Co-reporter:Chao Wei;Yan Zhang;Zhongchen Song;Yiru Xia;Heng Xu
Biomaterials Science (2013-Present) 2017 vol. 5(Issue 4) pp:669-677
Publication Date(Web):2017/03/28
DOI:10.1039/C6BM00960C
Stimuli-responsive nanocarriers have been limited for bench-to-bedside translation mainly because the stimuli sensitivity and responsive rate are not high enough to ensure sufficient drug concentration at the target sites for superior therapeutic benefits. Herein, we reported an enhanced bioreduction-responsive and biodegradable nanocarrier based on the amphiphilic poly(ester urethane) copolymers (PAUR-SeSe) bearing multiple diselenide groups on the backbone. The copolymer could spontaneously self-assemble into stable micelles in aqueous medium with an average diameter of 68 nm, which could be rapidly disassembled in a reductive environment as a result of the reduction-triggered cleavage of diselenide groups. Furthermore, the PAUR-SeSe micelles showed an enhanced drug release profile and cellular uptake compared with the disulfide-containing analogue (PAUR-SS). CCK8 assays revealed that the antitumor activity of DOX-loaded PAUR-SeSe micelles was much higher than that of DOX-loaded PAUR-SS micelles. Besides, the blank micelles and degradation products were nontoxic up to a tested concentration of 50 μg mL−1. Therefore, the enhanced therapeutic efficacy and good biocompatibility demonstrated that this drug nanocarrier had great potential for smart antitumor drug delivery applications.
Co-reporter:Yan Xiao;Sihuan Lang;Miaomiao Zhou;Jing Qin;Rui Yin;Jingming Gao;Andreas Heise
Journal of Materials Chemistry B 2017 vol. 5(Issue 3) pp:595-603
Publication Date(Web):2017/01/18
DOI:10.1039/C6TB02507B
A series of biodegradable and crosslinkable precursors based on poly(4-methyl-ε-caprolactone) (PMCL) were prepared by ring-opening polymerization (ROP), followed by the complete acrylation of both hydroxyl ends. Afterwards, biodegradable networks exhibiting totally amorphous character were obtained via photocrosslinking without organic solvent or high temperature. As a result, their mechanical properties varied significantly from brittle to elastic upon increasing the length of the PMCL precursors. Both covalent crosslinking and trapped entanglements between crosslinking segments were likely to contribute to the unique properties of the bioelastomer. In particular, networks formed by the precursors with large molecular weights presented high flexibility and resilience, which match the mechanical properties of soft tissues like blood vessels, bladder and cardiovascular tissue. Preliminary degradation and in vitro cytotoxicity studies of the crosslinked network showed excellent biodegradability and biocompatibility. Moreover, it was demonstrated that the liquid-like PMCL precursor made the patterning easily processable even in the absence of any solvent or heating.
Co-reporter:Jun Zhang;Yan Xiao;Xueli Luo;Lianlei Wen;Andreas Heise
Polymer Chemistry (2010-Present) 2017 vol. 8(Issue 21) pp:3261-3270
Publication Date(Web):2017/05/30
DOI:10.1039/C7PY00461C
Double hydrophilic block copolymers (DHBCs) based on poly(ε-caprolactone)s, poly(6-acetoxyl-ε-caprolactone)-b-poly(4-N-piperilactone) (PCCL-b-PPIL), were synthesized via ring-opening polymerization and deprotection. The self-assembly behaviour of these block copolymers in aqueous solutions was thoroughly explored via a combination of UV-vis spectroscopy, zeta potential measurement, 1H NMR spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). It was observed that “schizophrenic” aggregations were formed and triggered by pH, i.e., the copolymers could self-assemble into PCCL-core micelles at acidic pH and PPIL-core micelles at alkaline pH. In addition, pendant groups in each block of copolymers facilitated further chemical modification with fluorescent dyes such as 1-(hydroxymethyl)pyrene and FITC. The fluorescence properties of pyrene-functionalized copolymers were closely related to their aggregate morphology, which could be adjusted simply by altering the environmental pH values. Meanwhile, it is expected that this novel type of degradable schizophrenic block copolymer holds potential application in stimuli-responsive fluorescent probes.
Co-reporter:Yixing Dai, Shuo Wang, Weibin Shi, Meidong Lang
Carbohydrate Polymers 2017 Volume 176(Volume 176) pp:
Publication Date(Web):15 November 2017
DOI:10.1016/j.carbpol.2017.08.011
•CPA micelles would aggregate to 300–350 nm at pH 6.4.•The release rate could be regulated by altering grafting ratio of CMCS-g-PCL.•The release rate of CPA micelles at pH 6.4 was faster than pH 7.4.•CPA micelles showed a significant inhibitory effect on HUVECs proliferation.In this study, carboxymethyl chitosan-graft-poly-(ε-caprolactone) copolymers (CMCS-g-PCL) were synthesized and used to encapsulate apatinib to prepare apatinib-loaded CMCS-g-PCL (CPA) micelles. CPA micelles’ sizes were 100–150 nm at pH 7.4 while aggregated to 300–350 nm at pH 6.4, and the release rate at pH 6.4 was faster than pH 7.4, indicating CPA micelles have a pH-responsive activity. Furthermore, the release rate decreased with an increased grafting ratio of CMCS-g-PCL, which was shown by the results of release experiments from CPA-2 to CPA-10 micelles. A series of cell experiments demonstrated that blank micelles were non-toxic for human umbilical endothelial cells (HUVECs) below 0.125 mg/ml, CPA micelles had significant inhibiting effect on HUVECs as IC50 was near 3.125 μg/ml, and the drug effect could be adjusted by altering grafting ratio of CMCS-g-PCL. These results suggest that CPA micelles may be used as an effective drug delivery system for anti-angiogenesis cancer therapy.
Co-reporter:Yunlong Sun;Changlin Chen;Heng Xu
Journal of Inorganic and Organometallic Polymers and Materials 2017 Volume 27( Issue 5) pp:1351-1364
Publication Date(Web):30 May 2017
DOI:10.1007/s10904-017-0589-6
Nano-sized silica particles (SiO2 NPs) of 30 ± 5 nm were modified by the coupling agent of triethoxyvinylsilane and polymer 4-vinyl pyridine (P4VP) was “grafted” onto the surface of modified SiO2 NPs by adopting the “grafting from” way. Then, the P4VP brush of SiO2 NPs was quaternized by ethyl bromoacetate, iodoethane, 3-bromopropionic acid and 1,3-propanesulfonate to obtain four water-insoluble, functional and novel organic–inorganic silica nanocomposites (SiO2/P4VP-eb, SiO2/P4VP-ie, SiO2/P4VP-bpa and SiO2/P4VP-psl), respectively. The antibacterial performance of four functional silica nanocomposites above was investigated by using Escherichia coli ATTC25922 as model bacterium via the colony count method. When the sterilizing ratios of SiO2/P4VP-psl, SiO2/P4VP-bpa, SiO2/P4VP-eb and SiO2/P4VP-ie against E. coli with bacterium age of 4 h (OD600 nm = 2.5) reached 100%, the critical concentration value was 3, 5, 12 and 11 mg/mL, respectively. The results showed that although four functional silica nanocomposites all possessed excellent antibacterial ability, zwitterionic silica nanocomposites (SiO2/P4VP-psl, SiO2/P4VP-bpa) possessed stronger antibacterial ability than cationic silica nanocomposites (SiO2/P4VP-eb, SiO2/P4VP-ie).
Co-reporter:Yan Zhang, Ying Xu, Chao Wei, Yuanying Zhang, Liu Yang, Zhongchen Song, Meidong Lang
Materials Today Chemistry 2017 Volume 4(Volume 4) pp:
Publication Date(Web):1 June 2017
DOI:10.1016/j.mtchem.2017.03.004
•The poly(ε-caprolactone)-based hydrogels were endowed with oxidation and reduction-triggered degradation by the introduction of diselenide groups.•The drug release behaviour of hydrogels could be well controlled in a H2O2 or GSH concentration-dependent manner.•The phase transition temperature of the hydrogels was dependent on the composition and the aqueous concentration of the copolymers.•The hydrogels have excellent mechanical properties.Herein, novel multi-responsive injectable polyester hydrogels were reported based on the diselenide-containing poly(ε-caprolactone) copolymers ((mPEG-PCL-Se)2). The (mPEG-PCL-Se)2 solution remained a free-flowing state at ambient temperature but spontaneously turned into a semisolid hydrogel upon heating to physiologic temperature. The phase transition temperature was examined to be dependent on the composition and aqueous concentration of the copolymers. More importantly, the thermo-responsive hydrogels were endowed with oxidation and reduction-triggered degradation by the incorporation of diselenide groups. Accordingly, the degradation of poly(ε-caprolactone)-based hydrogels was greatly improved and the rate of degradation was well regulated by the concentration of hydrogen peroxide (H2O2) or glutathione (GSH). This superior stimuli-responsive degradation could lead to an enhanced drug release of encapsulated drug (Doxorubicin, DOX). Thus the oxidation and reduction-triggered degradable diselenide-containing poly(ε-caprolactone) hydrogels would offer great potential for the controlled drug delivery.Novel Diselenide-containing poly(ε-caprolactone)-based hydrogels were prepared and an accelerated degradation was observed at H2O2 or GSH in a concentration-dependent manner.Download high-res image (383KB)Download full-size image
Co-reporter:Yunlong Sun, Changlin Chen, Heng Xu, Kun Lei, Guanzhe Xu, Li Zhao, Meidong Lang
Applied Surface Science 2017 Volume 419(Volume 419) pp:
Publication Date(Web):15 October 2017
DOI:10.1016/j.apsusc.2017.05.016
•Functional, novel silicon wafer grafted by zwitterionic polymer (P4VP-psl) based on the poly(4-vinylpyridine) was prepared for the first time.•The surface chemical structure characterization of functional Si-P4VP-psl substratewas tested fully.•The excellent antifouling property of functional Si-P4VP-psl substrate was studied by Escherichia coli (E. coli), mononuclear macrophages (RAW 264.7) and bovine serum albumin.Silicon (111) wafer was modified by triethoxyvinylsilane containing double bond as an intermedium, and then P4VP (polymer 4-vinyl pyridine) brush was “grafted” onto the surface of silicon wafer containing reactive double bonds by adopting the “grafting from” way and Si-P4VP substrate (silicon wafer grafted by P4VP) was obtained. Finally, P4VP brush of Si-P4VP substrate was modified by 1,3-propanesulfonate fully to obtain P4VP-psl brush (zwitterionic polypyridinium salt) and the functional Si-P4VP-psl substrate (silicon wafer grafted by zwitterionic polypyridinium salt based on polymer 4-vinyl pyridine) was obtained successfully. The antifouling property of the silicon wafer, the Si-P4VP substrate and the Si-P4VP-psl substrate was investigated by using bovine serum albumin, mononuclear macrophages (RAW 264.7) and Escherichia coli (E. coli) ATTC25922 as model bacterium. The results showed that compared with the blank sample-silicon wafer, the Si-P4VP-psl substrate had excellent anti-adhesion ability against bovine serum albumin, cells and bacterium, due to zwitterionic P4VP-psl brush (polymer 4-vinyl pyridine salt) having special functionality like antifouling ability on biomaterial field.Download high-res image (176KB)Download full-size image
Co-reporter:Chao Wei, Yan Zhang, Heng Xu, Ying Xu, Yue Xu and Meidong Lang
Journal of Materials Chemistry A 2016 vol. 4(Issue 29) pp:5059-5067
Publication Date(Web):05 Jul 2016
DOI:10.1039/C6TB01040G
Well-defined diselenide-centered biodegradable tri-block copolymers methoxyl poly(ethylene glycol)-b-poly(ε-caprolactone)-b-methoxyl poly(ethylene glycol) (mPEG–PCL–Se)2 were precisely synthesized by the combination of ring opening polymerization using di(1-hydroxyethylene) diselenide as a new initiator and a facile coupling reaction. The amphiphilic block copolymers enabled the formation of self-assembled micelles which revealed an excellent reductive response to glutathione (GSH) due to the unique reduction-responsive cleavage of the diselenide bond. Such GSH response ensured an enhanced release of anticancer drugs (DOX) from the micelles in simulative tumor microenvironments; moreover, the drug release could be changed to some extent through fine-tuning the chemical composition of the copolymers. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements confirmed that the DOX-loaded micelles could be efficiently taken up by oral squamous carcinoma (HN30) cells and DOX was released into the nuclei of cancer cells following 4 h of incubation. The cell viability assays showed the diselenide-containing polymers were nontoxic up to a tested concentration (400 μg mL−1), while the DOX-loaded micelles exhibited an evident inhibition toward HN30 cells. Therefore, the reduction-labile biodegradable (mPEG–PCL–Se)2 may offer an alternative platform for tumor-targeting therapy.
Co-reporter:Yan Zhang, Xiaolin Du, Dan Hu, Jing Zhang, Yan Zhou, Guoquan Min, and Meidong Lang
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 12) pp:7720
Publication Date(Web):March 7, 2016
DOI:10.1021/acsami.6b01361
Surface chemistry and substrate topography could contribute significantly to providing a biochemical and topographical cues for governing the fate of cells on the cell–material interface. However, the synergies between these two properties have not been exploited extensively for biomaterial design. Herein, we achieved spatial-controlled patterning of chemical groups on the poly(ε-caprolactone) (PCL) surface by elegant UV-nanoimprint lithography (UN-NIL). The introduction of chemical groups on the PCL surface was developed by our newly 6-benzyloxycarbonylmethyl-ε-caprolactone (BCL) monomer, which not only solved the lack of functional groups along the PCL chain but also retained the original favorable properties of PCL materials. The synergetic effect of the chemical groups and nanopatterns on the human foreskin fibroblasts (HFFs) behaviors was evaluated in detail. The results revealed that the patterned functional PCL surfaces could induce enhanced cell adhesion and proliferation, further trigger changes in HFFs morphology, orientation and collagen secretion. Taken together, this study provided a method for straightforward fabrication of reactive PCL surfaces with topographic patterns by one-step process, and they would facilitate PCL as potential candidate for cell cultivation and tissue engineering.Keywords: cell behaviors; nanopattern; poly(ε-caprolactone); surface chemistry; UV-nanoimprint
Co-reporter:Jun Zhang, Yan Xiao, Heng Xu, Chen Zhou and Meidong Lang
Polymer Chemistry 2016 vol. 7(Issue 28) pp:4630-4637
Publication Date(Web):14 Jun 2016
DOI:10.1039/C6PY00932H
The introduction of reactive groups such as –NH2, –COOH etc. onto a poly(ε-caprolactone) (PCL) backbone was necessary for further modification but a well-controlled approach remains a challenge for synthetic chemistry. Carboxyl functionalized PCL was typically prepared via three steps involving the synthesis of the corresponding monomer with a carboxyl-protecting group, polymerization and the removal of the protection. Except for obtaining purified monomers and a decent polymerization, the most critical step in carboxyl PCL synthesis was the deprotection from the degradable main chain. Therefore, electronic effects and steric hindrance of the protecting group were taken into account with the aim for controllable polymerization and feasible deprotection. Substituents including –CH3, H and NO2 with discriminative electronegativity on the para position of the benzyl protecting group have been selected to investigate their behavior in monomer preparation, polymerization and deprotection, respectively. It turned out that the electron donating group (–CH3) displayed the highest selectivity in the monomer preparation, excellent control over the polymerization degree and the most efficient removal of the protecting groups without degradation of the backbone. In addition, the reactivity of the pendant carboxyl groups on PCL was demonstrated by amidation with 4-amino-2,2,6,6-tetramethylpiperidinyloxy (4-amino-TEMPO). Our results also provide guidance information on preparing well-defined biodegradable polymers with pendant reactive groups such as polypeptides, expanding the library of novel biomaterials.
Co-reporter:Xiaofei Ma, Yan Xiao, Heng Xu, Kun Lei, Meidong Lang
Materials Science and Engineering: C 2016 Volume 66() pp:92-99
Publication Date(Web):1 September 2016
DOI:10.1016/j.msec.2016.04.072
•Ciprofloxacin-eluting ureteral stents were prepared by the dipping method.•Degradation and release profiles were tailored by altering the copolymer composition.•The release mechanism at stage I was mainly controlled by chain scission of PLCL.•The release profile at stage II was dominated by an erosion-controlled mechanism.•CIP-loaded PLCL coatings showed well resistance against E. coli and S. aureus.Drug-eluting stents with biodegradable polymers as reservoirs have shown great potential in the application of interventional therapy due to their capability of local drug delivery. Herein, poly(l-lactide-co-ε-caprolactone) (PLCL) with three different compositions as carriers for ciprofloxacin lactate (CIP) was coated on ureteral stents by the dipping method. To simulate a body environment, degradation behavior of PLCL as both the bulk film and the stent coating was evaluated in artificial urine (AU, pH 6.20) respectively at 37 °C for 120 days by tracing their weight/Mn loss, water absorption and surface morphologies. Furthermore, the release profile of the eluting drug CIP on each stent exhibited a three-stage pattern, which was greatly affected by the degradation behavior of PLCL except for the burst stage. Interestingly, the degradation results on both macroscopic and molecular level indicated that the release mechanism at stage I was mainly controlled by chain scission instead of the weight loss or morphological changes of the coatings. While for stage II, the release profile was dominated by erosion resulting from the hydrolysis reaction autocatalyzed by acidic degradation residues. In addition, ciprofloxacin-loaded coatings displayed a significant bacterial resistance against E. coli and S. aureus without obvious cytotoxicity to Human foreskin fibroblasts (HFFs). Our results suggested that PLCL copolymers with tunable degradation rate as carriers for ciprofloxacin lactate could be used as a promising long-term antibacterial coating for ureteral stents.
Co-reporter:Yan Zhang;Miao Wang;Jinhai Ye
Journal of Polymer Science Part A: Polymer Chemistry 2016 Volume 54( Issue 16) pp:2571-2581
Publication Date(Web):
DOI:10.1002/pola.28134
ABSTRACT
Novel poly(ε-caprolactone)-b-poly(ethylene glycol)-b-poly(ε-caprolactone) (PCL-PEG-PCL) bearing pendant hydrophobic γ-(carbamic acid benzyl ester) groups (PECB) and hydrophiphilic amino groups (PECN) were synthesized based on the functionalized comonomer γ-(carbamic acid benzyl ester)-ε-caprolactone (CABCL). The thermal gelation behavior of the amphiphilic copolymer aqueous solutions was examined. The phase transition behavior could be finely tuned via the pendant groups, and an abnormal phenomenon occurred that the sol–gel transition temperature shifted to a higher temperature for PECB whereas a lower temperature for PECN. The micelles percolation was adopted to clarify the hydrogel mechanism, and the effect of the pendant groups on the micellization was further investigated in detail. The results demonstrated that the introduction of γ-(carbamic acid benzyl ester) pendant groups significantly decreased the crystallinity of the copolymer micelles whereas amino pendant groups made the micelles easy to aggregate. Thus, the thermal gelation of PEG/PCL aqueous solution could be finely tuned by the pendant groups, and the pendant groups modified PEG/PCL hydrogels are expected to have great potential biomedical application. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 2571–2581
Co-reporter:Zhengzhen Du, Yan Zhang, Heng Xu and Meidong Lang
Journal of Materials Chemistry A 2015 vol. 3(Issue 18) pp:3685-3694
Publication Date(Web):09 Apr 2015
DOI:10.1039/C5TB00196J
Novel nanocarriers for paclitaxel (PTX) were developed based on Pluronic-b-poly(ε-caprolactone) bearing pendant benzyl-oxycarbonylmethyl (BOM) groups and carboxyl groups (Pluronic-b-P(CL-co-BCL), FB)/(Pluronic-b-P(CL-co-CCL), FC). The formation and the physicochemical properties of paclitaxel-loaded polymeric micelles, including FB/PTX micelles and FC/PTX micelles, were investigated by various methods. The results demonstrated that paclitaxel was amorphous in the micellar core and the micelles were on nanoscale. Besides the hydrophobic–hydrophobic interaction in both micelles, there was π–π interaction in the FB/PTX micelles while hydrogen bonding interaction existed in the FC/PTX micelles. Thus the different interaction between the drug and the polymer endowed the polymers with different binding forces which determined the various properties of the nanocarriers. The comparative study revealed that the compatibility was improved due to the introduction of the pendant groups according to the calculation based on the Flory–Huggins interaction parameter (χdc). The two nanocarriers also displayed high encapsulation efficiency, which could reach 88.61 ± 5.33% and 90.7 ± 2.08%, and they could also provide a continuous and sustained in vitro PTX release and the release half time was greatly enhanced in comparison with commercial Taxol®. Furthermore, the in vitro anti-tumor efficiency revealed that the FC PTX-loaded micelles had the best anti-tumor activity against C6 glioma cells inducing cell apoptosis and the in vitro blood compatibility and the in vivo long-circulation characteristics were well retained for the FB and FC PTX-loaded micelles in comparison with the original Pluronic-b-PCL. Therefore, these findings indicated that the functionalized Pluronic-b-poly(ε-caprolactone) micelles would be efficient nanocarriers for paclitaxel.
Co-reporter:Hong Liu, Yan Xiao, Heng Xu, Yebin Guan, Jun Zhang and Meidong Lang
Chemical Communications 2015 vol. 51(Issue 50) pp:10174-10177
Publication Date(Web):13 May 2015
DOI:10.1039/C5CC03017J
Rationally designed polypeptides with similar molecular structures but varying patterns of hydrogen bonding between the side groups have been synthesized and demonstrated to possess distinct solubility and thermal behaviors. Further balancing the ratio of both isopropylamine and ethylenediamine side groups endows the random copolymer with reversible thermo-sensitivity.
Co-reporter:Chunhua Gu, Huan Zhang, Meidong Lang
Applied Surface Science 2014 Volume 301() pp:273-279
Publication Date(Web):15 May 2014
DOI:10.1016/j.apsusc.2014.02.059
Highlights
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Chemical modification of chitosan were conducted after phthaloyl protection of amino groups.
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Silver nanoparticles were prepared in the presence of chitosan-based copolymer micelles.
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The optimal time scale and weight ratios of silver to micelles were monitored by UV–vis spectrometer.
Co-reporter:Yutong Fu;Xinyu Xia;Yan Zhang;Jinhai Ye
Colloid and Polymer Science 2014 Volume 292( Issue 9) pp:2071-2082
Publication Date(Web):2014 September
DOI:10.1007/s00396-014-3261-5
Functional star-shaped 4-arm poly(ethylene glycol)-b-poly[(ε-caprolactone-co-γ-amino-ε-caprolactone)] (4-arm PEG-b-P(CL-co-ACL) was synthesized through ring-opening polymerization. The structure of the copolymer was confirmed by 1H NMR, Fourier transform infrared spectroscopy (FTIR), and gel permeation chromatography (GPC). To further understand the copolymers, the difference of the conversion rate between ε-caprolactone (CL) and γ-(carbamic acid benzyl ester)-ε-caprolactone (CABCL) and the detailed deprotection condition were studied. The thermal property of the copolymer was analyzed by WAXR and differential scanning calorimetry (DSC), which demonstrated that the thermal property could be well adjusted. The pH-responsive behavior of the copolymers was studied in detail by dynamic light scattering (DLS), pH titration, and pyrene fluorescence methods, which indicated that it could form micelles and exhibit pH responsibility. Moreover, the copolymer was nontoxic and had good biocompatibility according to the results by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay.
Co-reporter:Yan Zhang;Jinhong Li;Zhengzhen Du
Journal of Polymer Science Part A: Polymer Chemistry 2014 Volume 52( Issue 2) pp:188-199
Publication Date(Web):
DOI:10.1002/pola.26987
ABSTRACT
pH-responsive methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) bearing pendant carboxyl groups mPEG-b-P(2-CCL-co-6-CCL) was synthesized based on our newly monomer benzyloxycarbonylmethly functionalized ε-caprolactone. Their structure was confirmed by 1H NMR, 13C NMR, and Fourier transform infrared spectrum spectra. In addition, SEC results indicated that the copolymers had a relatively narrow polydispersity. WXRD and DSC demonstrated that the introduction of carboxymethyl groups had significant effect on the crystallinity of the copolymers. Furthermore, the solution behavior of mPEG-b-P(2-CCL-co-6-CCL) has been studied by various methods. The results indicated that mPEG-b-P(2-CCL-co-6-CCL) had a rich pH-responsive behavior and the micelles could be formed by pH induction, and the mPEG-b-P(2-CCL-co-6-CCL) could existed as unimers, micelles or large aggregates in different pH range accordingly. The mechanism of which was supposed to depend on the counteraction between the hydrophobic interaction from PCL and the ionization of the carboxyl groups along the polymer chain. Moreover, the mPEG-b-P(2-CCL-co-6-CCL) copolymers displayed good biocompatibility according to the preliminary cytotoxicity study. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 188–199
Co-reporter:Weibin Shi, Chunhua Gu, Han Jiang, Mengru Zhang, Meidong Lang
Materials Science and Engineering: C 2014 Volume 45() pp:502-509
Publication Date(Web):1 December 2014
DOI:10.1016/j.msec.2014.09.020
•The improvement of bulk hydrophilicity better accelerated drug release.•The higher weight ratio of CP implants had, the faster the drug released.•The shorter PCL chain in CP graft coploymers, the faster the drug released.•The optimum additive amount was 25% with CP9.•Drug release profile conformed to controllable Fick diffusional release mechanism.Bioresorbable polymer stents have been proposed as promising medical implants to avoid long-term safety concerns and other potential issues caused by traditional materials. As an important member, poly(ε-caprolactone) (PCL) was used as the implant matrix with different drug loadings. To better regulate drug release rate, the hydrophilicity of PCL was adjusted by addition of amphiphilic graft copolymers, chitosan-g-poly(ε-caprolactone) (CP). The in vitro release results indicated that the improvement of bulk hydrophilicity could accelerate drug release better than that of surface coating. The optimum additive amount was 25% with CP9. Further study showed that the effect of aspirin molecules displayed no obvious difference to that of CP macromolecules on drug release rate. Moreover, these release profiles were fitted with mathematical models. The similarities were evaluated with similarity factors. Scanning electron microscopy (SEM) images displayed surface/cross-section morphologies of pure PCL and modified implants before and after release.
Co-reporter:Yan Zhang, Yi Zhang, Min Chen, Yan Zhou, Meidong Lang
Materials Science and Engineering: C 2014 Volume 41() pp:52-58
Publication Date(Web):1 August 2014
DOI:10.1016/j.msec.2014.03.059
•The specific recognition between the galactose ligands on the galactosylated poly(ε-caprolactone) membrane and the ASGPR on the HepG2 cell surface.•The galactosylated poly(ε-caprolactone) membranes improved the cell-matrix interaction.•The galactosylated functionalized PCL scaffold is a potential candidate for liver tissue engineering.The lack of pendant functional groups on the PCL backbone has been a great challenge for surface bioactivation of poly(ε-caprolactone) (PCL). In the present study, covalently galactosylated PCL (GPCL) was developed through coupling between the amino-functionalized PCL (NPCL) and the lactobionic acid (LA) and its potential application in maintenance of physiological functions of HepG2 cells was further evaluated. The structure and properties of GPCL were explored by 1H NMR, FT-IR, GPC and DSC. Moreover, the incorporation of galactose ligands onto GPCL membranes not only promoted higher wettability, but also radically changed surface morphology in comparison with PCL and NPCL according to the contact angle measurement and atomic force microscopy. When HepG2 cells were seeded onto these membranes, the cells on GPCL membranes showed more pronounced cell adhesion and tended to form aggregates during the initial adhesion stage and then progressively grew into multi-layer structures compared to those without galactose ligands by the observation with fluorescence microscope and scanning electron microscopy. Furthermore, live–dead assay and functional tests demonstrated that HepG2 cells on GPCL membranes had superior viability and maintained better liver-specific functions. Collectively, GPCL has great potential for hepatic tissue engineering scaffolds.The specific recognition between the galactose ligands on the galactosylated poly(ε-caprolactone) membrane and the ASGPR on the HepG2 cell surface. The galactosylated poly(ε-caprolactone) membranes improved the cell-matrix interaction. The galactosylated functionalized PCL scaffold is a potential candidate for liver tissue engineering.
Co-reporter:Ming Yuan, Yan Xiao, Vanminh Le, Chao Wei, Yutong Fu, Jianwen Liu, Meidong Lang
Colloids and Surfaces A: Physicochemical and Engineering Aspects 2014 Volume 457() pp:116-124
Publication Date(Web):5 September 2014
DOI:10.1016/j.colsurfa.2014.04.062
•Flory–Huggins interaction parameter was used to reckon the drug–polymer affinity.•With CAB groups pending on PCL, copolymer showed enhanced 5-FU-polymer affinity.•mPEG-b-PCL copolymer with CAB groups pending (100% substitution) was synthesized.•A 5-FU micelle carrier superior to micelle prepared by mPEG-b-PCL was developed.•Tailored pendant groups on PCL lead to optimal drug loading and release behavior.Flory–Huggins interaction parameter (χpd) was introduced to qualitatively evaluate the drug–polymer compatibility between hydrophilic 5-fluorouracil (5-FU) and hydrophobic core block, which was formed by poly[γ-(carbamic acid benzyl ester)-ɛ-caprolactone] (PCABCL) and poly(ɛ-caprolactone) (PCL). The calculation results indicated that PCABCL had better affinity with 5-FU than PCL. Thus, a series of diblock polymers monomethoxy poly(ethylene glycol)-b-poly[γ-(carbamic acid benzyl ester)-ɛ-caprolactone] (mPEG45-b-PCABCLn) was synthesized, followed by the preparation of 5-FU loaded micelles. The introduction of γ-(carbamic acid benzyl ester) (CAB) group significantly decreased the crystallinity of copolymers and increased the hydrophilicity of the micellar core, leading to an improved drug loading content. These micelles had high stability and spherical morphology. The release behavior could be turned by the length of core-forming block. Moreover, micelles prepared by mPEG45-b-PCABCL19 displayed the highest 5-FU loading content and the most controlled release behavior. These blank micelles showed very low toxicity against HCT116 cancer cells. Meanwhile 5-FU loaded micelles exhibited a concentration dependent increase in HCT116 cell death by inducing cell apoptosis in vitro. These results indicated that these micelles have great potential in cancer therapy.Non-covalent bonding, such as hydrogen bonding interaction, polarity attraction, π–π interaction, etc., is widely existed between carriers and drugs. The presence of these forces is a vigorous supplement to hydrophobic interaction, which has great influence on drug loading and release behavior.
Co-reporter:Qingchun Zhang, Ke Tan, Yan Zhang, Zhaoyang Ye, Wen-Song Tan, and Meidong Lang
Biomacromolecules 2014 Volume 15(Issue 1) pp:
Publication Date(Web):November 22, 2013
DOI:10.1021/bm401309u
In tissue engineering, incorporation of bone morphogenetic protein-2 (BMP-2) into biomaterial scaffolds is an attractive strategy to stimulate bone repair. However, suboptimal release of BMP-2 remains a great concern, which may cause unfavorable bone formation as well as severe inflammation. In this study, genipin-cross-linked gelatin entrapped with recombinant human BMP-2 (rhBMP-2) was exploited to decorate the interior surface of three-dimensional porous poly(ε-caprolactone) (PCL) scaffolds. With gelatin-coating, PCL scaffolds demonstrated enhanced water uptake and improved compressive moduli. Intriguingly, a unique release profile of rhBMP-2 composed of a transient burst release followed by a sustained release was achieved in coated scaffolds. These coated scaffolds well supported growth and osteogenesis of human mesenchymal stem cells (hMSCs) in vitro, indicating the retaining of rhBMP-2 bioactivity. When hMSCs-seeded scaffolds were implanted subcutaneously in nude mice for 4 weeks, better bone formation was observed in gelatin/rhBMP-2-coated scaffolds. Specifically, the spatial distribution of newly formed bone was more uniform in gelatin-coated scaffolds than in uncoated scaffolds, which displayed preferential bone formation at the periphery. These results collectively demonstrated that gelatin-coating of porous PCL scaffolds is a promising approach for delivering rhBMP-2 to stimulate improved bone regeneration.
Co-reporter:Yan Zhang, Jianjing Liu, Yutong Fu, Ke Tan, Zhaoyang Ye and Meidong Lang
Journal of Materials Chemistry A 2013 vol. 1(Issue 11) pp:1614-1621
Publication Date(Web):14 Jan 2013
DOI:10.1039/C3TB00012E
A novel polyion complex (PIC) drug carrier was developed via electrostatic self-assembly in aqueous media based on our previous copolymer methoxy poly(ethylene glycol)-b-poly(γ-amino-ε-caprolactone) (mPEG-b-PACL) and anti-hepatotoxic drug ammonium glycyrrhizinate (AMG). The formation and the physicochemical properties of the polyion complex nanoparticles in aqueous solution were investigated by various methods. The results demonstrated that AMG was encapsulated successfully and the nanoparticles had a core–shell or tri-layer spherical structure based on the length of the PACL. The AMG/PACL PIC also displayed a high loading capacity and encapsulation efficiency of up to 41.8% and 91.7%, respectively. Furthermore, the nanoparticles enabled a continuous and sustained in vitro AMG release and the release half time was about 3 times that of the free AMG's. Results obtained by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and fluorescence microscopy revealed that AMG loaded nanoparticles demonstrated greater prevention of liver cell apoptosis induced by lipopolysaccharide (LPS). These findings indicated that methoxy poly(ethylene glycol) (mPEG)-b-poly(γ-amino-ε-caprolactone) could be an efficient AMG carrier and could even be used as a delivery template for some other negatively charged water-soluble drugs or gene delivery systems.
Co-reporter:Tianyi Wu, Qingchun Zhang, Weiping Ren, Xiang Yi, Zubin Zhou, Xiaochun Peng, Xiaowei Yu and Meidong Lang
Journal of Materials Chemistry A 2013 vol. 1(Issue 26) pp:3304-3313
Publication Date(Web):30 Apr 2013
DOI:10.1039/C3TB20261E
Infection of the bone (osteomyelitis) remains one of the most challenging problems in the field of orthopedic surgery. The limitations of systemic antibiotics administration include undesired side effects, systemic toxicity, patient discomfort, and development of bacterial resistance. In this study, we developed a bactericidal gentamicin-doped beta-tricalcium phosphate (TCP) scaffold reinforced with a gelatin/genipin hydrogel (G-TCP). Our data showed that the gentamicin-doped G-TCP had a much longer drug releasing period, while the gentamicin was completely released from pure TCP cements (B-TCP) within one day. In addition, the release profile of G-TCP exhibited an initial burst followed by a zero-order release. One standard strain, Staphylococcus aureus (S. aureus, ATCC25923) was selected to evaluate the antibacterial activity and therapeutic effect of this scaffold. G-TCP significantly inhibited growth of S. aureus both in vitro and in vivo. In a rat osteomyelitis model, osteomyelitis could be totally cured after implantation of G-TCP for three weeks. We propose that the gelatin/genipin–gentamicin TCP scaffold represents one of the promising gentamicin releasing bone scaffolds in treating osteomyelitis.
Co-reporter:Qingchun Zhang, Yun Jiang, Yan Zhang, Zhaoyang Ye, Wensong Tan, Meidong Lang
Polymer Degradation and Stability 2013 Volume 98(Issue 1) pp:209-218
Publication Date(Web):January 2013
DOI:10.1016/j.polymdegradstab.2012.10.008
Porous poly(ε-caprolactone) (PCL) scaffolds are widely used as in vivo implants in tissue engineering, and their long-term degradation behaviors are of great importance for their in vivo performances. However, the influence of porosity on long-term degradation of PCL scaffold in phosphate buffer solution (PBS) has been rarely reported so far. Herein, a 72-week degradation study of PCL scaffolds with various porosities was conducted to elucidate the changes of physico-chemical properties such as weight, molecular weight, morphology and compressive modulus. Within 72 weeks, PCL scaffolds experienced three stages: stable stage, mechanical loss stage and structural collapse stage. The higher porosity induced the severer loss of weight, molecular weight and compressive modulus. It was found that a minimal acid autocatalysis also happened in the scaffold samples with low porosities (less than 85%). Cellular response on the scaffolds with various porosities was further evaluated. The cell ingrowth improved on the scaffold with high porosity (e.g. S-10) in contrast to those with low porosity (e.g. S-6 and S-4). The combined results demonstrated that an optimal porosity of PCL scaffolds should be designed greater than 90% due to the appropriate degradation rate and good cell performance.
Co-reporter:Chunhua Gu;Huiyan Gu
Macromolecular Theory and Simulations 2013 Volume 22( Issue 7) pp:377-384
Publication Date(Web):
DOI:10.1002/mats.201300109
Binary blend compatibility of chitosan (CS) and poly(ϵ-caprolactone) (PCL) was simulated at different blending ratios in molecular and mesoscopic level. In molecular simulation, Flory–Huggins interaction parameters and mixing enthalpies were calculated to estimate the blend compatibility. Results showed that compatibility of CS/PCL blends reduced with increase of PCL content. Plots of free energy density and order parameter versus time step were used to illustrate system equilibrium and blend stability. When PCL content increased to 50%, a wide density spectrum were observed. Furthermore, experiments were carried out to make a comparison. DSC and SEM results showed the similar blending trend that better compatibility was achieved when CS content increased, which certificated molecular modeling conclusions.
Co-reporter:Chunhua Gu;Weibin Shi
Journal of Polymer Science Part B: Polymer Physics 2013 Volume 51( Issue 8) pp:659-667
Publication Date(Web):
DOI:10.1002/polb.23237
Abstract
Blends of chitosan and poly(ε-caprolactone-co-2-oxepane-1,5-dione) (PCO) were fabricated by solvent casting technique using 77% acetic acid as the cosolvent. The interactions between chitosan and PCO were analyzed by Fourier transform infrared spectroscopy, nuclear magnetic resonance, and differential scanning calorimetry. The miscibility became poorer with increase of PCO from 50% to 75%, which was supported by the Flory–Huggins interaction parameter and crystallinity of PCO. According to X-ray pattern, crystallinity of CS became weaker when PCO content was improved. Results indicated that there existed stronger interactions in comparison with PCL/CS blends. Therefore, the addition of functional polyester PCO made the brittle chitosan ductile. The elongation was significantly prolonged to 21.60 ± 4.92% with the break stress maintaining about 32 MPa, better than that of PCL blends. The degradation behavior showed slower degradation rate compared with pure CS and the morphology was illustrated by scanning electron microscopy. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2013
Co-reporter:Qingchun Zhang, Houyong Luo, Yan Zhang, Yan Zhou, Zhaoyang Ye, Wensong Tan, Meidong Lang
Materials Science and Engineering: C 2013 Volume 33(Issue 4) pp:2094-2103
Publication Date(Web):1 May 2013
DOI:10.1016/j.msec.2013.01.025
The physical properties of tissue engineering scaffolds such as microstructures play important roles in controlling cellular behaviors and neotissue formation. Among them, the pore size stands out as a key determinant factor. In the present study, we aimed to fabricate porous scaffolds with pre-defined hierarchical pore sizes, followed by examining cell growth in these scaffolds. This hierarchical porous microstructure was implemented via integrating different pore-generating methodologies, including salt leaching and thermal induced phase separation (TIPS). Specifically, large (L, 200–300 μm), medium (M, 40–50 μm) and small (S, < 10 μm) pores were able to be generated. As such, three kinds of porous scaffolds with a similar porosity of ~ 90% creating pores of either two (LS or MS) or three (LMS) different sizes were successfully prepared. The number fractions of different pores in these scaffolds were determined to confirm the hierarchical organization of pores. It was found that the interconnectivity varied due to the different pore structures. Besides, these scaffolds demonstrated similar compressive moduli under dry and hydrated states. The adhesion, proliferation, and spatial distribution of human fibroblasts within the scaffolds during a 14-day culture were evaluated with MTT assay and fluorescence microscopy. While all three scaffolds well supported the cell attachment and proliferation, the best cell spatial distribution inside scaffolds was achieved with LMS, implicating that such a controlled hierarchical microstructure would be advantageous in tissue engineering applications.Highlights► The scaffolds with dual-pore and triple-pore structures were fabricated. ► Triple-pore structure had better interconnectivity than dual-pore structures. ► Better cell migration and distribution were found on the triple-pore structures. ► The medium pore size (45–50 μm) was appropriate for cell migration. ► Scaffolds with triple-pore structure should be advantageous in tissue engineering.
Co-reporter:Yan Zhang;Li Zhao;Min Chen
Colloid and Polymer Science 2013 Volume 291( Issue 7) pp:1563-1571
Publication Date(Web):2013 July
DOI:10.1007/s00396-012-2889-2
Amphiphilic Pluronic-based pentablock copolymers with pendant amino groups have been successfully synthesized via ring opening polymerization of γ-(carbamic acid benzyl ester)-ε-caprolactone (γCABεCL) and ε-caprolactone (εCL) using Pluronic F127 as macroinitiator and Sn(Oct)2 as catalyst, and followed by hydrolysis of the Cbz protected groups under acidic conditions. The structure of the copolymer was confirmed by proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy spectra. In addition, gel permeation chromatography results demonstrated that the synthetic copolymer had a single and symmetrical peak. Moreover, the crystallinity and hydrophilicity could be well adjusted by the content of the functionalized monomer. Successful formation of aggregates was demonstrated by fluorescence method and transmission electron microscopy revealed that the micelles had a spherical morphology and the size was on nano scale according to the laser particle sizer results. The polymeric micelles had no obvious cytotoxicity even the micelles concentration reached 500 mg/L. Thus the Pluronic-b-poly(γ-amino-ε-caprolactone-co-ε-caprolactone) copolymers have great potential for the use in the biomedical fields.
Co-reporter:Xi Zhang;Yan Xiao;Meidong Lang
Polymer Journal 2013 45(4) pp:420-426
Publication Date(Web):2012-10-10
DOI:10.1038/pj.2012.166
Poly(ε-caprolactone)2-b-poly(L-lactide)2 miktoarm block copolymers were successfully synthesized via ring-opening polymerization using pentaerythritol as the initiator and a protection–deprotection procedure. 1H nuclear magnetic resonance (1H NMR) and size exclusion chromatography (SEC) were employed to characterize the miktoarm structure, molecular weight and molecular weight distribution. The microspheres of poly(ε-caprolactone)2-b-poly(L-lactide)2 ((PCL)2-b-(PLLA)2) were produced by an oil-in-water emulsion solvent extraction/evaporation method and studied with scanning electron microscopy (SEM). The hydrolytic degradation of microspheres with different architectures and compositions was performed at 37 °C in a phosphate-buffered saline solution (pH=7.4). The weight loss of the microspheres was strongly affected by the molecular architecture, chain length and composition. The compositional, or molar ratio, changes were monitored during the degradation using 1H NMR, SEC, differential scanning calorimetry and SEM, all of which suggested that the degradation proceeded from the surface to the interior and could be described using a combined degradation model with surface erosion and bulk degradation.
Co-reporter:Yi Zhang, Yan Zhang, Min Chen, Jinliang Yan, Zhaoyang Ye, Yan Zhou, Wensong Tan, Meidong Lang
Journal of Colloid and Interface Science 2012 Volume 368(Issue 1) pp:64-69
Publication Date(Web):15 February 2012
DOI:10.1016/j.jcis.2011.11.010
In this study, a series of membranes with different amino group densities were prepared to investigate the surface properties of the novel poly(γ-amino-ε-caprolactone-co-ε-caprolactone) (NPCL) copolymer synthesized by our laboratory. Meanwhile, the human mesenchymal stem cells’ (hMSCs) behavior on those membranes was examined. The molecular characteristics of the NPCL copolymers were characterized by nuclear magnetic resonance (NMR), size exclusion chromatography (SEC), and differential scanning calorimetry (DSC). Surface properties of membranes were characterized by water contact angle analysis, X-ray photoelectron spectroscopy analysis (XPS), and atomic force microscopy (AFM). It was found that the incorporation of amino groups to the poly(ε-caprolactone) (PCL) backbone resulted in an augmented wettability, a decreased crystallinity, and also an increased surface roughness on the NPCL membranes. In vitro cell experiments showed a significant enhancement in hMSCs’ adhesion, proliferation, and osteogenic differentiation on NPCL membranes compared with virgin PCL membrane, and demonstrated that surface properties of membrane played an important role in tailoring cell behavior.Graphical abstractHighlights► We prepared amino-functionalized PCL with different NH2 content. ► The amino groups endowed PCL with excellent surface hydrophilicity and morphology. ► hMSCs’ adhesion, proliferation, and osteogenic differentiation were promoted. ► Cell behavior was significantly mediated by surface properties.
Co-reporter:Xiujuan Huang, Yan Xiao, Wei Zhang, Meidong Lang
Applied Surface Science 2012 Volume 258(Issue 7) pp:2655-2660
Publication Date(Web):15 January 2012
DOI:10.1016/j.apsusc.2011.10.113
Abstract
Silver nanoparticles (Ag NPs) were prepared via in situ reduction of silver nitrate (AgNO3) using polymeric micelles as nanoreactors without any additional reductant. The micelles were constructed from the amphiphilic star-shaped copolymer composed of poly(ɛ-caprolactone) (PCL) segment, 2-(dimethylamino)ethyl methacrylate (DMAEMA or DMA) units and oligo(ethylene glycol)monomethyl ether methacrylate (OEGMA or OEG) units. The Ag NPs stabilized by those star-shaped copolymers were characterized using UV–vis spectrum, DLS, TEM and FTIR. It confirmed that PDMAEMA exhibited the reducing property unless pH was above 7. The Ag NPs were sphere-like with a diameter of 10–20 nm, which was independent of the architecture of the copolymer and AgNO3 concentration. Furthermore, the catalytic activity of these Ag NPs was investigated by monitoring the reduction of p-nitrophenol (4-NP) by NaBH4. The result showed that the Ag NPs formed by coordination reduction can be effectively applied in catalytic reaction.
Co-reporter:Xiujuan Huang;Yan Xiao
Macromolecular Research 2012 Volume 20( Issue 6) pp:597-604
Publication Date(Web):2012 June
DOI:10.1007/s13233-012-0082-6
A series of star-shaped poly(ɛ-caprolactone) (PCL)-based diblock and triblock copolymers containing 2-(dimethylamino)ethyl methacrylate (DMAEMA or DMA) and oligo(ethylene glycol)monomethyl ether methacrylate (OEGMA or OEG) were synthesized by one-pot atom transfer radical polymerization (ATRP) using a sixarm PCL-based macroinitiator. The precursor and the resultant copolymers were analyzed via proton nuclear magnetic resonance spectra (1H NMR) and size exclusion chromatography (SEC). The monomer reactivity ratios for DMAEMA (r1) and OEGMA (r2) were estimated to be near unity and r1×r2=1, which indicates the random distribution of the monomers in the final copolymers. Self-assembly behavior of these copolymers was investigated by fluorimetry, 1H NMR, dynamic light scattering (DLS), transmission electronic microscopy (TEM), potentiometric titrations, and zeta potential measurements. The results suggested that the star copolymers were responsive to salinity depending on their composition and structure.
Co-reporter:Cuizhen Li;Chunhua Gu;Yan Zhang
Polymer Bulletin 2012 Volume 68( Issue 1) pp:69-83
Publication Date(Web):2012 January
DOI:10.1007/s00289-011-0520-1
The pH-responsive amphiphilic poly(ε-caprolactone)-block-poly(acrylic acid) (PCL-b-PAA) copolymer was prepared by selective hydrolysis of one novel poly(ε-caprolactone)-block-poly(methoxymethyl acrylate) (PCL-b-PMOMA) block copolymer, which was synthesized by combining ring-opening polymerization (ROP) of ε-caprolactone (ε-CL) and atom transfer radical polymerization (ATRP) of methoxymethyl acrylate (MOMA). Selective hydrolysis of the hemiketal ester groups on the PMOMA block gave 100% deprotection without the cleavage of the PCL block. The self-assembly behavior of PCL-b-PAA was investigated by fluorescence spectroscopy, DLS and TEM. The spherical micelles were formed with the hydrophobic PCL block as the core and the hydrophilic PAA as the shell by a co-solvent evaporation method. Moreover, the size and size distribution of the micelles varied with pH value and ionic strength in aqueous solution. The cytotoxicity of the PCL-b-PAA was lower, which was confirmed by MTT assay.
Co-reporter:Qingqing Bian, Yan Xiao, Meidong Lang
Polymer 2012 Volume 53(Issue 8) pp:1684-1693
Publication Date(Web):3 April 2012
DOI:10.1016/j.polymer.2012.02.031
A novel star amphiphilic block copolymer star poly(ε-caprolactone)-b-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-DDAT [SPCL-b-P(NIPAAm-co-DMAAm)-DDAT] (DDAT: S-1-dodecyl-S′-(α,α′-dimethyl-α″-acetic acid)trithiocarbonate) was synthesized by combination of ring-opening polymerization (ROP) and reversible addition-fragment chain transfer (RAFT) polymerization. DDAT-terminated groups were further transformed into hydroxyl groups by one-pot strategy for aminolysis of DDAT and Michael addition reaction of an α,β-unsaturated ester of 2-hydroxyethyl acrylate (HEA). Biotinylated star copolymer SPCL-b-P(NIPAAm-co-DMAAm)-Biotin was obtained by coupling of biotin to the hydroxyl-terminated star copolymer using carbodiimide coupling chemistry. These star copolymers with DDAT, hydroxyl, and biotin end groups were capable of self assembling into core–shell structural micelles in aqueous solution. The variation of end groups significantly affected the micellar characters, such as hydrodynamic diameter (Dh), critical micellar concentration (CMC), and lower critical solution temperature (LCST). Biotinylated micelle exhibited a phase transition at 41.4 °C. The amount of biotin on the micelle surface as well as the specific recognition between biotinylated micelle and avidin was determined by 4′-hydroxyazobenzene-2-carboxylic acid/avidin (HABA/avidin) binding assay and dynamic light scattering (DLS). In addition, the biotinylated star copolymer displayed good biocompatibility according to a preliminary cytotoxicity study. The novel polymeric micelle with biodegradability, thermoresponse, and specific target recognition was expected to be a promising polymeric carrier material for targeted drug delivery.
Co-reporter:Qingchun Zhang, Ke Tan, Zhaoyang Ye, Yan Zhang, Wensong Tan, Meidong Lang
Materials Science and Engineering: C 2012 Volume 32(Issue 8) pp:2589-2595
Publication Date(Web):1 December 2012
DOI:10.1016/j.msec.2012.07.045
Common hydrogel, composed of synthetic polymers or natural polysaccharides could not support the adhesion of anchorage-dependent cells due to the lack of cell affinitive interface and high cell constraint. The use of porous polyester microspheres as cell-carriers and introduction of cell-loaded microspheres into the hydrogel system might overcome the problem. However, the preparation of the open porous microsphere especially using polycaprolactone (PCL) has been rarely reported. Here, the open porous PCL microspheres were fabricated via the combined emulsion/solvent evaporation and particle leaching method. The microspheres exhibited porous surface and inter-connective pore structure. Additionally, the pore structure could be easily controlled by adjusting the processing parameters. The surface pore size could be altered from 20 μm to 80 μm and the internal porosities were varied from 30% to 70%. The obtained microspheres were evaluated to delivery mesenchymal stem cells (MSCs) and showed the improved cell adhesion and growth when compared with the non-porous microspheres. Then, the MSCs loaded microspheres were introduced into agarose hydrogel. MSCs remained alive and sustained proliferation in microsphere/agarose composite in 5-day incubation while a decrement of MSCs viabilities was found in agarose hydrogel without microspheres. The results indicated that the microsphere/hydrogel composite had a great potential in cell therapy and injectable system for tissue regeneration.Highlights► The open porous polycaprolactone microspheres were fabricated using paraffin as a porogen. ► The microspheres exhibited porous surface and inter-connective pore structure. ► The surface and internal pore size and porosity of microsphere could be controlled. ► The porous microspheres exhibited an improved cell adhesion and proliferation. ► Mesenchymal stem cells survived and proliferated in microsphere/hydrogel composite.
Co-reporter:Jianjing Liu, Yan Zhang, Jinliang Yan and Meidong Lang
Journal of Materials Chemistry A 2011 vol. 21(Issue 18) pp:6677-6682
Publication Date(Web):28 Mar 2011
DOI:10.1039/C1JM10142K
A series of water-soluble and cationic methoxy poly(ethylene glycol)-b-poly(γ-amino-ε-caprolactone) (mPEG-b-PACL) has been synthesized via ring opening polymerization of γ-(carbamic acid benzyl ester)-ε-caprolactone (γCABεCL) using mPEG as a macroinitiator and Sn(Oct)2 as a catalyst, and subsequent hydrolysis of the Cbz protecting groups under acidic conditions. The well-defined structure of copolymers was confirmed by 1H NMR and FTIR spectra. In addition, size exclusion chromatography (SEC) results indicated that the copolymer had a symmetric peak and a relatively narrow polydispersivity. The thermal properties were influenced by hydrogen bonding originating from the amino groups on the backbone based on differential scanning calorimetry (DSC) results. Furthermore, the solution properties have been investigated in water by a zetamasters instrument and dynamic light scattering (DLS). The results demonstrated that the aggregates exhibited a rich pH-responsive behavior with an appropriate PACL length. Successful formation of aggregates with spherical morphology was demonstrated beyond a critical PACL length by transmission electron microscopy (TEM). The mPEG-b-PACL block copolymer did not have any significant cytotoxicity against human dermal fibroblasts up to 500 μg mL−1. Moreover, it has improved cell proliferation behavior according to MTT assays. Based on all these notable advantages, mPEG-b-PACL copolymer would be a potential candidate for biomedical and pharmaceutical applications.
Co-reporter:Jinliang Yan, Zhaoyang Ye, Houyong Luo, Min Chen, Yan Zhou, Wensong Tan, Yan Xiao, Yan Zhang and Meidong Lang
Polymer Chemistry 2011 vol. 2(Issue 6) pp:1331-1340
Publication Date(Web):12 Apr 2011
DOI:10.1039/C0PY00391C
We report in this paper a facile way to prepare novel amine-functionalized monomethoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL) amphiphilic block copolymers, which are subsequently fluorescently labeled. In our synthetic route, monomethoxy-poly(ethylene glycol)-b-poly[ε-caprolactone-co-γ-(carbamic acid benzyl ester)-ε-caprolactone] [mPEG-b-P(CL-co-CABCL)] copolymers were synthesized viaring-opening polymerization (ROP) of ε-caprolactone (CL) and a newly developed monomer, γ-(carbamic acid benzyl ester)-ε-caprolactone (CABCL) at varied ratios using mPEG as macroinitiator and Sn(Oct)2 as catalyst. Subsequent deprotection upon removal of carbobenzoxy (Cbz) group yielded monomethoxy-poly(ethylene glycol)-b-poly(ε-caprolactone-co-γ-amino-ε-caprolactone) [mPEG-b-P(CL-co-ACL)] copolymers bearing primary amine functional groups on the PCL block. The structures of polymers were characterized with NMR, FT-IR and GPC techniques. These amphiphilic block copolymers self-assembled into micelles in aqueous solution and the critical micelle concentration (CMC) was dependent on the compositions of the copolymers. In addition, the particle size and morphology of micelles were studied with DLS and TEM, respectively. In vitro study demonstrated that the micelles were nontoxic to human fibroblasts based on MTT and live/dead assays. Furthermore, a proof-of-concept usage of amino groups for bioconjugation was illustrated by tagging the copolymer with a fluorophore, fluorescein isothiocyanate (FITC). Internalization of FITC-labeled micelles by fibroblast cells was observed under fluorescence microscopy. Through facile conjugation of chemical moieties such as drugs, peptides, proteins or fluorophores, micelles prepared with these amine-functionalized mPEG-b-PCL copolymers hold great promise in biomedical applications.
Co-reporter:Yan Zhang, Jiashi Li, Meidong Lang, Xiaolin Tang, Lei Li, Xizhong Shen
Journal of Colloid and Interface Science 2011 Volume 354(Issue 1) pp:202-209
Publication Date(Web):1 February 2011
DOI:10.1016/j.jcis.2010.10.054
In this paper, folate conjugated poly(ε-caprolactone-co-4-maleate-ε-caprolactone) (P(CL-co-MCL)-folate) was prepared by a carbodiimide coupling reaction, i.e., the vitamin folic acid (FA) was covalently linked to the main chain of the maleate-functionalized polymer, poly(ε-caprolactone-co-4-maleate-ε-caprolactone) (P(CL-co-MCL)). Then the 5-Fluorouracil (5-FU) loaded nanoparticles of P(CL-co-MCL)-folate were achieved by solvent-evaporation method. Their properties were extensively studied by dynamic light scattering (DLS) and scan electron microscopy (SEM). DLS and SEM showed that the nanoparticles were in a well-defined spherical shape with a uniform size distribution. We also investigated the entrapment and in vitro release behavior, which indicated that the release speed of 5-FU could be well controlled and the release half-life period could reach 16.86 h, which was 26.4 times longer than that of pure 5-FU. The in vitro targeting test displayed that the 5-FU loaded P(CL-co-MCL)-folate nanoparticles exhibited an enhanced cell inhibition because folate targeting increased the concentration of 5-FU loaded P(CL-co-MCL)-folate nanoparticles in the tumor cells with folate receptor overexpressed. Meanwhile, the tumor inhibition of 5-FU loaded P(CL-co-MCL)-folate nanoparticles was much higher than that of pure 5-FU and that of 5-FU loaded P(CL-co-MCL) nanoparticles. Therefore, P(CL-co-MCL)-folate nanoparticles would be highly beneficial for biomedical and pharmaceutical applications.Graphical abstractThe nanoparticles based poly(ε-caprolactone) have improved the solubility of the anticancer drug 5-Fluorouracil, and increased the concentration at the site of the tumor to improve the tumor inhibition.
Co-reporter:Xiujuan Huang, Yan Xiao, Meidong Lang
Journal of Colloid and Interface Science 2011 Volume 364(Issue 1) pp:92-99
Publication Date(Web):1 December 2011
DOI:10.1016/j.jcis.2011.08.028
Comicellization of a star block copolymer poly(ε-caprolactone)-block-poly(diethylamino)ethyl methacrylate (S(PCL-b-PDEAEMA)) and a linear block copolymer methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-b-PCL) was developed to enhance the stability and lower the cytotoxicity of the micelles. The two copolymers self-assembled into the mixed micelles with a common PCL core surrounded by a mixed PDEAEMA/mPEG shell in aqueous solution. This core–shell structure was transformed to the core–shell–corona structure at high pH due to the collapse of the PDEAEMA segment. The properties of the polymeric micelles were greatly dependent on the weight ratio of the two copolymers and the external pH. As increasing the mPEG-b-PCL content, the size and the zeta potential of the mixed micelles were lowered while the pH-dependent stability and the biocompatibility were improved. Moreover, an increase in pH accelerated the release of indomethacin (IND) from the mixed micelles in vitro. These results augured that the mixed micelles could be applied as a stable pH-sensitive release system.Graphical abstractThe mixed micelles constructed from the star and linear copolymers were transformed from a core–shell structure into a core–shell–corona one with pH value.Highlights► pH-sensitive mixed micelles were readily formed by comicellization of two copolymers. ► The mixed micelles could be kept stable in wide pH range. ► The mixed micelles exhibited low cytotoxicity and high positive zeta potential. ► An increase in pH accelerated the release of drug from mixed micelles in vitro.
Co-reporter:Yue Zeng;Yan Zhang
Chinese Journal of Chemistry 2011 Volume 29( Issue 2) pp:343-350
Publication Date(Web):
DOI:10.1002/cjoc.201190088
Abstract
In this paper, aliphatic polyesters functionalized with pendant carboxylic groups were synthesized via several steps. Firstly, substituted cyclic ketone, 2-(benzyloxycarbonyl methyl)cyclopentanone (BCP) was prepared through the reaction of enamine with benzyl-2-bromoacetate, and subsequently converted into the relevant functionalized δ-valerolactone derivative, 5-(benzyloxy carbonylmethyl)-δ-valerolactone (BVL) by the Baeyer-Villiger oxidation. Secondly, the ring-opening polymerization of BVL with ε-caprolactone was carried out in bulk using stannous octoate as the catalyst to produce poly(ε-caprolactone-co-δ-valerolactone) bearing the benzyl-protected carboxyl functional groups [P(CL-co-BVL)]. Finally, the benzyl-protecting groups of P(CL-co-BVL) were effectively removed by H2 using Pd/C as the catalyst to obtain poly(ε-caprolactone-co-δ-valerolactone) bearing pendant carboxylic acids [P(CL-co-CVL)]. The structure and the properties of the polymer have been studied by Nuclear Magnetic Resonance (NMR), Fourier Infrared Spectroscopy (FT-IR) and Differential Scan Calorimetry (DSC) etc. The NMR and FT-IR results confirmed the polymer structure, and the 13C NMR spectra have clearly interpreted the sequence of ε-caprolactone and 5-(benzyloxycarbonylmethyl)-δ-valerolactone in the copolymer. When the benzyl-protecting groups were removed, the aliphatic polyesters bearing carboxylic groups were obtained. Moreover, the hydrophilicity of the polymer was improved. Thus, poly(ε-caprolactone-co-δ-valerolactone) might have great potential in biomedical fields.
Co-reporter:Jinliang Yan, Zhaoyang Ye, Min Chen, Zhanzhan Liu, Yan Xiao, Yan Zhang, Yan Zhou, Wensong Tan, and Meidong Lang
Biomacromolecules 2011 Volume 12(Issue 7) pp:
Publication Date(Web):May 20, 2011
DOI:10.1021/bm200375x
This study aimed to optimize poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL)-based amphiphilic block copolymers for achieving a better micellar drug delivery system (DDS) with improved solubilization and delivery of doxorubicin (DOX). First, the Flory–Huggins interaction parameters between DOX and the core-forming segments [i.e., poly(ε-caprolactone) (PCL) and poly[(ε-caprolactone-co-γ-(carbamic acid benzyl ester)-ε-caprolactone] (P(CL-co-CABCL))] was calculated to assess the drug–polymer compatibility. The results indicated a better compatibility between DOX and P(CL-co-CABCL) than that between DOX and PCL, motivating the synthesis of monomethoxy-poly(ethylene glycol)-b-poly[(ε-caprolactone-co-γ-(carbamic acid benzyl ester)-ε-caprolactone] (mPEG-b-P(CL-co-CABCL)) block copolymer. Second, two novel block copolymers of mPEG-b-P(CL-co-CABCL) with different compositions were prepared via ring-opening polymerization of CL and CABCL using mPEG as a macroinitiator and characterized by 1H NMR, FT-IR, GPC, WAXD, and DSC techniques. It was found that the introduction of CABCL decreased the crystallinity of mPEG-b-PCL copolymer. Micellar formation of the copolymers in aqueous solution was investigated with fluorescence spectroscopy, DLS and TEM. mPEG-b-P(CL-co-CABCL) copolymers had a lower critical micelle concentration (CMC) than mPEG-b-PCL and subsequently led to an improved stability of prepared micelles. Furthermore, both higher loading capacity and slower in vitro release of DOX were observed for micelles of copolymers with increased content of CABCL, attributed to both improved drug–core compatibility and favorable amorphous core structure. Meanwhile, DOX-loaded micelles facilitated better uptake of DOX by HepG2 cells and were mainly retained in the cytosol, whereas free DOX accumulated more in the nuclei. However, possibly because of the slower intracellular release of DOX, DOX-loaded micelles were less potent in inhibiting cell proliferation than free DOX in vitro. Taken together, the introduction of CABCL in the core-forming block of mPEG-b-PCL resulted in micelles with superior properties, which hold great promise for drug delivery applications.
Co-reporter:Xiujuan Huang;Yan Xiao
Macromolecular Research 2011 Volume 19( Issue 2) pp:113-121
Publication Date(Web):2011 February
DOI:10.1007/s13233-011-0202-8
A series of amphiphilic six-armed copolymers, containing poly(ɛ-caprolactone) (PCL) and poly(2-(diethylamino) ethyl methacrylate) (PDEAEMA or PDEA) as the arm and cyclotriphosphazene as the core, were obtained by a combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The star block S(PCL-b-PDEAEMA) copolymers were characterized by 1H NMR spectroscopy and size exclusive chromatography (SEC). These copolymers could self-assembly into micelles in an aqueous solution at low pH with a low critical aggregation concentration (CAC) in the range of 2 to 10 mg/L, which depend on the composition of the copolymers. The original aggregates could further form larger micelles and/or vesicles by adjusting the external stimulus, which was examined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The lower critical solution temperature (LCST) of the star copolymers were determined to be 49.7 and 26.3 °C at pH 6.5 and 7.4, respectively, demonstrating a pH-dependent thermo-response.
Co-reporter:Yan Wang, Jing Dai, Qingchun Zhang, Yan Xiao, Meidong Lang
Applied Surface Science 2010 Volume 256(Issue 20) pp:6107-6112
Publication Date(Web):1 August 2010
DOI:10.1016/j.apsusc.2010.03.127
Abstract
Scaffolds comprising hydroxyapatite (HAP) or poly(ɛ-caprolactone)-grafted hydroxyapatite (g-HAP) and poly(ɛ-caprolactone) (PCL) were prepared using the thermally induced phase separation/salt leaching technique. The g-HAP nanoparticles were evaluated by Fourier Transformation Infrared Spectroscopy (FTIR) and thermal gravimetric analysis (TGA). Power X-ray Diffraction (XRD) patterns confirmed the successful grafting on the surface of HAP. The effects on mechanical strength, porosity and thermal property of scaffolds by the introduction of nanoparticles were extensively investigated. The compressive modulus of the scaffold was greatly improved by the addition of g-HAP nanoparticles. Especially the compressive modulus of the g-HAP/PCL scaffold containing 20 wt% of g-HAP was 59.4% higher than that of the corresponding HAP/PCL scaffold.
Co-reporter:Weifeng Dai;Yan Zhang;Zhengzhen Du
Journal of Materials Science: Materials in Medicine 2010 Volume 21( Issue 6) pp:1881-1890
Publication Date(Web):2010 June
DOI:10.1007/s10856-010-4049-x
The macromonomer of 2-hydroxyethyl methyacrylate-caprolactone (HPCL) was synthesized by the ring-opening polymerization (ROP) of ε-caprolactone, which was initiated by 2-hydroxyethyl methyacrylate (HEMA). Then, the graft terpolymers of NIPAAm-co-AAc-co-HEMA-g-PCL (PHNA-CL) with varying mole ratios were subsequently synthesized by free radical polymerization of HEMA-PCL, N-isopropylacrylamide (NIPAAm) and acrylic acid (AAc). PHNA-CL was further self-assembled in different types of solvent. All the as-prepared copolymers were characterized by 1H NMR, FT-IR and GPC. Micellization behaviors of micelles were studied by TEM and DLS. The micelles exhibited a phase transition temperature which can be readily adjusted by changing pH value of the micellization system. Micelle loaded with doxorubicin (DOX) was used to evaluate the drug release behavior. The release of DOX from micelles could be controlled by changing pH value and temperature in buffer solutions. The micelles are potentially to be used as a new anticancer drug carrier for intracellular delivery.
Co-reporter:Yueying He, Yan Zhang, Yan Xiao, Meidong Lang
Colloids and Surfaces B: Biointerfaces 2010 80(2) pp: 145-154
Publication Date(Web):
DOI:10.1016/j.colsurfb.2010.05.038
Co-reporter:Jinliang Yan, Yi Zhang, Yan Xiao, Yan Zhang, Meidong Lang
Reactive and Functional Polymers 2010 70(7) pp: 400-407
Publication Date(Web):1 July 2010
DOI:10.1016/j.reactfunctpolym.2010.03.008
A novel functional ε-caprolactone monomer containing protected amino groups, γ-(carbamic acid benzyl ester)-ε-caprolactone (γCABεCL), was successfully synthesized. A series of copolymers [poly(CL-co-CABCL)] were prepared by ring-opening polymerization of ε-caprolactone (CL) and γCABεCL in bulk using tin (II)-2-ethylhexanoate [Sn(Oct)2] as catalyst. The morphology of the copolymers changed from semi-crystalline to amorphous with increasing γCABεCL monomer content. They were further converted into deprotected copolymers [poly(CL-co-ACL)] with free amino groups by hydrogenolysis in the presence of Pd/C. After deprotection, the free amino groups on the copolymer were further modified with biotin. The monomer and the corresponding copolymers were characterized by 1H NMR, 13C NMR, FT-IR, mass, GPC and DSC analysis. The obtained data have confirmed the desired monomer and copolymer structures.
Co-reporter:Weifeng Dai, Jiayun Zhu, Aoyu Shangguan, Meidong Lang
European Polymer Journal 2009 Volume 45(Issue 6) pp:1659-1667
Publication Date(Web):June 2009
DOI:10.1016/j.eurpolymj.2009.03.010
The novel comb-type biodegradable graft copolymers based on ε-caprolactone and l-lactide were synthesized. Firstly, 2-oxepane-1,5-dione (OPD) was synthesized by the Baeyer–Villiger oxidation of 1,4-cyclohexanedione, and was subsequently copolymerized with ε-caprolactone (CL) to produce poly(2-oxepane-1,5-dione-co-ε-caprolactone) (POCL) catalyzed by stannous(II) 2-ethylhexanoate in toluene. Then, POCL was converted into poly(4-hydroxyl-ε-caprolactone-co-ε-caprolactone) (PHCL) using sodium borohydride as reductant. Finally, poly(4-hydroxyl-ε-caprolactone-co-ε-caprolactone)-g-poly(l-lactide) (PHCL-g-PLLA) were prepared successfully by bulk ring-opening polymerization of l-lactide using PHCL as a macro-initiator. All the copolymers have been characterized by 1H and 13C NMR, DSC, and GPC. Compared with the random copolymer of poly(CL-co-LA), the elongation is highly increased. And the thermal analysis showed that the crystallization rate of the PCL backbone in the graft copolymers was greatly reduced compared to the PCL homopolymer. The hydrolytic degradation of the copolymer was much faster in a phosphate buffer (pH = 7.4) at 37 °C, which is confirmed by the weight loss and change of intrinsic viscosity.
Co-reporter:Weifeng Dai, Hui Huang, Zhengzhen Du, Meidong Lang
Polymer Degradation and Stability 2008 Volume 93(Issue 12) pp:2089-2095
Publication Date(Web):December 2008
DOI:10.1016/j.polymdegradstab.2008.09.001
The synthesis, characterization, and degradability of the novel aliphatic polyester bearing pendant N-isopropylamide functional group are reported for the first time. 2-(N-Isopropyl-2-carbamoylethyl)cyclohexanone (CCH) was first synthesized by the Michael reaction of N-isopropylacrylamide with cyclohexanone and was subsequently converted into 6-(N-isopropyl-2-carbamoylethyl)-ɛ-caprolactone (CCL) by the Baeyer-Villiger oxidation reaction using 3-chloroperoxybenzoic acid (mCPBA) as the oxidant. Finally, the novel functionalized poly(ɛ-caprolactone) bearing the pendant N-isopropylamide functional groups, poly(6-(N-isopropyl-2-carbamoylethyl)-ɛ-caprolactone-co-ɛ-caprolactone)s (poly(CCL-co-CL)), were carried out successfully by bulk ring-opening polymerization of CCL and ɛ-CL initiated by Sn(Oct)2. Poly(CCL-co-CL) were characterized by 1H NMR, 13C NMR, SEC and DSC. The copolymer containing 9.1 mol% CCL formed flexible films and was used to study its degradability. A phosphate buffer (pH = 7.4) with temperature 37 °C was adopted to proceed the degrading study all through. Compared with poly(ɛ-caprolactone), the hydrolytic degradation of poly(CCL-co-CL) was much faster, which is confirmed by the weight loss and change of intrinsic viscosity.
Co-reporter:WeiFeng Dai;ChaoHua Wang;Xi Zhang;JinMing Zhang
Science China Chemistry 2008 Volume 51( Issue 11) pp:1044-1050
Publication Date(Web):2008 November
DOI:10.1007/s11426-008-0095-3
The electron-withdrawing groups (EWGs) in the electrophilic alkenes employed in the Michael addition reaction are almost only CO2R, CN, COR, NO2, and SO2Ph. Although amides (CONR1R2) are also typical electron-withdrawing groups and are of great importance in organic synthesis, they are scarcely employed as the EWGs of the electrophilic alkenes in the Michael addition reaction. In this work, the Michael reactions of acrylamide and its derivatives with cyclanones were successfully carried out in the presence of enough radical inhibitors. The amide groups play a key role in producing the preferred products. The N-substituted acrylamides, including N-monosubstituted and N,N-disubstituted acrylamides could react with cyclohexanone (CHn) to give the expected 2-carbamoylethyl derivatives; however, acrylamide reacting with cyclohexanone only produced ene-lactam. Cyclanones also have effects on the products, while the ring size of cyclanones influences the reaction yield and the α-substituent decides the ratio of resulting isomeric ene-lactams.
Co-reporter:Yan Xiao, Sihuan Lang, Miaomiao Zhou, Jing Qin, Rui Yin, Jingming Gao, Andreas Heise and Meidong Lang
Journal of Materials Chemistry A 2017 - vol. 5(Issue 3) pp:NaN603-603
Publication Date(Web):2016/12/06
DOI:10.1039/C6TB02507B
A series of biodegradable and crosslinkable precursors based on poly(4-methyl-ε-caprolactone) (PMCL) were prepared by ring-opening polymerization (ROP), followed by the complete acrylation of both hydroxyl ends. Afterwards, biodegradable networks exhibiting totally amorphous character were obtained via photocrosslinking without organic solvent or high temperature. As a result, their mechanical properties varied significantly from brittle to elastic upon increasing the length of the PMCL precursors. Both covalent crosslinking and trapped entanglements between crosslinking segments were likely to contribute to the unique properties of the bioelastomer. In particular, networks formed by the precursors with large molecular weights presented high flexibility and resilience, which match the mechanical properties of soft tissues like blood vessels, bladder and cardiovascular tissue. Preliminary degradation and in vitro cytotoxicity studies of the crosslinked network showed excellent biodegradability and biocompatibility. Moreover, it was demonstrated that the liquid-like PMCL precursor made the patterning easily processable even in the absence of any solvent or heating.
Co-reporter:Chao Wei, Yan Zhang, Zhongchen Song, Yiru Xia, Heng Xu and Meidong Lang
Biomaterials Science (2013-Present) 2017 - vol. 5(Issue 4) pp:NaN677-677
Publication Date(Web):2017/02/03
DOI:10.1039/C6BM00960C
Stimuli-responsive nanocarriers have been limited for bench-to-bedside translation mainly because the stimuli sensitivity and responsive rate are not high enough to ensure sufficient drug concentration at the target sites for superior therapeutic benefits. Herein, we reported an enhanced bioreduction-responsive and biodegradable nanocarrier based on the amphiphilic poly(ester urethane) copolymers (PAUR-SeSe) bearing multiple diselenide groups on the backbone. The copolymer could spontaneously self-assemble into stable micelles in aqueous medium with an average diameter of 68 nm, which could be rapidly disassembled in a reductive environment as a result of the reduction-triggered cleavage of diselenide groups. Furthermore, the PAUR-SeSe micelles showed an enhanced drug release profile and cellular uptake compared with the disulfide-containing analogue (PAUR-SS). CCK8 assays revealed that the antitumor activity of DOX-loaded PAUR-SeSe micelles was much higher than that of DOX-loaded PAUR-SS micelles. Besides, the blank micelles and degradation products were nontoxic up to a tested concentration of 50 μg mL−1. Therefore, the enhanced therapeutic efficacy and good biocompatibility demonstrated that this drug nanocarrier had great potential for smart antitumor drug delivery applications.
Co-reporter:Yan Zhang, Jianjing Liu, Yutong Fu, Ke Tan, Zhaoyang Ye and Meidong Lang
Journal of Materials Chemistry A 2013 - vol. 1(Issue 11) pp:NaN1621-1621
Publication Date(Web):2013/01/14
DOI:10.1039/C3TB00012E
A novel polyion complex (PIC) drug carrier was developed via electrostatic self-assembly in aqueous media based on our previous copolymer methoxy poly(ethylene glycol)-b-poly(γ-amino-ε-caprolactone) (mPEG-b-PACL) and anti-hepatotoxic drug ammonium glycyrrhizinate (AMG). The formation and the physicochemical properties of the polyion complex nanoparticles in aqueous solution were investigated by various methods. The results demonstrated that AMG was encapsulated successfully and the nanoparticles had a core–shell or tri-layer spherical structure based on the length of the PACL. The AMG/PACL PIC also displayed a high loading capacity and encapsulation efficiency of up to 41.8% and 91.7%, respectively. Furthermore, the nanoparticles enabled a continuous and sustained in vitro AMG release and the release half time was about 3 times that of the free AMG's. Results obtained by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and fluorescence microscopy revealed that AMG loaded nanoparticles demonstrated greater prevention of liver cell apoptosis induced by lipopolysaccharide (LPS). These findings indicated that methoxy poly(ethylene glycol) (mPEG)-b-poly(γ-amino-ε-caprolactone) could be an efficient AMG carrier and could even be used as a delivery template for some other negatively charged water-soluble drugs or gene delivery systems.
Co-reporter:Hong Liu, Yan Xiao, Heng Xu, Yebin Guan, Jun Zhang and Meidong Lang
Chemical Communications 2015 - vol. 51(Issue 50) pp:NaN10177-10177
Publication Date(Web):2015/05/13
DOI:10.1039/C5CC03017J
Rationally designed polypeptides with similar molecular structures but varying patterns of hydrogen bonding between the side groups have been synthesized and demonstrated to possess distinct solubility and thermal behaviors. Further balancing the ratio of both isopropylamine and ethylenediamine side groups endows the random copolymer with reversible thermo-sensitivity.
Co-reporter:Tianyi Wu, Qingchun Zhang, Weiping Ren, Xiang Yi, Zubin Zhou, Xiaochun Peng, Xiaowei Yu and Meidong Lang
Journal of Materials Chemistry A 2013 - vol. 1(Issue 26) pp:NaN3313-3313
Publication Date(Web):2013/04/30
DOI:10.1039/C3TB20261E
Infection of the bone (osteomyelitis) remains one of the most challenging problems in the field of orthopedic surgery. The limitations of systemic antibiotics administration include undesired side effects, systemic toxicity, patient discomfort, and development of bacterial resistance. In this study, we developed a bactericidal gentamicin-doped beta-tricalcium phosphate (TCP) scaffold reinforced with a gelatin/genipin hydrogel (G-TCP). Our data showed that the gentamicin-doped G-TCP had a much longer drug releasing period, while the gentamicin was completely released from pure TCP cements (B-TCP) within one day. In addition, the release profile of G-TCP exhibited an initial burst followed by a zero-order release. One standard strain, Staphylococcus aureus (S. aureus, ATCC25923) was selected to evaluate the antibacterial activity and therapeutic effect of this scaffold. G-TCP significantly inhibited growth of S. aureus both in vitro and in vivo. In a rat osteomyelitis model, osteomyelitis could be totally cured after implantation of G-TCP for three weeks. We propose that the gelatin/genipin–gentamicin TCP scaffold represents one of the promising gentamicin releasing bone scaffolds in treating osteomyelitis.
Co-reporter:Zhengzhen Du, Yan Zhang, Heng Xu and Meidong Lang
Journal of Materials Chemistry A 2015 - vol. 3(Issue 18) pp:NaN3694-3694
Publication Date(Web):2015/04/09
DOI:10.1039/C5TB00196J
Novel nanocarriers for paclitaxel (PTX) were developed based on Pluronic-b-poly(ε-caprolactone) bearing pendant benzyl-oxycarbonylmethyl (BOM) groups and carboxyl groups (Pluronic-b-P(CL-co-BCL), FB)/(Pluronic-b-P(CL-co-CCL), FC). The formation and the physicochemical properties of paclitaxel-loaded polymeric micelles, including FB/PTX micelles and FC/PTX micelles, were investigated by various methods. The results demonstrated that paclitaxel was amorphous in the micellar core and the micelles were on nanoscale. Besides the hydrophobic–hydrophobic interaction in both micelles, there was π–π interaction in the FB/PTX micelles while hydrogen bonding interaction existed in the FC/PTX micelles. Thus the different interaction between the drug and the polymer endowed the polymers with different binding forces which determined the various properties of the nanocarriers. The comparative study revealed that the compatibility was improved due to the introduction of the pendant groups according to the calculation based on the Flory–Huggins interaction parameter (χdc). The two nanocarriers also displayed high encapsulation efficiency, which could reach 88.61 ± 5.33% and 90.7 ± 2.08%, and they could also provide a continuous and sustained in vitro PTX release and the release half time was greatly enhanced in comparison with commercial Taxol®. Furthermore, the in vitro anti-tumor efficiency revealed that the FC PTX-loaded micelles had the best anti-tumor activity against C6 glioma cells inducing cell apoptosis and the in vitro blood compatibility and the in vivo long-circulation characteristics were well retained for the FB and FC PTX-loaded micelles in comparison with the original Pluronic-b-PCL. Therefore, these findings indicated that the functionalized Pluronic-b-poly(ε-caprolactone) micelles would be efficient nanocarriers for paclitaxel.
Co-reporter:Chao Wei, Yan Zhang, Heng Xu, Ying Xu, Yue Xu and Meidong Lang
Journal of Materials Chemistry A 2016 - vol. 4(Issue 29) pp:NaN5067-5067
Publication Date(Web):2016/07/05
DOI:10.1039/C6TB01040G
Well-defined diselenide-centered biodegradable tri-block copolymers methoxyl poly(ethylene glycol)-b-poly(ε-caprolactone)-b-methoxyl poly(ethylene glycol) (mPEG–PCL–Se)2 were precisely synthesized by the combination of ring opening polymerization using di(1-hydroxyethylene) diselenide as a new initiator and a facile coupling reaction. The amphiphilic block copolymers enabled the formation of self-assembled micelles which revealed an excellent reductive response to glutathione (GSH) due to the unique reduction-responsive cleavage of the diselenide bond. Such GSH response ensured an enhanced release of anticancer drugs (DOX) from the micelles in simulative tumor microenvironments; moreover, the drug release could be changed to some extent through fine-tuning the chemical composition of the copolymers. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements confirmed that the DOX-loaded micelles could be efficiently taken up by oral squamous carcinoma (HN30) cells and DOX was released into the nuclei of cancer cells following 4 h of incubation. The cell viability assays showed the diselenide-containing polymers were nontoxic up to a tested concentration (400 μg mL−1), while the DOX-loaded micelles exhibited an evident inhibition toward HN30 cells. Therefore, the reduction-labile biodegradable (mPEG–PCL–Se)2 may offer an alternative platform for tumor-targeting therapy.
Co-reporter:Jianjing Liu, Yan Zhang, Jinliang Yan and Meidong Lang
Journal of Materials Chemistry A 2011 - vol. 21(Issue 18) pp:NaN6682-6682
Publication Date(Web):2011/03/28
DOI:10.1039/C1JM10142K
A series of water-soluble and cationic methoxy poly(ethylene glycol)-b-poly(γ-amino-ε-caprolactone) (mPEG-b-PACL) has been synthesized via ring opening polymerization of γ-(carbamic acid benzyl ester)-ε-caprolactone (γCABεCL) using mPEG as a macroinitiator and Sn(Oct)2 as a catalyst, and subsequent hydrolysis of the Cbz protecting groups under acidic conditions. The well-defined structure of copolymers was confirmed by 1H NMR and FTIR spectra. In addition, size exclusion chromatography (SEC) results indicated that the copolymer had a symmetric peak and a relatively narrow polydispersivity. The thermal properties were influenced by hydrogen bonding originating from the amino groups on the backbone based on differential scanning calorimetry (DSC) results. Furthermore, the solution properties have been investigated in water by a zetamasters instrument and dynamic light scattering (DLS). The results demonstrated that the aggregates exhibited a rich pH-responsive behavior with an appropriate PACL length. Successful formation of aggregates with spherical morphology was demonstrated beyond a critical PACL length by transmission electron microscopy (TEM). The mPEG-b-PACL block copolymer did not have any significant cytotoxicity against human dermal fibroblasts up to 500 μg mL−1. Moreover, it has improved cell proliferation behavior according to MTT assays. Based on all these notable advantages, mPEG-b-PACL copolymer would be a potential candidate for biomedical and pharmaceutical applications.
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