Co-reporter:Xiaomei Dai, Yu Zhao, Yunjian Yu, Xuelei Chen, Xiaosong Wei, Xinge Zhang, and Chaoxing Li
ACS Applied Materials & Interfaces September 13, 2017 Volume 9(Issue 36) pp:30470-30470
Publication Date(Web):August 23, 2017
DOI:10.1021/acsami.7b09638
The emergence of antibiotic-resistant bacterial strains has made conventional antibiotic therapies less efficient. The development of a novel nanoantibiotic approach for efficiently ablating such bacterial infections is becoming crucial. Herein, a collection of poly(5-(2-ethyl acrylate)-4-methylthiazole-g-butyl)/copper sulfide nanoclusters (PATA-C4@CuS) was synthesized for efficient capture and effective ablation of levofloxacin-resistant Gram-negative and Gram-positive bacteria upon tissue-penetrable near-infrared (NIR) laser irradiation. In this work, we took advantage of the excellent photothermal and photodynamic properties of copper sulfide nanoparticles (CuSNPs) upon NIR laser irradiation and thiazole derivative as a membrane-targeting cationic ligand toward bacteria. The conjugated nanoclusters could anchor the bacteria to trigger the bacterial aggregation quickly and efficiently kill them. These conjugated nanoclusters could significantly inhibit levofloxacin-resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Bacillus amyloliquefaciens at 5.5 μg/mL under NIR laser irradiation (980 nm, 1.5 W cm–2, 5 min), which suggested that the heat and reactive oxygen species (ROS) generated from the irradiated CuSNPs attached to bacteria were effective in eliminating and preventing the regrowth of the bacteria. Importantly, the conjugated nanoclusters could promote healing in bacteria-infected rat wounds without nonspecific damage to normal tissue. These findings highlight the promise of the highly versatile multifunctional nanoantibiotics in bacterial infection.Keywords: antibiotic-resistant bacteria; bacterial infection; copper sulfide nanoclusters; NIR laser; photodynamic and photothermal therapy;
Co-reporter:Xiaomei Dai, Xuelei Chen, Jing Zhao, Yu Zhao, Qianqian Guo, Tianqi Zhang, Chunli Chu, Xinge Zhang, and Chaoxing Li
ACS Applied Materials & Interfaces April 26, 2017 Volume 9(Issue 16) pp:13837-13837
Publication Date(Web):April 6, 2017
DOI:10.1021/acsami.6b15821
To explore the structure–activity relationship of membrane-targeting cationic ligands on a silver nanoparticle surface in an antibiotic-resistant antibacterial and antibiofilm activity assay, a series of functionalized silver nanocomposites were synthesized. Tuning the structural configuration, molecular weight, and side-chain length of the cationic ligands on the nanoparticle surface provided silver nanocomposites with effective antibacterial activity against both antibiotic-resistant Gram-negative and Gram-positive bacteria, including bacterial biofilms. These silver nanocomposites did not trigger hemolytic activity. Significantly, the bacteria did not develop resistance to the obtained nanocomposites even after 30 generations. A study of the antibacterial mechanism confirmed that these nanocomposites could irreversibly disrupt the membrane structure of bacteria and effectively inhibit intracellular enzyme activity, ultimately leading to bacterial death. The silver nanocomposites (64 μg/mL) could eradicate 80% of an established antibiotic-resistant bacterial biofilm. The strong structure–activity relationship toward antibacterial and antibiofilm activity suggests that variations in the conformational property of the functional ligand could be valuable in the discovery of new nano-antibacterial agents for treating pathogenic bacterial infections.Keywords: antibacterial mechanism; antibiotic-resistance; biofilms; cationic ligand; silver nanoparticles; structure−activity relationship;
Co-reporter:Xiaomei Dai, Qianqian Guo, Yu Zhao, Peng Zhang, Tianqi Zhang, Xinge Zhang, and Chaoxing Li
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 39) pp:25798
Publication Date(Web):September 13, 2016
DOI:10.1021/acsami.6b09267
With the increased prevalence of antibiotic-resistant bacteria infections, there is a pressed need for innovative antimicrobial agent. Here, we report a benign ε-polylysine/silver nanoparticle nanocomposite (EPL-g-butyl@AgNPs) with polyvalent and synergistic antibacterial effects. EPL-g-butyl@AgNPs exhibited good stability in aqueous solution and effective antibacterial activity against both Gram-negative (P. aeruginosa) and Gram-positive (S. aureus) bacteria without emergence of bacterial resistance. Importantly, the nanocomposites eradicated the antibiotic-resistant bacteria without toxicity to mammalian cells. Analysis of the antibacterial mechanism confirmed that the nanocomposites adhered to the bacterial surface, irreversibly disrupted the membrane structure of the bacteria, subsequently penetrated cells, and effectively inhibited protein activity, which ultimately led to bacteria apoptosis. Notably, the nanocomposites modulated the relative level of CD3+ T cells and CD68+ macrophages and effectively promoted infected wound healing in diabetic rats. This work improves our understanding of the antibacterial mechanism of AgNPs-based nanocomposites and offers guidance to activity prediction and rational design of effective antimicrobial nanoparticles.Keywords: antibacterial mechanism; antibiotic-resistant bacteria; nanocomposites; silver nanoparticles; wound healing
Co-reporter:Jinxia An, Xiaomei Dai, Yu Zhao, Qianqian Guo, Zhongming Wu, Xinge Zhang and Chaoxing Li
Polymer Chemistry 2015 vol. 6(Issue 36) pp:6529-6542
Publication Date(Web):06 Aug 2015
DOI:10.1039/C5PY00795J
To improve the pharmacokinetic and pharmacodynamic profiles of clinical anticancer drugs for cancer therapy, the development of effective drug delivery systems with precise biological functions is critically required. In the current study, we developed a PEGylated and core-cross-linked polymeric nanovehicle, LA-pDAGEA/pPEGA-b-p(DMDEA-co-BADS), with reduction- and pH-dependent degradation and fluorescence imaging function for tumor-targeted delivery of hydrophobic drugs. The multifunctional copolymers were synthesized using RAFT polymerization. By utilizing the intrinsic fluorescence of nanovehicles resulting from the boron–dipyrromethene dye-conjugated chain transfer agent (BODIPY), the cellular internalization process was exhibited. Cellular uptake and the competition inhibition assay show that the nanovehicles could be internalized into HepG2 cells via receptor-mediated endocytosis. Moreover, the drug-loaded nanovehicles were capable of significantly inhibiting cancer cell proliferation. Our newly developed multifunctional nanovehicles may thus facilitate the development of efficient drug delivery systems for application in diagnosis and therapy of cancer.
Co-reporter:Zhentan Lu, Xinge Zhang, Zhongyu Li, Zhongming Wu, Jia Song and Chaoxing Li
Polymer Chemistry 2015 vol. 6(Issue 5) pp:772-779
Publication Date(Web):26 Sep 2014
DOI:10.1039/C4PY00931B
With the increasing concern over drug-resistant bacterial infections, in particular hospital-acquired infections, there is an urgent need to develop effective and safe antibacterial agents. Herein, a study aiming at developing a good antibacterial agent with high antibacterial activity and low cytotoxicity to promote public health is reported. Composite copolymer hybrid silver nanoparticles (AgNPs) were synthesized via the reduction of NaBH4 in the presence of copolymers and AgNO3. The composite copolymers containing 2-(dimethylamino)ethyl methacrylate (DMAEMA) and poly(ethylene glycol) methyl ether methacrylate (PEGMA) segments were prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization, and then the copolymers were quaternized to increase AgNPs adhesion to bacterial membranes through electrostatic interactions. The copolymer hybrid AgNPs showed high antibacterial activity against P. aeruginosa (Gram-negative bacteria) and S. aureus (Gram-positive bacteria), which could inhibit bacterial proliferation even if the concentration was 8 μg mL−1. Furthermore, copolymer hybrid AgNPs had negligible haemolysis and low cytotoxicity. The nanoparticles destroyed the bacterial membrane irreversibly and then caused the release of cytoplasmic constituents and cell death finally. These results suggest that copolymer hybrid AgNPs have potential use as antibacterial agents in clinical applications.
Co-reporter:Zhentan Lu, Xinge Zhang, Yu Zhao, Yinan Xue, Tingting Zhai, Zhongming Wu and Chaoxing Li
Polymer Chemistry 2015 vol. 6(Issue 2) pp:302-310
Publication Date(Web):06 Oct 2014
DOI:10.1039/C4PY00715H
We report here an innovative study to develop a photodynamic therapy agent with high antibacterial activity to improve public health. A macromolecular photosensitizer with cation-enhanced antibacterial activity was successfully synthesized through atom transfer radical polymerization. The macromolecular photosensitizer has good stability under physiological conditions and generates a high yield of singlet oxygen (1O2) in aqueous solution. The macromolecular photosensitizer also shows antibacterial activity towards both gram-positive and gram-negative bacteria. Bacterial growth was inhibited at concentrations of the macromolecular photosensitizer as low as 0.3 nmol mL−1; this is the lowest reported inhibitory concentration for a photodynamic therapy antibacterial agent. The macromolecular photosensitizer also showed good cytocompatibility in the dark. We investigated the mechanism of bacterial apoptosis using an absorption study at 260 nm and SEM. We concluded that 1O2 irreversibly disrupts the structure of the bacterial membrane, which ultimately leads to bacterial apoptosis. These optimized features were integrated into a single glycopolymer. These results show that the macromolecular photosensitizer has the ideal properties of a photodynamic therapy antibacterial agent. This study provides a new route with which to design photodynamic therapy antibacterial agents for biomedical applications.
Co-reporter:Xiaomei Dai, Jinxia An, Yanan Wang, Zhongming Wu, Yu Zhao, Qianqian Guo, Xinge Zhang and Chaoxing Li
RSC Advances 2015 vol. 5(Issue 85) pp:69325-69333
Publication Date(Web):05 Aug 2015
DOI:10.1039/C5RA10393B
The development of antibacterial materials is recently more and more important and urgent due to the emergence of antibiotic-resistant bacteria. To address the problem, series of new amphiphiles based on ε-polylysine (ε-PL) were synthesized by alkylation reaction with alkyl bromide, and concurrently their antibacterial activity and cytotoxicity were evaluated. The amphiphiles with a large concentration of positive charges and lipid chain promoted their adsorption to bacterial membranes through electrostatic interaction and hydrophobic interaction, subsequently killed both Gram-positive (S. aureus and B. amyloliquefaciens) and Gram-negative (E. coli and P. aeruginosa) bacteria. Morphology observed using SEM shows that these derivatives could cause leakage of intracellular contents. Analysis of the antimicrobial mechanism displays that these derivatives against the bacteria started with disruption of the bacterial membrane, which caused the leakage of cytoplasm, and killed the bacteria. Among the amphiphiles, ε-PL-g-butyl2 presented the most effective antibacterial activity and its minimum inhibitory concentration as low as 3.9 μg mL−1. Importantly, the effective antibacterial concentration of ε-PL-g-butyl2 displayed no cytotoxicity against human cells. This work not only highlights the great promise of using ε-PL-g-butyl2 as a highly effective antibacterial agent but also provides the important tool for understanding the interactions between the microorganisms and amphiphiles-based ε-PL.
Co-reporter:Jinxia An, Xiaomei Dai, Zhongming Wu, Yu Zhao, Zhentan Lu, Qianqian Guo, Xinge Zhang, and Chaoxing Li
Biomacromolecules 2015 Volume 16(Issue 8) pp:
Publication Date(Web):July 27, 2015
DOI:10.1021/acs.biomac.5b00693
To reduce side-effects of anticancer drugs, development of nanocarriers with precise biological functions is a critical requirement. In this study, the multifunctional nanoparticles combining imaging and therapy for tumor-targeted delivery of hydrophobic anticancer drugs were prepared via self-assembly of amphiphilic copolymers obtained using RAFT polymerization, specifically, acid-labile ortho ester and galactose. First, boron-dipyrromethene dye-conjugated chain transfer agent provides fluorescent imaging capability for diagnostic application. Second, nanoparticles were stable under physiological conditions but degraded in acidic tumor microenvironment, leading to enhanced anticancer efficacy. Third, the application of biocompatible glycopolymers efficiently increased the target-to-background ratio through carbohydrate–protein interactions. Data from cell viability, cellular internalization, flow cytometry, biodistribution and anticancer efficacy tests showed that the drug-loaded nanoparticles were capable of inhibiting cancer cell proliferation with significantly enhanced capacity. Our newly developed multifunctional nanoparticles may thus facilitate the development of effective drug delivery systems for application in diagnosis and therapy of cancer.
Co-reporter:Qianqian Guo, Tianqi Zhang, Jinxia An, Zhongming Wu, Yu Zhao, Xiaomei Dai, Xinge Zhang, and Chaoxing Li
Biomacromolecules 2015 Volume 16(Issue 10) pp:
Publication Date(Web):September 23, 2015
DOI:10.1021/acs.biomac.5b01020
To explore the effect of polymer structure on their self-assembled aggregates and their unique characteristics, this study was devoted to developing a series of amphiphilic block and random phenylboronic acid-based glycopolymers by RAFT polymerization. The amphiphilic glycopolymers were successfully self-assembled into spherically shaped nanoparticles with narrow size distribution in aqueous solution. For block and random copolymers with similar monomer compositions, block copolymer nanoparticles exhibited a more regular transmittance change with the increasing glucose level, while a more evident variation of size and quicker decreasing tendency in I/I0 behavior in different glucose media were observed for random copolymer nanoparticles. Cell viability of all the polymer nanoparticles investigated by MTT assay was higher than 80%, indicating that both block and random copolymers had good cytocompatibility. Insulin could be encapsulated into both nanoparticles, and insulin release rate for random glycopolymer was slightly quicker than that for the block ones. We speculate that different chain conformations between block and random glycopolymers play an important role in self-assembled nanoaggregates and underlying glucose-sensitive behavior.
Co-reporter:Jinxia An, Xinge Zhang, Qianqian Guo, Yu Zhao, Zhongming Wu, Chaoxing Li
Colloids and Surfaces A: Physicochemical and Engineering Aspects 2015 Volume 482() pp:98-108
Publication Date(Web):5 October 2015
DOI:10.1016/j.colsurfa.2015.04.035
•The composite nanoparticles, a sandwich structure, were prepared.•The mesoporous nanoparticles exhibit high drug loading capacity.•The nanoparticles can be used for T2-weighted contrast enhancement in MR imaging.•The glycopolymer modified nanoparticles show targeted drug delivery property.It is a challenge for cancer therapy to develop efficient and safe transport vehicles. In the current study, glycopolymer modified magnetic mesoporous silica nanoparticles were designed to improve drug bioavailability and anticancer efficacy. The nanoparticles enhanced intracellular uptake by virtue of multivalent binding to glycoprotein receptor over-expressed on the surface of liver cancer cells. Moreover, size of the nanoparticles was adjustable by changing the amount of TEOS and/or galactose monomer. The nanoparticles can be manipulated by an external magnetic field and used for T2-weighted contrast enhancement in magnetic resonance imaging due to the high saturation magnetization (1.5 emu/g). Importantly, the novel nanoparticles had a high loading ability of drug (11.9%), and were taken up by HepG2 cells (10.5%), which was nearly three times more than NIH3T3 cells. Competition inhibition assay further confirmed that the glycopolymer conjugated nanoparticles could target cancer cells via receptor-mediated endocytosis. Hence, the well-defined nanoparticles exhibited great potential in MR imaging and targeted drug delivery.
Co-reporter:Lin Mei, Zhentan Lu, Xinge Zhang, Chaoxing Li, and Yanxia Jia
ACS Applied Materials & Interfaces 2014 Volume 6(Issue 18) pp:15813
Publication Date(Web):August 29, 2014
DOI:10.1021/am502886m
Herein, a nontoxic nanocomposite is synthesized by reduction of silver nitrate in the presence of a cationic polymer displaying strong antimicrobial activity against bacterial infection. These nanocomposites with a large concentration of positive charge promote their adsorption to bacterial membranes through electrostatic interaction. Moreover, the synthesized nanocomposites with polyvalent and synergistic antimicrobial effects can effectively kill both Gram-positive and Gram-negative bacteria without the emergence of bacterial resistance. Morphological changes obtained by transmission electron microscope observation show that these nanocomposites can cause leakage and chaos of intracellular contents. Analysis of the antimicrobial mechanism confirms that the lethal action of nanocomposites against the bacteria started with disruption of the bacterial membrane, subsequent cellular internalization of the nanoparticles, and inhibition of intracellular enzymatic activity. This novel antimicrobial material with good cytocompatibility promotes healing of infected wounds in diabetic rats, and has a promising future in the treatment of other infectious diseases.Keywords: antibacterial material; bacterial infection; cationic polymers; silver nanoparticles; wound healing
Co-reporter:Lin Mei, Xinge Zhang, Yanan Wang, Wei Zhang, Zhentan Lu, Yuting Luo, Yu Zhao and Chaoxing Li
Polymer Chemistry 2014 vol. 5(Issue 8) pp:3038-3044
Publication Date(Web):15 Jan 2014
DOI:10.1039/C3PY01578E
Pathogenic bacteria pose a catastrophic threat to human health worldwide. Herein, cationic polymer-functionalized gold nanoparticles were synthesized via the reduction of chloroauric acid in the presence of cationic polymers as multivalent inhibitors of pathogenic bacteria. The cationic polymers were prepared by reversible addition–fragmentation chain transfer polymerization and the tertiary amino groups of the polymers were quaternized to improve their antimicrobial activity. These nanocomposites had large concentrations of positive charge, which promoted their adsorption onto negatively charged bacterial membranes through electrostatic interactions. Through a study of their antibacterial properties, it was observed that these nanocomposites with multivalent antibacterial effects could rapidly and efficiently kill Gram-positive and Gram-negative bacteria. Morphological changes observed via scanning electron microscopy confirmed that the synthesized nanocomposites caused disruption of the cytoplasmic membrane and leakage of cytoplasm. This novel antimicrobial material with effective antibacterial activity and better biocompatibility can promote the healing of bacteria-infected wounds and has promising applications in the biomedical field.
Co-reporter:Lei Sun, Xinge Zhang, Zhongming Wu, Chao Zheng and Chaoxing Li
Polymer Chemistry 2014 vol. 5(Issue 6) pp:1999-2009
Publication Date(Web):01 Nov 2013
DOI:10.1039/C3PY01416A
We design novel oral glucose sensitive nanocarriers for simulating insulin release using a modification of mesoporous silica nanoparticles (MSN) surfaces with a sensitive shell and conduct in vivo testing of these nanocarriers in diabetic rats. Here, MSN are coated with pH-sensitive dextran–maleic acid (Dex–Ma) and then grafted with glucose-sensitive 3-amidophenylboronic acid (APBA). These core–shell nanocarriers are confirmed by FT-IR, TEM, TGA, N2 adsorption–desorption method and elemental analysis. The results indicate that the MSN core can efficiently increase the loading capacity of insulin. In vitro insulin release shows good glucose-trigged behavior, in addition the rate of insulin release can be easily adjusted by changing the shell thickness. The cell viability of the nanocarriers against calu-3 cells demonstrates excellent cytocompatibility, and the nanocarriers can be internalized into cells. According to the studies of diabetic rats in vivo, the oral insulin-loaded nanocarriers produce an obvious hypoglycemic effect compared with insulin directly given orally. Study of the ligated intestinal loops absorption indicates that the material can enhance the permeation of insulin across the epidermis of intestine and facilitate the uptake of insulin. Therefore, the simple and effective pH- and glucose-sensitive nanocarrier can be regarded as a potential self-regulated tool to simulate insulin release in vivo.
Co-reporter:Yu Zhao, Xinge Zhang, Yanan Wang, Zhongming Wu, Jinxia An, Zhentan Lu, Lin Mei, Chaoxing Li
Carbohydrate Polymers 2014 Volume 105() pp:63-69
Publication Date(Web):25 May 2014
DOI:10.1016/j.carbpol.2014.01.068
•We use chitosan and dextran which is natural polysaccharides as the materials of hydrogel.•We use the hydrogel for wound healing, and it has better antibacterial properties than other wound dressings.•The hydrogel are synthesized in 37 °C easily and show good swelling properties and regular porous structure.Many synthetic hydrogels for drug delivery have been based on polyethylene glycol which is non-natural, non-biodegradable and only terminal-functionalizable. The polysaccharides dextran and chitosan not only are highly hydrophilic, biodegradable and pendant-functionalizable, but also more closely mimic the nature extracellular matrix glycosaminoglycans. Here, a biomimetic hydrogel based on chitosan and dextran was synthesized by the Michael addition reaction. The hydrogels have good swelling and cytocompatibility against NIH3T3. Moreover, vancomycin-loaded hydrogels were formed in situ, and could kill both Gram-positive bacteria and Gram-negative bacteria, indicating that the hydrogel as a wound dressing could provide protection against bacterial infection. Notably, the drug release was controlled via modifying the compositions. Therefore, the biomimetic polysaccharide hydrogels as a promising carrier have potential application for wound healing.
Co-reporter:Qianqian Guo, Zhongming Wu, Xinge Zhang, Lei Sun and Chaoxing Li
Soft Matter 2014 vol. 10(Issue 6) pp:911-920
Publication Date(Web):18 Nov 2013
DOI:10.1039/C3SM52485J
Research into polymers with glucose-sensitivity in physiological conditions has expanded recently due to their therapeutic potential in diabetes. Herein, to explore the glucose-responsive properties of a new polymer under physiological conditions, we synthesized an amphiphilic block glycopolymer based on phenylboronic acid and a carbohydrate, which was named poly(D-gluconamidoethyl methacrylate-block-3-acrylamidophenylboronic acid) (p(AAPBA-b-GAMA)). Based on the cross-linking between the diol groups of the carbohydrates and phenylboronic acid, the glycopolymers self-assembled to form nanoparticles (NPs). The glucose-sensitivity was revealed by the swelling behavior of the NPs at different glucose concentrations and was found to be dependent on the glucose level. The morphology of the NPs revealed by transmission electron microscopy showed that the NPs were spherical in shape with good dispersity. The cell viability of the NPs investigated by MTT assay was more than 90%, indicating that the glycopolymers had good cytocompatibility. Insulin could be loaded onto the glycopolymer NPs with high efficiency (up to 10%), and insulin release increased with enhancement of the glucose level in the medium. Such a glucose-responsive glycopolymer is an excellent candidate that holds great potential in the treatment of diabetes.
Co-reporter:Lei Sun, Xinge Zhang, Jinxia An, Cui Su, Qianqain Guo and Chaoxing Li
RSC Advances 2014 vol. 4(Issue 39) pp:20208-20215
Publication Date(Web):23 Apr 2014
DOI:10.1039/C4RA01812E
Currently, the major challenge for cancer treatment is to develop simple and smart nanocarriers that can efficiently retain the encapsulated drug during blood circulation, recognize tumor cells and quickly release the drug under stimulation. In this paper, such a pH-sensitive core–shell composite nanoparticles is prepared based on a 3-aminophenylboronic acid modified mesoporous silica nanoparticles (MSN–APBA) core coated with a lactobionic acid grafted chitosan (CS–LA) shell via boronate ester bonds. The MSN core increases drug loading capacity and stability, and lactobionic acid offers abundant diols which can form pH sensitive boronate ester bonds with APBA on MSN. Meanwhile, the lactobionic acid-conjugated shell could also efficiently target the asialoglycoprotein receptor over expressing hepatoma cells. The successful synthesis of CS–LA and MSN–APBA is confirmed by the results of TGA, TEM, DLS, FT-IR, 1H-NMR and N2 adsorption–desorption. Doxorubicin hydrochloride (DOX) is applied as a model drug and the behaviors of drug loading/release are investigated. The drug loading behavior is pH-dependent, and its drug encapsulation efficiency is near 80% and loading capacity is 13.05%. The results of cumulative in vitro release indicate that at neutral pH, the pores of the MSN are effectively capped with a polymer shell and the drug release is strongly inhibited, almost zero release. While at acidic pH, the hydrolysis of the boroester bond takes place and thus results in a rapid release of the entrapped drug. The cytotoxicity assay indicates high cell biocompatibility of this material and it is suitable as a drug carrier. When loaded with DOX, it presents distinctly cytotoxic behavior to HepG2 cells, due to the sustained release of drug. These results imply that the core–shell nanoparticles are promising platforms to construct simple and effective pH-responsive controlled drug delivery systems for cancer therapy.
Co-reporter:Zhentan Lu, Xinge Zhang, Zhongming Wu, Tingting Zhai, Yinan Xue, Lin Mei and Chaoxing Li
RSC Advances 2014 vol. 4(Issue 37) pp:19495-19501
Publication Date(Web):15 Apr 2014
DOI:10.1039/C4RA01412J
Photodynamic therapy (PDT) is attracting ongoing attention for treatment of cancer as a noninvasive technique. A BODIPY-based macromolecular photosensitizer, p(GEMA-co-BODIPYMA)-2I, with high water solubility, specificity recognition to cancer cells and no dark cytotoxicity was prepared, which achieved enhanced therapeutic efficacy and reduced side-effects. P(GEMA-co-BODIPYMA)-2I generated 1O2 (ΦΔ = 0.79) rapidly in aqueous system and confocal laser scanning microscopy (CLSM) images showed that p(GEMA-co-BODIPYMA)-2I was avidly taken up specifically by cancer cells, however, couldn't be uptaken by normal cells. The novel photosensitizer displayed high photocytotoxicity for cancer cells, but not normal cells. The cell viability of normal cells was over 80% when the concentration was 20 nmol mL−1 under illumination for 10 min and that for cancer cells was 0.4% under the same conditions. Our facile strategy provides a novel avenue for the effective development of photosensitizers for cancer therapy.
Co-reporter:Zhentan Lu, Lin Mei, Xinge Zhang, Yanan Wang, Yu Zhao and Chaoxing Li
Polymer Chemistry 2013 vol. 4(Issue 24) pp:5743-5750
Publication Date(Web):19 Jul 2013
DOI:10.1039/C3PY00639E
Fluorescent probes have attracted ongoing attention in early detection of tumor cells. The development of novel fluorescent materials with high cellular internalization efficiency, good photostability, and high specificity for tumor cells is in urgent demand. Herein, a highly water-soluble, multivalent and highly specific BODIPY-conjugated glycopolymer was synthesized by Atom Transfer Radical Polymerization (ATRP) for direct tumor cell imaging, which showed good photostability. The fluorescence quantum yield of a BODIPY-conjugated glycopolymer increased to 0.52 compared with 0.31 of BODIPYMA due to the introduction of galactose. The cell viability of BODIPY-conjugated glycopolymers against HepG2 and NIH3T3 cells was more than 80%, indicating that the glycopolymers have low cytotoxicity to living cells. Moreover, simple incubation of living cells with a BODIPY-conjugated glycopolymer led to efficient internalization into HepG2 and clear visualization in cytoplasm, due to the high brightness of BODIPY and good specificity between HepG2 and galactose as compared to NIH3T3 cells. These results suggest that BODIPY-conjugated glycopolymers have potential use as fluorescent probes in live cell imaging. Further fine-tuning the fluorescent property and targeting ability of BODIPY-conjugated glycopolymers can lead to more complicated imaging applications and subcellular target detection.
Co-reporter:Xuejiao Zhang;Peien Yu;Yucai Han;Yangguang Li;Chaoxing Li
Journal of Pharmaceutical Sciences 2013 Volume 102( Issue 1) pp:145-153
Publication Date(Web):
DOI:10.1002/jps.23344
Abstract
Mixed copolymer nanoparticles (NPs) self-assembled from β-cyclodextrin-grafted hyperbranched polyglycerol (HPG-g-CD) and lactobionic acid (LA)-grafted hyperbranched polyglycerol (HPG-g-LA) were applied as carriers for a hydrophobic antitumor drug, paclitaxel (PTX), achieving hepatocellular carcinoma-targeted delivery. The resulting NPs exhibited high drug loading capacity and substantial stability in aqueous solution. In vitro drug release studies demonstrated a controlled drug release profile with increased release at acidic pH. Remarkably, tumor proliferation assays showed that PTX-loaded mixed copolymer NPs inhibited asialoglycoprotein (ASGP) receptor positive HepG2 cell proliferation in a concentration-dependent manner in comparison with ASGP receptor negative BGC-823 cells. Moreover, the competition assay demonstrated that the small molecular LA inhibited the cellular uptake of the PTX-loaded mixed copolymer NPs, indicating the ASGP receptor-mediated endocytosis in HepG2 cells. In addition, the intracellular uptake tests by confocal laser scanning microscopy showed that the mixed copolymer NPs were more efficiently taken up by HepG2 cells compared with HPG-g-CD NPs. These results suggest a feasible application of the mixed copolymer NPs as nanocarriers for hepatoma-targeted delivery of potent antitumor drugs. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:145–153, 2013
Co-reporter:Yanxia Wang, Xinge Zhang, Jing Mu and Chaoxing Li
New Journal of Chemistry 2013 vol. 37(Issue 3) pp:796-803
Publication Date(Web):18 Dec 2012
DOI:10.1039/C2NJ40998D
Poly(3-methacrylamido phenylboronic acid) (PMAPBA) homopolymer and poly(ethylene glycol)-block-poly(2-acryloxyethyl-galactose) (PEG-b-PAEG) glycopolymer were prepared successfully by reversible addition fragmentation chain transfer (RAFT) polymerization and atom transfer radical polymerization (ATRP), respectively. The formation of boronate crosslinked nanoparticles based on the complexation of PMAPBA and PEG-b-PAEG was confirmed by dynamic light scattering (DLS), thermal analysis, and Alizarin red S (ARS) based colorimetric and fluorescence assays. The nanoparticles showed significant pH, salt, and sugar sensitivity. At pH 5.0 and 6.0, the aggregation and precipitation of the nanoparticles were observed. The particle size increased significantly as pH increased from 7 to 11. The nanoparticles showed obvious sensitivity to glucose, galactose, mannose, and sucrose at pH 10. Due to shielding of the negatively charged phenylboronic acid groups, the aggregation of the boronate crosslinked nanoparticles was found with increase of the salt concentration.
Co-reporter:Lei Sun, Xinge Zhang, Chao Zheng, Zhongming Wu, and Chaoxing Li
The Journal of Physical Chemistry B 2013 Volume 117(Issue 14) pp:3852-3860
Publication Date(Web):March 21, 2013
DOI:10.1021/jp400442x
This study prepares a kind of core–shell hybrid nanoparticles, which is worm-like, pH gated, and glucose-sensitive. It has a mesoporous silica nanoparticle (MSN) core and polymer shell (cross-linked and non-cross-linked), bearing 3-acrylamidophenylboronic acid (AAPBA) and N-isopropylacrylamide (NIPAM) as sensor moieties. The shell of the nanoparticles has presented a distinct transition from swollen state to collapsed state as the temperature increases, which offers easy access to drug loading. Here, insulin is applied as a model drug and the behaviors of its loading/release are investigated. Insulin loading is up to 15% via mesoporous silica core. In vitro experiment shows that the cumulative release of insulin is dependent on glucose concentration, and the glucose sensitivity could be adjusted simply by different pH values. Simultaneously, compared with the non-cross-linked shell, the cross-linked shell, using dextran-maleic acid (Dex-Ma) as a macromolecule cross-link, enables insulin to release more persistently. Also, cell viability assay indicates that these nanoparticles have good biocompatibility. Consequently, the novel, pH gated, glucose-sensitive core–shell nanoparticles may have potential applications as a vehicle of self-regulated insulin delivery system.
Co-reporter:Qianqian Guo;Chenyan Liu;Tingting Tang;Jian Huang;Guowei Wang
Journal of Polymer Science Part A: Polymer Chemistry 2013 Volume 51( Issue 21) pp:4572-4583
Publication Date(Web):
DOI:10.1002/pola.26874
ABSTRACT
Using core-first strategy, the amphiphilic A4B4 star-shaped copolymers [poly(ethylene oxide)]4[poly(ε-caprolactone)]4 [(PEO)4(PCL)4], [poly(ethylene oxide)]4[poly(styrene)]4 [(PEO)4(PS)4], and [poly(ethylene oxide)]4[poly(tert-butyl acrylate)]4 [(PEO)4(PtBA)4] were synthesized by mechanisms transformation combining with thiol-ene reaction. First, using a designed multifunctional mikto-initiator with four active hydroxyl groups and four allyl groups, the four-armed star-shaped polymers (PEO-Ph)4/(OH)4 with four active hydroxyl groups at core position were obtained by sequential ring-opening polymerization (ROP) of ethylene oxide monomers, capping reaction of living oxyanion with benzyl chloride, and transformation of allyl groups into hydroxyl groups by thiol-ene reaction. Then, the A4B4 star-shaped copolymers (PEO)4(PS)4 or (PEO)4(PtBA)4 were obtained by atom transfer radical polymerization (ATRP) of styrene or tert-butyl acrylate (tBA) monomers from macroinitiator of (PEO-Ph)4/(Br)4, which was obtained by esterification of (PEO-Ph)4/(OH)4 with 2-bromoisobutyryl bromide. The A4B4 star-shaped copolymers (PEO)4(PCL)4 were also obtained by ROP of ε-caprolactopne monomers from macroinitiator of (PEO-Ph)4/(OH)4. The target copolymers and intermediates were characterized by size-exclusion chromatography, matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy, and nuclear magnetic resonance in detail. This synthetic route might be a versatile one to various AnBn (n ≥ 3) star-shaped copolymers with defined structure and compositions. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4572–4583
Co-reporter:C. Zheng;X. G. Zhang;L. Sun;Z. P. Zhang
Journal of Materials Science: Materials in Medicine 2013 Volume 24( Issue 4) pp:931-939
Publication Date(Web):2013 April
DOI:10.1007/s10856-013-4863-z
The development of peptides and proteins is hampered by their rapid clearance in liver and other body tissues by proteolytic enzymes, so these drugs are difficult to administer except for the injection. Here, we designed and fabricated a novel biodegradable and redox-responsive submicron capsules through the layer-by-layer technique with poly(l-aspartic acid) and chitosan for transmucosal delivery of proteins and peptides. TEM graphs reveal that the intact submicron capsules were obtained and the shell of submicron capsules was about 40 nm. The mucoadhesion test indicates that the adsorption amount of the mucin could achieve up to 96.2 μg per 2 mg. The cell viability test shows that all types of submicron capsules had good cytocompatibility and the cell viability was above 90 %. As a drug model, the insulin could be loaded in the submicron capsules, and the loading efficiency was about 5 %. The release amount of insulin could be regulated by the levels of GSH. Therefore, the mucoadhesive submicron capsules as vehicles have a potential for the mucosal delivery (e.g. nasal and buccal) of therapeutic peptide and protein drugs.
Co-reporter:Lin Mei, Zhentan Lu, Wei Zhang, Zhongming Wu, Xinge Zhang, Yanan Wang, Yuting Luo, Chaoxing Li, Yanxia Jia
Biomaterials 2013 34(38) pp: 10328-10337
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.09.045
Co-reporter:Zhongming Wu, Xinge Zhang, Honglei Guo, Chaoxing Li and Demin Yu
Journal of Materials Chemistry A 2012 vol. 22(Issue 42) pp:22788-22796
Publication Date(Web):11 Sep 2012
DOI:10.1039/C2JM34082H
Glucose-responsive polymer gels provide an attractive option for the design of a self-regulated insulin delivery system. Here, this paper reported the biocompatibility, glucose-sensitive behavior, and in vivo application of a dispersion of nanogels with three interpenetrating polymer networks of poly(N-isopropylacrylamide), dextran and poly(3-acrylamidophenylboronic acid) (P(NIPAM–Dex–PBA)). The nanogels had an average hydrodynamic radius of about 150 nm, and particle size increased with increasing content of dextran. The swelling behavior of the nanogels at different glucose concentrations revealed definite glucose sensitivity of P(NIPAM–Dex–PBA) particles. Furthermore, the analysis of relative cell proliferation suggested that the nanogels had good biocompatibility with L-929 mouse fibroblast cells. The loading amount of insulin, as a model drug, was up to 16.2%, and the drug release was dependent on the composition of dextran in the particles and the concentration of glucose present in release medium. In vivo experiments revealed that insulin-loaded nanogels decreased the blood glucose levels in diabetic rats and maintained 51% of the baseline level for almost 2 hours. The hypoglycemic effect of the drug-loaded nanogels was similar to that of free insulin after administration. Importantly, the drug-loaded nanogels could keep blood glucose levels stable and avoided blood sugar fluctuations compared with free insulin.
Co-reporter:Yanxia Wang, Xinge Zhang, Yucai Han, Cui Cheng, Chaoxing Li
Carbohydrate Polymers 2012 Volume 89(Issue 1) pp:124-131
Publication Date(Web):5 June 2012
DOI:10.1016/j.carbpol.2012.02.060
Amphiphilic poly(acrylic acid-co-acrylamidophenylboronic acid)-block-poly(2-acryloxyethyl galactose)-block-poly(acrylic acid-co-acrylamidophenylboronic acid) (((PAA-co-PAAPBA)-b-)2PAEG) copolymer was fabricated: The poly(2-acryloyloxyethyl pentaacetylgalactoside) (PAEAcG) with narrow molecular weight distributions (Mw/Mn ≤ 1.22) was prepared by atom transfer radical polymerization (ATRP) using dibromo-p-xylene (DBX) as initiator. Then the well-defined triblock copolymer poly(t-butyl acrylate)-b-poly(2-acryloyloxyethyl pentaacetylgalactoside)-b-poly(t-butyl acrylate) (PtBA-b-PAEAcG-b-PtBA) was synthesized by ATRP of tBA using PAEAcG homopolymer with dibromo end groups as macroinitiator. After hydrolysis of t-butyl acrylate block, amide linkage and deacetylation, the final copolymer ((PAA-co-PAAPBA)-b-)2PAEG was obtained. Because of characteristics of three different segments, amphiphilic ((PAA-co-PAAPBA)-b-)2PAEG can self-assemble into pH- and glucose-responsive nanoparticles studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Furthermore, the in vitro release profiles of insulin also revealed obvious pH- and glucose-sensitivity of the nanoparticles. The analysis of cell viability suggested that the copolymer nanoparticles had good cytocompatibility.Highlights► It is the first time that the kinetic for the ATRP of 2-acryloyloxyethyl pentaacetylgalactoside is studied. ► We find that a degree of control for the ATRP of tBA using poly(2-acryloyloxyethyl pentaacetylgalactoside) macroinitiators. ► DLS, TEM and the in vitro release study reveal obvious pH- and glucose-sensitivity of the glycopolymer nanoparticles. ► The sugar blocks improve the cytocompatiblity of the glycopolymer nanoparticles.
Co-reporter:Cui Cheng, Xinge Zhang, Jixin Xiang, Yanxia Wang, Chao Zheng, Zhentan Lu and Chaoxing Li
Soft Matter 2012 vol. 8(Issue 3) pp:765-773
Publication Date(Web):08 Nov 2011
DOI:10.1039/C1SM06085F
It is well-known that the phenylboronic acid derivatives have chemical interactions with sugars. Hence, stable nanoparticles with core-shell structure were formed by the covalent complexation between boronic acid groups of poly(3-acrylamidophenylboronic acid) (pAPBA) and hydroxyl groups of poly(2-lactobionamidoethyl methacrylate) (pLAMA). The image taken by transmission electron microscopy (TEM) shows that the nanoparticles had a size of about 200 nm and were irregular spheres. The methyl thiazolyl tetrazolium (MTT) assay suggests that the nanoparticles were non-cytotoxic on the human colorectal carcinoma (Caco-2) cells. The confocal laser scanning microscope (CLSM) images show that the nanoparticles could internalize into Caco-2 cells. The insulin-loaded nanoparticles by intranasal administration led to a significant decrease in the plasma glucose levels and the histological assessment revealed that the nanoparticles would not develop lesions in the nasal epithelium. The nanoparticles are promising carriers for peptide and protein drugs in nasal delivery.
Co-reporter:Lei Sun, Xinge Zhang, Chao Zheng, Zhongming Wu, Xiaoting Xia and Chaoxing Li
RSC Advances 2012 vol. 2(Issue 26) pp:9904-9913
Publication Date(Web):15 Aug 2012
DOI:10.1039/C2RA21408C
In this paper, a novel core–shell microgel was prepared based on poly(N-isopropylacrylamide-co-3-acrylamidophenylboronic acid-co-dextran-maleic acid) (p(NIPAM-co-AAPBA-co-Dex-Ma)) coated silica nanoparticles via radical polymerization. The core–shell microgels presented glucose- and temperature-sensitivity, and the shell thickness could be easily regulated by the molar ratio of the comonomers. The polymer shell was active in drug loading as it underwent a distinct transition from a swollen state to a collapsed state as the temperature increased. Insulin was applied as a model drug and the behaviors of insulin loading/release were investigated. The insulin loading was temperature-dependent and up to 20%. The cumulative release of insulin in vitro showed that insulin release was dependent on glucose concentration. The glucose sensitivity of the microgels could be adjusted simply by adjusting the pH. The cytotoxicity assay indicated that the core–shell microgels have good biocompatibility. These results showed that the core–shell microgels have potential for a controlled insulin release system.
Co-reporter:Cui Cheng, Xinge Zhang, Yanxia Wang, Lei Sun and Chaoxing Li
New Journal of Chemistry 2012 vol. 36(Issue 6) pp:1413-1421
Publication Date(Web):16 Apr 2012
DOI:10.1039/C2NJ20997G
The boronic acid group has been known to bind to sugars and living animal cells. Herein, a novel amphiphilic block copolymer poly(2-lactobionamidoethyl methacrylate)-block-poly(3-acrylamidophenylboronic acid) (p(LAMA-b-AAPBA)) was prepared by reversible addition fragmentation chain transfer (RAFT) polymerization. Due to the interaction between lactose moieties and phenylboronic acid moieties in p(LAMA-b-AAPBA), the copolymer could easily form nanoparticles in a spherical shape. The p(LAMA-b-AAPBA) nanoparticles had mean sizes from 238 to 403 nm with a zeta potential of about −20 mV. To study the feasibility of p(LAMA-b-AAPBA) nanoparticles acting as the potential nanocarrier for protein delivery, insulin, as a drug model, was encapsulated into the nanoparticles, the loading capacity was about 11%. Moreover, the nanoparticles demonstrated a sustained release of insulin and had no cytotoxicity on Chinese hamster ovary cells (CHO) and human colorectal carcinoma (Caco-2) cells. Confocal laser scanning microscopy showed that the nanoparticles could be taken up by Caco-2 cells, indicating that the stimuli-response of phenylboronic acid to carbohydrates on the cell surface facilitated the nanoparticles to bind to Caco-2 cells. Thus, the p(LAMA-b-AAPBA) nanoparticles can be considered as a promising carrier for protein transport.
Co-reporter:Xuejiao Zhang, Xinge Zhang, Zhongming Wu, Xiujun Gao, Cui Cheng, Zhen Wang, Chaoxing Li
Acta Biomaterialia 2011 Volume 7(Issue 2) pp:585-592
Publication Date(Web):February 2011
DOI:10.1016/j.actbio.2010.08.029
Abstract
The development of successful formulations for poorly water soluble drugs remains a longstanding, critical, and challenging issue in cancer therapy. A β-cyclodextrin (CD) functionalized hyperbranched polyglycerol (HPG) has been prepared as a potential water insoluble drug carrier. The HPG-g-CD molecules could self-assemble into multimolecular spherical micelles in water, the size of which ranged from 200 to 300 nm, with good dispersity. A high loading capacity and high encapsulation efficiency of paclitaxel, as a model, were obtained. The release profiles of different co-polymer compositions showed a burst release followed by continuous extended release. Furthermore, MTT analysis showed that HPG-g-CD had good biocompatibility, indicating that HPG-g-CD may be considered a promising hydrophobic drug delivery system.
Co-reporter:Xuejiao Zhang, Xinge Zhang, Zhongming Wu, Xiujun Gao, Shujun Shu, Zhen Wang, Chaoxing Li
Carbohydrate Polymers 2011 Volume 84(Issue 4) pp:1419-1425
Publication Date(Web):2 April 2011
DOI:10.1016/j.carbpol.2011.01.057
We prepared a β-CD functionalized hyperbranched polyglycerol (HPG) with the purpose of enhancing the nasal transport of insulin in rats. Insulin-loaded HPG-g-CD nanoparticles (NPs) were prepared and the size of the NPs ranged from 198 to 340 nm with a positive charge. The NPs exhibited a great capacity of associating insulin, reaching the efficiency as high as 88.21%. In vitro release showed that the release rate of insulin was much faster under acidic condition than physiological condition. In vitro cytotoxicity against Caco-2 cells showed that HPG-g-CDs had good biocompatibility. The in vivo evaluation in rats demonstrated that insulin-loaded HPG-g-CD NPs had the ability to significantly decrease the blood glucose concentrations. Furthermore, the capability of HPG-g-CD NPs to cross the nasal mucosal epithelia was proved by confocal laser scanning microscopy (CLSM). Consequently, the results suggest that the HPG-g-CD NPs are promising carriers for nasal insulin delivery.
Co-reporter:Shujun Shu, Chunyang Sun, Xinge Zhang, Zhongming Wu, Zhen Wang, Chaoxing Li
Acta Biomaterialia 2010 Volume 6(Issue 1) pp:210-217
Publication Date(Web):January 2010
DOI:10.1016/j.actbio.2009.06.020
Abstract
Biodegradable hollow capsules encapsulating protein drugs were prepared via layer-by-layer assembly of water-soluble chitosan and dextran sulfate on protein-entrapping amino-functionalized silica particles and the subsequent removal of the silica. In order to enhance the encapsulated efficiency and decrease its burst release, we designed this new system to fulfill these two goals. Bovine serum albumin (BSA), which was used as model protein, was entrapped in the nanocapsules. This system demonstrated a good capacity for the encapsulation and loading of BSA. The burst release was decreased to less than 10% in phosphate-buffered saline within 2 h. No significant conformation change was noted from the released BSA in comparison with native BSA by using circular dichroism spectroscopy. Cell viability study suggested that the nanocapsules had good biocompatibility. The drug release kinetics mechanism is Fickian diffusion. These kinds of novel composite nanocapsules may offer a promising delivery system for water-soluble proteins and peptides.
Co-reporter:Xiujun Gao;Xuejiao Zhang;Cui Cheng;Zhen Wang
Polymer Bulletin 2010 Volume 65( Issue 8) pp:787-805
Publication Date(Web):2010 November
DOI:10.1007/s00289-010-0273-2
Nanoparticles based on an amphiphilic copolymer with polylactic acid (PLA) grafted onto hyperbranched polyglycerol (HPG) were prepared by the use of BSA as a model protein. The characteristics of the nanoparticles were evaluated using particle size analyzer, transmission electron microscopy, and X-ray photoelectron spectroscopy. The secondary structure of BSA released from nanoparticles were analysed by circular dichroism experiments. Cell viability of nanoparticles was also evaluated by using NIH 3T3 cells. The mechanism of BSA release was studied by fitting experimental data to three model equations. Results indicated that BSA diffusion and the polymeric relaxation jointly governed the overall release process. The detailed analysis of BSA release was performed using the first-order kinetic model equation, which gave a good fit to the experimental release data. The influence of different copolymer structures and BSA loading capacities on release profiles were also evaluated for the potential of using nanoparticles as controlled release protein delivery systems.
Co-reporter:Da-yong Teng, Zhong-ming Wu, Xin-ge Zhang, Yan-xia Wang, Chao Zheng, Zhen Wang, Chao-xing Li
Polymer 2010 Volume 51(Issue 3) pp:639-646
Publication Date(Web):5 February 2010
DOI:10.1016/j.polymer.2009.12.003
A novel injectable in situ cross-linked hydrogel has been designed via Michael type addition between thiol-modified chitosan (CS–NAC) and PEG diacrylate (PEGDA). Hydrogel was rapidly formed in situ under physiological conditions. The gelation time depended on the content of free thiols in CS–NAC, temperature, and concentration of CS–NAC and PEGDA. Thermogravimetric analysis showed the thermal stabilities of hydrogels. SEM observation results confirmed a porous 3D structure. Rheological studies showed that the cross-linking density and elasticity of hydrogel had a correlation to the content of CS–NAC and PEGDA. Swelling studies revealed that these hydrogels had a high initial swelling and were degradable under physiological conditions. And swelling was highly temperature-dependent and was directly related to the amount of cross-linking. Biological activities of the hydrogels were evaluated by in vitro cell compatibility on HDFs and A549 cells and the results indicated that the hydrogel was biocompatible.
Co-reporter:Shujun Shu, Xinge Zhang, Zhongming Wu, Zhen Wang, Chaoxing Li
Biomaterials 2010 31(23) pp: 6039-6049
Publication Date(Web):
DOI:10.1016/j.biomaterials.2010.04.016
Co-reporter:Xiujun Gao, Xinge Zhang, Zhongming Wu, Xuejiao Zhang, Zhen Wang, Chaoxing Li
Journal of Controlled Release 2009 Volume 140(Issue 2) pp:141-147
Publication Date(Web):3 December 2009
DOI:10.1016/j.jconrel.2009.08.003
Amphiphilic copolymers with polylactic acid (PLA) chains grafted onto hyperbranched polyglycerol (HPG) have been synthesized and characterized. The copolymer nanoparticles with corona and core structure were formed by self-assembly in aqueous solution. The loading capacity and association efficiency were up to 23% and 86%, respectively. Protein release profiles with different copolymer compositions and BSA concentrations all showed a burst effect followed by a continuous release phase. The released BSA from the copolymer nanoparticles remained in its original structure over a period of 4 days, as testified by circular dichroism spectroscopy. Furthermore, cell viability research suggested good biocompatibility of the copolymer nanoparticles, which have a promising potential for protein delivery system.Supposed mechanisms of BSA encapsulation into the nanoparticles from the HPG-PLA copolymer (nanoprecipitation method).
Co-reporter:Xinge Zhang, Zhongming Wu, Xiujun Gao, Shujun Shu, Huijie Zhang, Zhen Wang, Chaoxing Li
Carbohydrate Polymers 2009 Volume 77(Issue 2) pp:394-401
Publication Date(Web):10 June 2009
DOI:10.1016/j.carbpol.2009.01.018
The objective of this work was to investigate the possibility of chitosan bearing β-cyclodextrin (CDen-g-CS) nanocomplexes for controlled protein release. CDen-g-CS was synthesized by a one-step procedure with N-succinylated chitosan and mono(6-(2-aminoethyl)amino-6-deoxy)-β-cyclodextrin in the presence of the water-soluble carbodiimide. The amount of β-CD grafted was up to 62.1 wt%. In vitro cytotoxicity against NIH 3T3 cells showed that CDen-g-CS was not cytotoxic and no significant difference of cytotoxicity was found between CDen-g-CS groups. Self-assembled nanocomplexes between CDen-g-CS and insulin were in the size range of 190–328 nm, with positive electrical charge (+3.7 to +25.5 mV) and high loading efficiency (37.7%). Insulin release in vitro was affected by the medium pH and the composition of copolymer. These results demonstrated that CDen-g-CS copolymer was a new promising vehicle for controlled protein release.
Co-reporter:Shujun Shu, Xin Wang, Xinge Zhang, Xuejiao Zhang, Zhen Wang and Chaoxing Li
New Journal of Chemistry 2009 vol. 33(Issue 9) pp:1882-1887
Publication Date(Web):08 May 2009
DOI:10.1039/B903208H
Polyelectrolyte
nanoparticles were prepared by mixing chitosan (CS) and polyaspartic acid functionalized with cysteamine (PASP–CA) under mild conditions. The nanoparticles (NPs) included thiol moieties that were cross-linked to render the NPs stable at physiological pH. It was demonstrated that reacting the thiol moieties to form disulfide bonds led to improved stability. NPs without disulfide bonds were readily deconstructed at physiological pH. The disulfide bond cross-linked NPs can remain more stable in physiological pH solution and decrease the loss of protein drugs caused by simulating the gastric pH environment, and can release the drugs in the simulated pH environment of the intestine. This approach has potential for the in vivo application of NPs for the oral delivery of protein drugs.
Co-reporter:Shujun Shu, Xinge Zhang, Dayong Teng, Zhen Wang, Chaoxing Li
Carbohydrate Research 2009 Volume 344(Issue 10) pp:1197-1204
Publication Date(Web):6 July 2009
DOI:10.1016/j.carres.2009.04.018
Water-soluble chitosan (WSC)–poly(l-aspartic acid) (PASP)–polyethylene glycol (PEG) nanoparticles (CPP nanoparticles) were prepared spontaneously under quite mild conditions by polyelectrolyte complexation. These nanoparticles were well dispersed and stable in aqueous solution, and their physicochemical properties were characterized by turbidity, FTIR spectroscopy, dynamic light scattering (DLS), transmission electron microscope (TEM), and zeta potential. PEG was chosen to modify WSC–PASP nanoparticles to make a protein-protective agent. Investigation on the encapsulation efficiency and loading capacity of the bovine serum albumin (BSA)-loaded CPP nanoparticles was also conducted. Encapsulation efficiency was obviously decreased with the increase of initial BSA concentration. Furthermore, its in vitro release characteristics were evaluated at pH 1.2, 2.5, and 7.4. In vitro release showed that these nanoparticles provided an initial burst release, followed by a slowly sustained release for more than 24 h. The BSA released from CPP nanoparticles showed no significant conformational change compared with native BSA, which is superior to the BSA released from nanoparticles without PEG. A cell viability study suggested that the nanoparticles had good biocompatibility. This nanoparticle system was considered promising as an advanced drug delivery system for the peptide and protein drug delivery.
Co-reporter:Dayong Teng;Weibin Yin;Zhen Wang;Chaoxing Li
Journal of Polymer Research 2009 Volume 16( Issue 3) pp:311-316
Publication Date(Web):2009 May
DOI:10.1007/s10965-008-9231-1
A new glycoconjugate polyacrylamide with water-solubility and additional activated groups was prepared by attaching glucosamine to the preactivated polymer, Poly(N-acryloylmorpholine-co-N-acryloxysuccinimide) [poly(NAM-co-NAS)]. The structures of glycoconjugate polyacrylamide were characterized by 1H-NMR, FTIR and GPC. The glucosamine conjugates degrees were determined by the modified Schales’ method and the contents of activated groups were measured by the isopropylamine method. The results showed that this new glycopolymer is water-soluble and has additional activated groups. And high molecular weight confirmed the high number of activated groups per polymer chain, though the N-oxysuccinimide groups were partly shielded by the N-morpholine groups.
Co-reporter:Xin Wang;Chao Zheng;Zhongming Wu;Dayong Teng;Zhen Wang;Chaoxing Li
Journal of Biomedical Materials Research Part B: Applied Biomaterials 2009 Volume 88B( Issue 1) pp:150-161
Publication Date(Web):
DOI:10.1002/jbm.b.31161
Abstract
The purpose of this work was to investigate chitosan-N-acetyl-L-cysteine (chitosan-NAC) nanoparticles as a potential carrier system for the nasal delivery of insulin. For the study, we used insulin-loaded chitosan-NAC nanoparticles (140–210 nm in diameter) prepared by in situ gelation with tripolyphosphate (TPP), with positive zeta potential values of +19.5–31.7 mV and insulin loading capacities of 13–42%. The physicochemical properties of the nanoparticles were affected by the number of thiol groups present. Mucoadhesive properties, which were evaluated by measuring the in vitro absorbed mass of mucin, of chitosan-NAC nanoparticles were >1.8-fold that of unmodified chitosan nanoparticles. In aqueous solution, chitosan-NAC nanoparticles exhibited fast swelling behavior. Insulin was released from chitosan-NAC nanoparticles in vitro in an initial burst followed by slow release. Intranasal administration of chitosan-NAC nanoparticles in rats enhanced the absorption of insulin by the nasal mucosa compared with unmodified chitosan nanoparticles and control insulin solution. In light of these observations, the novel thiolated chitosan nanoparticles represent a promising vehicle for nasal insulin administration. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009
Co-reporter:Xingju Jin, Xinge Zhang, Zhongming Wu, Dayong Teng, Xuejiao Zhang, Yanxia Wang, Zhen Wang and Chaoxing Li
Biomacromolecules 2009 Volume 10(Issue 6) pp:
Publication Date(Web):April 27, 2009
DOI:10.1021/bm8010006
This study is devoted to developing amphiphilic, random glycopolymers based on phenylboronic acid, which self-assemble to form nanoparticles (NPs), as a glucose-sensitive agent. Maleimide-glucosamine was copolymerized with 3-acryl aminophenylboronic acid in methanol at 70 °C. Using the nanoprecipitation method, NPs with a narrow size distribution were successfully generated. Transmission electron microscopic analysis showed that the NPs were well dispersed as individual, spherically shaped particles. The swelling behavior of the NPs and the in vitro release profiles of insulin at different glucose concentrations revealed definite glucose sensitivity of the glycopolymers. Further, circular dichroism spectroscopy demonstrated that the overall tertiary structure of the released insulin was not altered compared with standard insulin. The analysis of relative cell proliferation suggested that the glycopolymer NPs had good biocompatibility. The glycopolymers that responded to changes in the glucose concentration of the surrounding environment are being aimed for use in self-regulated insulin delivery.
Co-reporter:Dayong Teng, Jingli Hou, Xinge Zhang, Xin Wang, Zhen Wang, Chaoxing Li
Journal of Colloid and Interface Science 2008 Volume 322(Issue 1) pp:333-341
Publication Date(Web):1 June 2008
DOI:10.1016/j.jcis.2008.03.014
Glucosamine-carrying temperature- and pH-sensitive microgels with an average diameter of about 100 nm were successfully prepared by free radical precipitation polymerization. The thermo- and pH-responsive properties of the microgels were designed by the incorporation of N-isopropylacrylamide (NIPAM) and acrylic acid (AAc) to copolymerize with acrylamido-2-deoxyglucose (AADG). The stimuli sensitivity of the microgels was studied by the measurement of their sizes and volume phase transition temperature (VPTT) under different surrounding conditions. The results showed that the microgels were responsive to temperature, pH, and ionic strength, and could have a desired VPTT by modifying AADG and AAc contents. The effect of temperature and pH on insulin release from the microgels was also investigated. The release of drug at the tumor-surrounding environment is faster than that under normal physiological conditions. A preliminary in vitro cell study showed that the glucosamine-carrying microgels are more biocompatible to mouse fibroblast cells, compared to the microgels without glucosamine. These glucosamine-carrying dual-sensitive microgels may be promising carriers for targeted drug delivery to tumors.A preliminary in vitro cell study showed that the glucosamine-carrying microgels are nontoxic and more biocompatible to mouse fibroblast cells, compared to the microgels without glucosamine.
Co-reporter:Xuejiao Zhang, Xinge Zhang, Peien Yu, Yucai Han, ... Chaoxing Li
Journal of Pharmaceutical Sciences (January 2013) Volume 102(Issue 1) pp:145-153
Publication Date(Web):1 January 2013
DOI:10.1002/jps.23344
Mixed copolymer nanoparticles (NPs) self-assembled from β-cyclodextrin-grafted hyperbranched polyglycerol (HPG-g-CD) and lactobionic acid (LA)-grafted hyperbranched polyglycerol (HPG-g-LA) were applied as carriers for a hydrophobic antitumor drug, paclitaxel (PTX), achieving hepatocellular carcinoma-targeted delivery. The resulting NPs exhibited high drug loading capacity and substantial stability in aqueous solution. In vitro drug release studies demonstrated a controlled drug release profile with increased release at acidic pH. Remarkably, tumor proliferation assays showed that PTX-loaded mixed copolymer NPs inhibited asialoglycoprotein (ASGP) receptor positive HepG2 cell proliferation in a concentration-dependent manner in comparison with ASGP receptor negative BGC-823 cells. Moreover, the competition assay demonstrated that the small molecular LA inhibited the cellular uptake of the PTX-loaded mixed copolymer NPs, indicating the ASGP receptor-mediated endocytosis in HepG2 cells. In addition, the intracellular uptake tests by confocal laser scanning microscopy showed that the mixed copolymer NPs were more efficiently taken up by HepG2 cells compared with HPG-g-CD NPs. These results suggest a feasible application of the mixed copolymer NPs as nanocarriers for hepatoma-targeted delivery of potent antitumor drugs.
Co-reporter:Chao Zheng, Qianqian Guo, Zhongming Wu, Lei Sun, Zhengpu Zhang, Chaoxing Li, Xinge Zhang
European Journal of Pharmaceutical Sciences (16 July 2013) Volume 49(Issue 4) pp:474-482
Publication Date(Web):16 July 2013
DOI:10.1016/j.ejps.2013.04.027
Nasal drug delivery system has been a very promising route for delivery of proteins and peptides for the reason that it can avoid degradation in gastrointestinal tract and metabolism by liver enzymes. However, the bioavailability of proteins and peptides is still low due to the rapid clearance of mucociliary. Here, to prolong the residence time of drugs and improve their absorption, we prepared amphiphilic glycopolymer poly(2-lactobionamidoethyl methacrylate-random-3-acrylamidophenylboronic acid) (p(LAMA-r-AAPBA), and the glycopolymer could assemble into the nanoparticles with narrow size distribution. Insulin, as a model drug, was efficiently encapsulated within the nanoparticles, and loading capacity was up to 12%. In vitro study revealed that the insulin release could be controlled by modifying the composition of glycopolymers. Cell viability showed that p(LAMA-r-AAPBA) nanoparticles had good cytocompatibility. Moreover, the mechanism of nanoparticle internalization into Calu-3 cells was a combination mechanism of clathrin-mediated endocytosis and lipid raft/caveolae-mediated endocytosis. Importantly, there was a significant decrease in the blood glucose levels after the nasal administration of p(LAMA-r-AAPBA) nanoparticles to diabetic rats. Therefore, p(LAMA-r-AAPBA) glycopolymers have a potential application as a nasal delivery systems for proteins and peptides.Download high-res image (109KB)Download full-size image
Co-reporter:Zhongming Wu, Xinge Zhang, Honglei Guo, Chaoxing Li and Demin Yu
Journal of Materials Chemistry A 2012 - vol. 22(Issue 42) pp:NaN22796-22796
Publication Date(Web):2012/09/11
DOI:10.1039/C2JM34082H
Glucose-responsive polymer gels provide an attractive option for the design of a self-regulated insulin delivery system. Here, this paper reported the biocompatibility, glucose-sensitive behavior, and in vivo application of a dispersion of nanogels with three interpenetrating polymer networks of poly(N-isopropylacrylamide), dextran and poly(3-acrylamidophenylboronic acid) (P(NIPAM–Dex–PBA)). The nanogels had an average hydrodynamic radius of about 150 nm, and particle size increased with increasing content of dextran. The swelling behavior of the nanogels at different glucose concentrations revealed definite glucose sensitivity of P(NIPAM–Dex–PBA) particles. Furthermore, the analysis of relative cell proliferation suggested that the nanogels had good biocompatibility with L-929 mouse fibroblast cells. The loading amount of insulin, as a model drug, was up to 16.2%, and the drug release was dependent on the composition of dextran in the particles and the concentration of glucose present in release medium. In vivo experiments revealed that insulin-loaded nanogels decreased the blood glucose levels in diabetic rats and maintained 51% of the baseline level for almost 2 hours. The hypoglycemic effect of the drug-loaded nanogels was similar to that of free insulin after administration. Importantly, the drug-loaded nanogels could keep blood glucose levels stable and avoided blood sugar fluctuations compared with free insulin.
![D-GLUCONAMIDE, N-[2-[(2-METHYL-1-OXO-2-PROPENYL)OXY]ETHYL]-](http://img.cochemist.com/ccimg/498600/498555-04-7.png)
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![D-Gluconamide, 4-O-β-D-galactopyranosyl-N-[2-[(2-methyl-1-oxo-2-propen-1-yl)oxy]ethyl]-](/data/chemimg/104300/566872-06-8.png)
![D-Gluconamide, 4-O-β-D-galactopyranosyl-N-[2-[(2-methyl-1-oxo-2-propen-1-yl)oxy]ethyl]-](/data/chemimg/104300/566872-06-8_b.png)
![(3r,4r,5s,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-[(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-one](http://img.cochemist.com/ccimg/6000/5965-65-1.png)
![(3r,4r,5s,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-[(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-one](http://img.cochemist.com/ccimg/6000/5965-65-1_b.png)
