the incorporated drugs for sustained release.
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Binary and ternary complexes based on polycaprolactone-graft-poly (N, N-dimethylaminoethyl methacrylate) for targeted siRNA delivery.
Biomaterials
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Small interfering RNA (siRNA) is a powerful gene silencing tool and has promising prospects in basic research and the development of therapeutic reagents. However, the lack of an effective and safe tool for siRNA delivery hampers its application. Here, we introduced binary and ternary complexes that effectively mediated siRNA-targeted gene silencing. Both complexes showed excellent siRNA loading even at the low N/P/C ratio of 3:1:0. FACS and confocal microscopy demonstrated that nearly all cells robustly internalized siRNAs into the cytoplasm, where RNA interference (RNAi) occurred. Luciferase assay and Western blot verified that silencing efficacy reached >80%, and introducing folate onto the ternary complexes further enhanced silencing efficacy by about 10% over those without folate at the same N/P/C ratio. In addition, the coating of PGA-g-mPEG decreased the zeta potential almost to electroneutrality, and the MTT assay showed decreased cytotoxicity. In vivo distribution measurement and histochemical analysis executed in C57BL/6 and Hela tumor-bearing BALB/c nude mice showed that complexes accumulated in the liver, lungs, pancreas and tumors and were released slowly for a long time after intravenous injection. Furthermore, ternary complexes showed higher siRNA fluorescence intensity than binary complexes at the same N/P ratio in tumor tissues, those with folate delivered more siRNAs to tumors than those without folate, and more folate induced more siRNA transport to tumors. In addition, in vivo functional study showed that both binary and ternary complexes mediated down-regulation of ApoB in liver efficiently and consequently blocked the secretion of fatty acids into the blood, resulted in lipid accumulation in liver, liver steatosis and hepatic dysfunction. In conclusion, these complexes provided a powerful means of administration for siRNA-mediated treatment of liver-related diseases and various cancers, especial for pancreatic and cervical cancer.
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