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ABSTRACT: Well-defined amphiphilic linear-dendritic prodrugs (MPEG-b-PAMAM-DOX) are synthesized by conjugating doxorubicin (DOX), to MPEG-b-PAMAM through the acid-labile hydrazone bond. The amphiphilic prodrugs form self-assembled nanoparticles in deionized water and encapsulate the hydrophobic anticancer drug 10-hydroxycamptothecin (HCPT) with a high drug loading efficiency. Studies on drug release and cellular uptake of the co-delivery system reveal that both drugs are released in a pH-dependent manner and effectively taken up by MCF-7 cells. In vitro methyl thiazolyl tetrazolium (MTT) assays and drug-induced apoptosis tests demonstrate the HCPT-loaded nanoparticles suppress cancer cell growth more efficiently than the MPEG-b-PAMAM-DOX prodrugs, free HCPT, and physical mixtures of MPEG-b-PAMAM-DOX and HCPT at equivalent DOX or HCPT doses.
Macromolecular Bioscience 02/2013; · 3.89 Impact Factor
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ABSTRACT: A novel glucose-sensitive nanogel was conveniently prepared through one-pot thiol-ene copolymerization of pentaerythritol tetra(3-mercaptopropionate), poly(ethylene glycol) diacrylate, methoxyl poly(ethylene glycol) acrylate and N-acryloyl-3-aminophenylboronic acid. The formation of core-shell nanogel was verified by proton nuclear magnetic resonance, dynamic laser scattering (DLS) and transmission electron microscopy. The successful incorporation of phenylboronic acid (PBA) in the nanogel was confirmed through Fourier transform infrared spectroscopy, inductively coupled plasma mass spectrometry and fluorescence technology. Owing to the presence of PBA, the nanogel exhibited high glucose sensitivity in phosphate-buffered saline determined by DLS and fluorescence technology. The increased amount of glucose causes an increase in the hydrodrodynamic radius and a decrease in the fluorescence intensity of PBA-alizarin red S (ARS) complex in the nanogel at pH 7.4 because of the competitive substitution of ARS to form the hydrophilic PBA-glucose complex. ARS and insulin were loaded into this glucose-sensitive nanogel. In vitro release profiles revealed that the drug release from the nanogel could be triggered by the presence of glucose. The more glucose in the release medium, the more drug was released and the faster the release rate. Furthermore, in vitro methyl thiazolyl tetrazolium assay, lactate dehydrogenase assay and hemolysis test suggested that the nanogel was biocompatible. Therefore, the PBA-incorporated nanogel with high glucose-sensitivity and good biocompatibility may have great potential for self-regulated drug release.
Acta biomaterialia 02/2013; · 3.98 Impact Factor
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ABSTRACT: An electroactive amino/carboxyl-capped aniline tetramer (AT) is covalently grafted to the surface of hydroxyapatite (HA) nanoparticles to generate novel electroactive HA-AT nanoparticles. The amount of AT ranges from 16.5 to 34.0 wt% and is characterized by thermogravimetric analysis (TGA). The HA-AT nanoparticles are characterized by Fourier transform IR (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), X-ray diffraction, and scanning electron microscopy (SEM). For the excellent electroactivity of HA-AT, the mixture of HA-AT and PLA shows much better adhesion ability and proliferation ability than that of HA and a PLA matrix. At a 15 wt% AT grafting amount, the matrix shows the best biocompatibility.
Macromolecular Bioscience 02/2013; · 3.89 Impact Factor
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ABSTRACT: In this study, we report thermosensitive hydrogels based on poly(ethylene glycol)-block-poly(γ-propargyl-L-glutamate) (PEG-PPLG). 13C NMR spectra, DLS, and circular dichroism spectra were employed to study the mechanism of the sol-gel phase transition. Mouse fibroblast L929 cells were encapsulated and cultured within the hydrogel matrices, and the encapsulated cells were shown to be highly viable in the gel matrices, suggesting that the hydrogels have excellent cytocompatibilities. The mass loss of the hydrogels in vitro was accelerated by the presence of proteinase K compared to the control group. In vivo biocompatibility studies revealed that the in situ formed gels in the subcutaneous layer last for ~21 days, and H&E staining study suggested acceptable biocompatibility of our materials in vivo. The presence of alkynyl side groups in the PEG-PPLG copolymers allowed convenient further functionalization with azide-modified bioactive molecules, such as biotin and galactose. The biofunctionalized PEG-polypeptide block copolymers showed sol-gel phase transitions similar to the parent copolymers. Interestingly, the incorporation of galactose groups into the hydrogels was found to improve cell adhesion, likely due to the adsorption of fibronectin (FN) in cell-extracellular matrix (ECM). Since bioactive materials have shown unique advantages in biomedical applications, especially tissue engineering and regenerative medicine applications, we believe our novel functionalizable thermosensitive hydrogels have potential to serve as a versatile platform for the development of new biofunctional materials, e.g. bioadhesive and bioresponsive hydrogels.
Biomacromolecules 01/2013; · 5.48 Impact Factor
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ABSTRACT: Polymers bearing pendant galactosyl group are attractive for targeted intracellular antitumor drug delivery to hepatoma cells (e.g. HepG2 and SMMC7721 cells) with asialoglycoprotein receptor (ASGP-R). Herein, a series of galactopeptides were synthesized through ring-opening polymerization of N-carboxyanhydride, deprotection of benzyl group and subsequent Huisgens cycloaddition "click" reaction with azide-modified galactosyl group. The copolypeptides were revealed to have excellent hemocompatabilities, and cell and tissue compatibilities, which rendered their potential for drug delivery applications. The hepatoma-targeted micellar nanoparticle (i.e. nanomedicine) was fabricated by cooperative self-assembly of galactopeptide and doxorubicin (DOX) induced by two-stage physical interactions. In vitro DOX release from nanomedicine was accelerated in the intracellular acidic condition. Through the recognition between galactose ligand and ASGP-R of HepG2 cells, the endocytosis of galactosylated nanomedicine was significantly promoted, which was demonstrated by confocal laser scanning microscopy and flow cytometry. Remarkably, the galactose-decorated nanomedicine retained much higher antitumor activity toward HepG2 cells in contrast to the nanomedicine without galactosyl group in vitro and in vivo. The above superiorities indicated that the galactosylated nanomedicine possessed great promising for hepatoma-targeted chemotherapy.
Journal of Controlled Release 12/2012; · 5.73 Impact Factor
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ABSTRACT: The pH sensitivity of a series of PbAEs synthesized from primary amines and diacrylates is studied. By changing alkyl groups of the amine monomers, the pKb can be tuned across a broad range (from 3.5 to 7.2). Micelles formed from a PEG-PbAE block copolymer retain the pH sensitivity of PbAE and can stably load hydrophobic molecules under neutral pH, while quickly dissociate and release their cargoes at pH ≈ 6.0. When the chemotherapy drug DOX is loaded, the micelles show efficient cell proliferation inhibition to HeLa cells and fast intracellular release. Thus, the primary-amine-based PbAEs are shown to be promising in the construction of intracellular targeting drug delivery systems.
Macromolecular Bioscience 08/2012; 12(10):1375-83. · 3.89 Impact Factor
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ABSTRACT: Thermosensitive hydrogels based on PEG and poly(l-glutamate)s bearing different hydrophobic side groups were separately synthesized by the ring-opening polymerization (ROP) of l-glutamate N-carboxyanhydrides containing different alkyl protected groups, that is, methyl, ethyl, n-propyl, and n-butyl, using mPEG(45)-NH(2) as macroinitiator. The resulting copolymers underwent sol-gel transitions in response to temperature change. Interestingly, the polypeptides containing methyl and ethyl showed significantly lower critical gelation temperatures (CGTs) than those bearing n-propyl and butyl side groups. Based on the analysis of (13)C NMR spectra, DLS, circular dichroism spectra, and ATR-FTIR spectra, the sol-gel transition mechanism was attributed to the dehydration of poly(ethylene glycol) and the increase of β-sheet conformation content in the polypeptides. The in vivo gelation test indicated that the copolymer solution (6.0 wt %) immediately changed to a gel after subcutaneous injection into rats. The mass loss of the hydrogel in vitro was accelerated in the presence of proteinase K, and the MTT assay revealed that the block copolymers exhibited no detectable cytotoxicity. The present work revealed that subtle variation in the length of a hydrophobic side group displayed the decisive effect on the gelation behavior of the polypeptides. In addition, the thermosensitive hydrogels could be promising materials for biomedical applications due to their good biocompatibility, biodegradability, and the fast in situ gelation behavior.
Biomacromolecules 06/2012; 13(7):2053-9. · 5.48 Impact Factor
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ABSTRACT: Construction of high density glycosylated surfaces is important in the investigation of interactions between pathogens and surface carbohydrates. In this work, we provided a flexible method for glycosyl surface fabrication by combination of surface-initiated atom transfer radical polymerization (SI-ATRP) and copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. Through this strategy, we got a very high surface glycosyl density of about 4 nmol/cm(2) with the surface "click" efficiency of nearly 50%. Then the carbohydrate decorated surfaces were used to mimic cell surfaces and specific recognition of mannose with Escherichia coli was observed. We believe the methodology provided here can be used as a facile way for construction of a wide range of functional biosurfaces.
Colloids and surfaces. B, Biointerfaces 05/2012; 93:188-94. · 2.60 Impact Factor
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ABSTRACT: A novel and facile strategy has been designed to prepare biodegradable microgels with thermo- and pH-responsive property.
The microgels were synthesized by the crosslinking of N-isopropylacrylamide with vinyl groups functionalized poly(L-glutamic acid) (PGA). The resultant microgels exhibited pH-dependent
phase transition behaviors in aqueous solutions and underwent abrupt lower critical solution temperature decrease when the
pH was reduced below the pK
a of PGA. Dynamic light scattering measurement revealed that the microgels exhibited shrinkage as the temperature increased
or the pH decreased.
KeywordsThermo-responsive–pH-responsive–Microgels–Polypeptide–Biodegradable
Colloid and Polymer Science 04/2012; 289(4):447-451. · 2.33 Impact Factor
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ABSTRACT: Biodegradable and pH-sensitive PEAs based on dual amino acids are designed, synthesized, and characterized. Insulin can be loaded into the PEA microspheres by a solid-in-oil-in-oil technique with high encapsulation efficiency. The feasibility of PEA microspheres as oral insulin delivery carriers is evaluated in vitro and in vivo. The hydrophobic leucine groups on PEA seem to play an important role in the pH-dependent release mechanism and cytotoxicity of PEA microspheres. Oral administration of insulin-loaded PEA microspheres to streptozotocin-induced diabetic rats at 60 IU kg(-1) is able to reduce fasting plasma glucose levels to 49.4%. These results indicate that PEA microspheres are potential new vehicles for insulin oral delivery.
Macromolecular Bioscience 02/2012; 12(4):547-56. · 3.89 Impact Factor
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ABSTRACT: A biodegradable electroactive hydrogel (AP-g-GA), aniline pentamer (AP) grafting gelatin (GA), is synthesized by a coupling reaction between the carboxyl group of AP and the amino side group of GA in aqueous solution. The electroactivity of the physical hydrogel is confirmed by UV-vis and CV. The hydrophobic AP changes the hydrogel's porous structure of the natural GA and the gel-time, which is confirmed by the rheological behavior of the AP-g-GA and GA. With an increase in the content of AP, the hydrogel gradually forms a porous structure, from "honeycomb" to "bamboo raft". The porous scaffolds can be crosslinked with 3.5% EDC in 90% ethanol. MTT assays show that the AP-g-GA exhibits reduced cytotoxicity compared to EM AP due to the introduction of the biocompatible GA moiety. The in vitro cell cultures suggest that the AP-g-GA#1 (with 1.9% AP) shows the best biocompatibility and cell adhesion ability.
Macromolecular Bioscience 02/2012; 12(2):241-50. · 3.89 Impact Factor
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Progress in Polymer Science. 01/2012; 37(2):237-280.
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ABSTRACT: Stimuli-sensitive synthetic polypeptides are unique biodegradable and biocompatible synthetic polymers with structures mimicking natural proteins. These polymers exhibit reversible secondary conformation transitions and/or hydrophilic-hydrophobic transitions in response to changes in environmental conditions such as pH and temperature. The stimuli-triggered conformation and/or phase transitions lead to unique self-assembly behaviors, making these materials interesting for controlled drug and gene delivery applications. Therefore, stimuli-sensitive synthetic polypeptide-based materials have been extensively investigatid in recent years. Various polypeptide-based materials, including micelles, vesicles, nanogels, and hydrogels, have been developed and tested for drug- and gene-delivery applications. In addition, the presence of reactive side groups in some polypeptides facilitates the incorporation of various functional moieties to the polypeptides. This Review focuses on recent advances in stimuli-sensitive polypeptide-based materials that have been designed and evaluated for drug and gene delivery applications. In addition, recent developments in the preparation of stimuli-sensitive functionalized polypeptides are discussed.
Advanced healthcare materials. 01/2012; 1(1):48-78.
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Journal of Controlled Release 11/2011; 152 Suppl 1:e255-6. · 5.73 Impact Factor
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Journal of Controlled Release 11/2011; 152 Suppl 1:e11-3. · 5.73 Impact Factor
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ABSTRACT: A permeation enhancer, positively charged deoxycholyl-hyperbranched oligoethylenimine (DCO), was prepared and used to form complexes with negatively charged insulin based on electrostatic interaction. DCO/insulin complexes can be loaded into poly (l-glutamic acid) (PGA) microspheres by the oil-in-oil (O/O) emulsion and solvent evaporation technique. Because of the specific pH sensitive properties of PGA, these insulin encapsulated microspheres are stable in the stomach and disaggregate in the small intestine, and the bioavailability of oral insulin administration will be improved due to DCO's permeation enhancement function.
Journal of Controlled Release 11/2011; 152 Suppl 1:e184-6. · 5.73 Impact Factor
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ABSTRACT: A novel pH-responsive poly(amino acid) grafted with oligocation was prepared through the combination of ring-opening polymerization (ROP) and subsequent atom transfer radical polymerization (ATRP). Firstly, poly(γ-2-chloroethyl-L-glutamate) (PCELG) with a pendent 2-chloroethyl group was synthesized through ROP of γ-2-chloroethyl-L-glutamate N-carboxyanhydride (CELG NCA) using n-hexylamine as the initiator. Then, PCELG was used to initiate the ARTP of 2-aminoethyl methacrylate hydrochloride (AMA), yielding poly(L-glutamate)-graft-oligo(2-aminoethyl methacrylate hydrochloride) (PLG-g-OAMA). The pK(a) of PLG-g-OAMA was 7.3 established by the acid-base titration method. The amphiphilic poly(amino acid) could directly self-assemble into a vesicle in PBS. The vesicle was characterized by TEM and DLS. Hydrophilic DOX·HCl was loaded into the hollow core of the vesicle. The in vitro release behavior of DOX·HCl from the vesicle in PBS could be adjusted by the solution pH. In vitro cell experiments revealed that the vesicle could reduce the toxicity of the DOX·HCl. In addition, the preliminary gel retardation assay displayed that PLG-g-OAMA could efficiently bind DNA at a PLG-g-OAMA/DNA weight ratio of 0.3 or above, indicating its potential use as a gene carrier. More in-depth studies of the PLG-g-OAMA vesicle for drug and gene co-delivery in vitro and in vivo are in progress.
Nanotechnology 11/2011; 22(49):494012. · 3.98 Impact Factor
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ABSTRACT: A polypeptide-based double hydrophilic graft copolymer was synthesized by the sequential grafting of poly(N-isopropylacrylamide) (PNIPAM) and 2-hydroxyethyl methacrylate (HEMA) onto poly(l-glutamic acid) (PGA) backbone. The copolymers were sensitive to both temperature and pH. The phase transition and aggregation behaviors of the graft copolymers in aqueous solutions were investigated by the turbidity measurements and dynamic laser scattering (DLS). The light transmittance decrease of the copolymers at temperature above lower critical solution temperature (LCST) was remarkably weakened at pH around 6.5 due to the coil to α helix change of PGA chain induced by pH. The copolymers can self-assembly into micelles with PNIPAM cores in the aqueous solution at pH 8.0 and 60°C. Subsequently, polymerization of HEMA led to the facile preparation of crosslinked micelles, which were observed directly by transmission electron microscopy (TEM). The temperature controlled shrinkage behaviors of crosslinked micelles highly depended on the pH values of the solution. The crosslinked micelles aggregated at pH 5.0 due to the increased hydrophobic interactions among them induced by the protonation of PGA component. These crosslinked micelles have promising applications as intelligent drug delivery vehicles.
Journal of Colloid and Interface Science 07/2011; 359(2):436-42. · 3.07 Impact Factor
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ABSTRACT: Novel amphiphilic alternating polyesters, poly((N-phthaloyl-l-glutamic anhydride)-co-(2-(2-(2-methoxyethoxy)ethoxy)methyl)oxirane) (P(PGA-co-ME(2)MO)), were synthesized by alternating copolymerization of PGA and ME(2)MO. The structures of the synthesized polyesters were characterized by (1)H NMR, (13)C NMR, FT-IR, and GPC analyses. Because of the presence of oligo(ethylene glycol) (OEG) side chains, the polyesters could self-assemble into thermosensitive micelles. Dynamic light scattering (DLS) showed that these micelles underwent thermoinduced size decrease without intermicellar aggregation. In vitro methyl thiazolyl tetrazolium (MTT) assay demonstrated that the polyesters were biocompatible to Henrietta Lacks (HeLa) cells, rendering their potential for drug delivery applications. Two hydrophobic drugs, rifampin and doxorubicin (DOX), were loaded into the polyester micelles and observed to be released in a zero-order sustained manner. The sustained release could be accelerated in lower pH or in the presence of proteinase K, due to the degradation of the polyester under these conditions. Remarkably, in vitro cell experiments showed that the polyester micelles accomplished fast release of DOX inside cells and higher anticancer efficacy as compared with the free DOX. With enhanced stability during circulation condition and accelerated drug release at the target sites (e.g., low pH or enzyme presence), these novel polyesters with amphiphilic structures are promising to be used in sustained release drug delivery systems.
Biomacromolecules 06/2011; 12(7):2466-74. · 5.48 Impact Factor
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Journal of Polymer Science Part A Polymer Chemistry 04/2011; 49(12):2665 - 2676. · 3.92 Impact Factor
