Co-reporter:Jingyi Zhu, Mingkang Zhang, Diwei Zheng, Bin Yang, Ning Ma, Runqing Li, Jun Feng, and Xianzheng Zhang
Chemistry of Materials March 14, 2017 Volume 29(Issue 5) pp:2227-2227
Publication Date(Web):February 15, 2017
DOI:10.1021/acs.chemmater.6b05120
Nonspecific cell attack and rapid in vivo recognition/clearance have been the unsurmountable hurdles against the application of positively charged nanoparticles (pcNPs). The frequently used active targeting approach by grafting specific ligands onto pcNPs suffers from their strong electrostatic interaction with normal cells. We herein put forward a biohybrid strategy to solve this long-standing dilemma in the development of tumor-specific pcNPs. pcNPs are arranged to put on a biological “coat” derived from cancer cell membranes. This design renders pcNPs the high recognition to the homotypic cancer cells with even higher uptake efficiency than the parent pcNPs, while considerably inhibiting the adsorption by biological components, the macrophage capture, and the uptake by the heterotypic cells (e.g., normal and macrophage cells). Encouragingly, the tumor self-targeting by coating pcNPs with the cancer cell membranes proved to be achievable, allowing the role transition to an “attacker” upon reaching the homologous tumor developed from the source cancer cells. This approach paves a facile way to overcome the current limitations for in vivo application of pcNPs.
Co-reporter:Jing-Yi Zhu, Shuang-Shuang Wan, Di-Wei Zheng, Qi Lei, Ren-Xi Zhuo, Jun FengXian-Zheng Zhang
ACS Applied Materials & Interfaces 2017 Volume 9(Issue 1) pp:
Publication Date(Web):December 14, 2016
DOI:10.1021/acsami.6b14730
Intracellularly biotriggered decomposition of gene vectors is generally thought to benefit transfection. However, the bioresponsiveness is far from satisfactory, and the exact role of biodecomposition in the transfection process remains unclear to date. To overcome the challenges, highly rapid bioresponse of vectors has to be achieved so as to greatly amplify the intracellular deviation compared with the noncontrolled pattern. To this end, a supramolecular polyrotaxane has been elaborately designed by integrating reversible dynamics of supramolecular assembly and chemically labile bonds, in order to effectively propel intracellular decomposition. Inside tumor cells, the redox-responsive bulk dissociation of the supramolecular vector readily took place and was further accelerated by the lysosomal-acidity-triggered terminal decomposition. Both the in vitro and in vivo experiments have demonstrated that this supramolecule could mediate considerably more rapid gene accumulation in nuclei than the nonresponsive controls including PEI25K, the gold standard of nonviral vectors. Along with the structural decomposition, the supramolecule simultaneously underwent the transition of fluorescence quenching, favoring the evaluation over the bioresponsiveness inside cells. Based on the resulting data, it is suggested that the biotriggered volume expansion of supramolecule/DNA complexes may be the major factor accounting for that dramatically accelerated transnuclear gene transport during cellular mitosis, thus affecting the transfection. This study offers an understanding of the intracellular gene transport from a new viewpoint.Keywords: biocontrolled gene delivery; fluorescence quenching; intracellular biodecomposition; supramolecular polyrotaxane; velocity of nuclear uptake;
Co-reporter:J. Y. Zhu;J. J. Hu;M. K. Zhang;W. Y. Yu;D. W. Zheng;X. Q. Wang;J. Feng;X. Z. Zhang
Nanoscale (2009-Present) 2017 vol. 9(Issue 48) pp:19026-19030
Publication Date(Web):2017/12/14
DOI:10.1039/C7NR06080G
Based on boronate formation, this study reports a post-targeting methodology capable of readily installing versatile targeting modules onto a cargo-loaded nanoplatform in aqueous mediums. This permits the targeted nanodelivery of broad-spectrum therapeutics (drug/gene) in a ready-to-use manner while overcoming the PEGylation-dilemma that frequently occurs in conventional targeting approaches.
Co-reporter:Jing-Yi Zhu, Di-Wei Zheng, Ming-Kang Zhang, Wu-Yang Yu, Wen-Xiu Qiu, Jing-Jing Hu, Jun Feng, and Xian-Zheng Zhang
Nano Letters 2016 Volume 16(Issue 9) pp:5895-5901
Publication Date(Web):August 11, 2016
DOI:10.1021/acs.nanolett.6b02786
The ultimate goal in cancer therapy and diagnosis is to achieve highly specific targeting to cancer cells. Coated with the source cancer cell membrane specifically derived from the homologous tumors, the nanoparticles are identified with the self-recognition internalization by the source cancer cell lines in vitro and the highly tumor-selective targeting “homing” to the homologous tumor in vivo even in the competition of another heterologous tumor. As the result, MNP@DOX@CCCM nanovehicle showed strong potency for tumor treatment in vivo and the MR imaging. This bioinspired strategy shows great potential for precise therapy/diagnosis of various tumors merely by adjusting the cell membrane source accordingly on the nanoparticle surface.Keywords: cancer cell membrane; cancer cell self-recognition; magnetic iron oxide; MRI; Tumor self-targeting (TST);
Co-reporter:Hui-Zhen Jia, Wei Wang, Di-Wei Zheng, Xuli Wang, Wu-Yang Yu, Shi-Ying Li, Ren-Xi Zhuo, Yi-Fang Zhao, Jun Feng, and Xian-Zheng Zhang
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 11) pp:6784
Publication Date(Web):March 10, 2016
DOI:10.1021/acsami.6b01046
It is challenging but imperative to merge together specific inorganic nanomaterials with macromolecular and small-molecule therapeutics into one nanoentity for all-in-one theranostic/remedy. We establish a versatile nanotechnology to nanoentrap magnetic nanoparticles, doxorubicin, and DNA, thus allowing the combination of magnetic targeting, magnetic resonance (MR) imaging, gene transport, and bioresponsive chemotherapy. We hope this nanotechnology can prompt the development of complex inorganic/organic nanosystems for various applications.Keywords: all-in-one nanoentrapment; combined gene/drug therapy; inorganic nanoparticles (iNPs); magnetic resonance imaging; magnetic targeting
Co-reporter:Xing Dong;Bin Yang;Hui-zhen Jia;Jing-yi Zhu;Ren-xi Zhuo;Xian-zheng Zhang
Macromolecular Bioscience 2016 Volume 16( Issue 2) pp:175-181
Publication Date(Web):
DOI:10.1002/mabi.201500298
This study reports a linear-hyperbranched supramolecular amphiphile and its vesicular nanoassembly with acidity-sensitive susceptibility including volume extension and membrane rupture. Involvement of a host-guest interaction in the amphiphilic construction allows not only facile control of the assembly types (solid and hollow nanoparticles), but also the one-step achievement of both polymersome fabrication and drug encapsulation. The pH-dependency of assembly stability leads to the controlled release of encapsulated hydrophilic agents in an acidity-accelerated manner. By blocking the endosomal acidification progression using NH4Cl treatment, the lysosomal acid environment is suggested to play an important role in the drug release behavior inside cells and contributes much to nuclei-tropic drug transport.
Co-reporter:Huizhen Jia;Si Chen;Renxi Zhuo;Xianzheng Zhang
Science China Chemistry 2016 Volume 59( Issue 11) pp:1397-1404
Publication Date(Web):2016 November
DOI:10.1007/s11426-016-0230-9
A polymeric polyethylenimine (PEI)-based prodrug of anticancer doxorubicin (DOX) (PEI-hyd-DOX) was designed by attaching DOX to PEI via an acid-labile hydrazone bond, for the achievement of biocontrollable gene and drug co-delivery in response to the intracellular acid microenvironments in the late endosome/lysosome compartments. The cytotoxicity of PEI-hyd-DOX was evaluated by the MTT assay and the cellular uptake was monitored using confocal laser scanning microscopy. The polymeric prodrug can respond with a high sensitivity to the specific acid condition inside cells, thus permitting the precise biocontrol over intracellular drug liberation with high drug efficacy. The chemical attachment of drug molecules also led to the relatively reduced toxicity and the enhanced transfection efficiency compared with parent PEI. The resulting data adumbrated the potential of PEI-hyd-DOX to co-deliver DOX and therapeutic gene for the combination of chemotherapy and gene therapy.
Co-reporter:Bin Yang, Xing Dong, Qi Lei, Renxi Zhuo, Jun Feng, and Xianzheng Zhang
ACS Applied Materials & Interfaces 2015 Volume 7(Issue 39) pp:22084
Publication Date(Web):September 23, 2015
DOI:10.1021/acsami.5b07549
On the basis of host–guest interactions, this study reported a kind of linear–hyperbranched supramolecular amphiphile and its assembled vesicles for the combined achievement of drug encapsulation and DNA delivery. Amine-attached β-cyclodextrin-centered hyperbranched polyglycerol and linear adamantane-terminated octadecane were arranged to spontaneously interlink together and then self-assemble into nanoscale vesicles. As the model of a hydrophilic agent, DOX·HCl was demonstrated to be readily loaded into the hollow cavity of the vesicles. The drug release pattern could be controlled by adjusting the environmental acidity, favoring the intracellularly fast drug liberation in response to the cellular lysosomal microenvironment. The nanovesicles displayed superior serum-tolerant transgene ability and significantly lower cytotoxicity compared to those of PEI25K, the gold standard of gene delivery vectors. The drug-loaded nanovesicle can co-deliver DNA payloads into cells and allow the preferable accumulation of two payloads in nuclei. The drug encapsulation was found to have little influence on the transfection. This co-delivery vehicle presents a good example of rational design of cationic supramolecular vesicles for stimulus-responsive drug/DNA transport.Keywords: drug encapsulation; gene delivery; host−guest interaction; nanovesicles; supramolecular assembly
Co-reporter:Hui-Zhen Jia, Wei Zhang, Jun-Yi Zhu, Bin Yang, Si Chen, Gang Chen, Yi-Fang Zhao, Jun Feng, Xian-Zheng Zhang
Journal of Controlled Release 2015 Volume 216() pp:9-17
Publication Date(Web):28 October 2015
DOI:10.1016/j.jconrel.2015.08.006
This study reported a flexible nanoplatform constructed on the pH-dependent self-assembly of two kinds of hyperbranched polymers, and then validated its potency as the controllable siRNA/drug co-delivery vehicle for the combination of chemotherapy with RNA interfering (RNAi) therapy. By virtue of pH-reversible phenylboronate linking, phenylboronic acid-tethered hyperbranched oligoethylenimine (OEI600-PBA) and 1,3-diol-rich hyperbranched polyglycerol (HBPO) can be spontaneously interlinked together into a core–corona nanoconstruction. The special buildup of compactly clustering OEI600-PBA units around hydrophobic HBPO aggregate offered significant advantages over parent OEI600-PBA, including strengthened affinity to siRNA, ability of further loading anticancer drug, easier cellular transport, and acidity-responsive release of payloads. To evaluate the co-delivery capability, Beclin1 siRNA and antitumor DOX were used as the therapeutic models in order to suppress the post-chemotherapy survival of tumor cells caused by drug-induced autophagy. The nanoassembly-mediated single delivery of DOX displayed even better anticancer effects than free DOX, demonstrating the superiority of our pH-responsive nano-design. The nanoassembly-mediated co-delivery of siRNA together with DOX can effectively silence Beclin1 gene, suppress DOX-induced autophagy, and consequently provide strong synergism with a significant enhancement of cell-killing effects in cultured cancerous cells. The in vivo combinational treatment was shown to make the tumor more sensitive to DOX chemotherapy while displaying substantially improved safety as compared with the monochemotherapy.Hyperbranched–hyperbranched polymeric nanoassembly with pH-dependent stability has been built to realize controlled co-delivery of anticancer drug and siRNA for synergistic tumor therapy.
Co-reporter:Hui-Zhen Jia;Wei-Hai Chen;Xuli Wang;Qi Lei;Wei-Na Yin;Yan Wang;Ren-Xi Zhuo;Xian-Zheng Zhang
Advanced Science 2015 Volume 2( Issue 12) pp:
Publication Date(Web):
DOI:10.1002/advs.201500108
Co-reporter:Hui-Zhen Jia, Wei Zhang, Xu-Li Wang, Bin Yang, Wei-Hai Chen, Si Chen, Gang Chen, Yi-Fang Zhao, Ren-Xi Zhuo, Jun Feng and Xian-Zheng Zhang
Biomaterials Science 2015 vol. 3(Issue 7) pp:1066-1077
Publication Date(Web):18 Dec 2014
DOI:10.1039/C4BM00382A
This study plans to develop a nanoparticle technology that can assemble different polymeric “building blocks” with various desired functionalities into one nanosystem in a pH-dependent manner. For this purpose, polymeric building blocks were specifically designed with hyperbranched architectures, and orthogonal pH-reversible phenylboronic acid-diols were taken as “joints” to integrate them together. To verify the idea, a corona-core dual-polymer nanoassembly was prepared as the vehicle for lysosomotropic gene/drug co-delivery. Phenylboronic acid modified hyperbranched oligoethylenimine (OEI-PBA) was arranged to cluster around the hydrophobic core composed of hyperbranched polyglycerol, just by mixing two polymers in an appropriate ratio at neutral conditions. Compared with the parent OEI-PBA, this nanoassembly demonstrated better capture of plasmid DNA, highly enhanced activity for cellular transport and gene transfection (up to 100 fold), the ability to further load hydrophobic drugs, lysosome acidity-targeting pH-dependent release of both carried cargoes, and improved cell-biocompatibility. To evaluate its potential for combinational gene/drug therapy, in vitro experiments using the therapeutic p53 gene and antitumor doxorubicin as models were carried out. This intracellular co-delivery led to apparently synergetic anti-cancer effects in cultured cancer cells. This dynamic paradigm shows interesting features including easy manipulation, reversible conjugation, lysosome-targeting pH-responsiveness, high co-delivery efficiency, and functional expandability by further accommodating other building blocks.
Co-reporter:Jing-Yi Zhu, Qi Lei, Bin Yang, Hui-Zhen Jia, Wen-Xiu Qiu, Xuli Wang, Xuan Zeng, Ren-Xi Zhuo, Jun Feng, Xian-Zheng Zhang
Biomaterials 2015 52() pp: 281-290
Publication Date(Web):
DOI:10.1016/j.biomaterials.2015.02.048
Co-reporter:Bin Yang;Huizhen Jia;Xuli Wang;Si Chen;Xianzheng Zhang;Renxi Zhuo
Advanced Healthcare Materials 2014 Volume 3( Issue 4) pp:596-608
Publication Date(Web):
DOI:10.1002/adhm.201300162
By exploiting boronic acid coupling and host–guest chemistry, a pH-responsive drug/gene co-delivery nanoplatform is designed for cancer treatments with the excellently serum-tolerant transfection activity and the capability to load and release hydrophobic drugs in an acidity-accelerated manner. Via boronate linkage, γ-CD is allowed to spontaneously attach onto phenylboronic-acid-modified oligoethylenimine (PEI1.8K-PB2.9) at neutral condition. The formed vehicle/DNA nanoformulation is thus surrounded densely by γ-CD moieties to biomimic the carbohydrate-rich cell surface, providing a novel approach to overcome serum-susceptible drawbacks frequently associated with synthetic gene carriers. PEI1.8K-PB2.9-γ-CD conjugates demonstrate significantly improved cell-biocompatibility and transfection activity over PEI1.8K-PB2.9. Noticeably, serum-associated inhibition effect is negligible for PEI1.8K-PB2.9-γ-CD-mediated transfection whereas marked transfection reduction occurs for PEI25K and PEI1.8K-PB2.9 upon serum exposure. Consequently, PEI1.8K-PB2.9-γ-CDs afford much higher transfection efficiency, that is, 25-fold higher luciferase expression over PEI25K in presence of 30% serum. An anticancer drug of doxorubicin (DOX) is shown to be readily accommodated into the nanoformulation via host–guest chemistry and intracellularly co-delivered together with plasmid DNA. Due to the acidity-labile feature of boronate linkage, DOX/γ-CD inclusion complexes would be mostly detached from the nanoformulation triggered by acidity, leading to faster drug release. Furthermore, drug inclusion does not alter the serum-compatible transfection efficiency of PEI1.8K-PB2.9-γ-CD.
Co-reporter:Bin Yang, Yin Lv, Jing-yi Zhu, Yun-tao Han, Hui-zhen Jia, Wei-hai Chen, Jun Feng, Xian-zheng Zhang, Ren-xi Zhuo
Acta Biomaterialia 2014 Volume 10(Issue 8) pp:3686-3695
Publication Date(Web):August 2014
DOI:10.1016/j.actbio.2014.05.018
Abstract
The present work reports the construction of a drug delivery nanovehicle via a pH-sensitive assembly strategy for improved cellular internalization and intracellular drug liberation. Through spontaneous formation of boronate linkage in physiological conditions, phenylboronic acid-modified cholesterol was able to attach onto catechol-pending methoxypoly(ethylene glycol)-block-poly(l-lysine). This comb-type polymer can self-organize into a micellar nanoconstruction that is able to effectively encapsulate poorly water-soluble agents. The blank micelles exhibited negligible in vitro cytotoxicity, yet doxorubicin (DOX)-loaded micelles could effectively induce cell death at a level comparable to free DOX. Owing to the acid-labile feature of the boronate linkage, a reduction in environmental pH from pH 7.4 to 5.0 could trigger the dissociation of the nanoconstruction, which in turn could accelerate the liberation of entrapped drugs. Importantly, the blockage of endosomal acidification in HeLa cells by NH4Cl treatment significantly decreased the nuclear uptake efficiency and cell-killing effect mediated by the DOX-loaded nanoassembly, suggesting that acid-triggered destruction of the nanoconstruction is of significant importance in enhanced drug efficacy. Moreover, confocal fluorescence microscopy and flow cytometry assay revealed the effective internalization of the nanoassemblies, and their cellular uptake exhibited a cholesterol dose-dependent profile, indicating the contribution of introduced cholesterol functionality to the transmembrane process of the nanoassembly.
Co-reporter:Xuli Wang, Ye Yang, Huizhen Jia, Wanjian Jia, Scott Miller, Beth Bowman, Jun Feng and Fenghuang Zhan
Biomaterials Science 2014 vol. 2(Issue 7) pp:961-971
Publication Date(Web):14 Apr 2014
DOI:10.1039/C4BM00020J
To improve bone metastasis chemotherapy, a peptide-conjugated diblock copolymer consisting of a chimeric peptide, poly(ethylene glycol) and poly(trimethylene carbonate) (Pep-b-PEG-b-PTMC) is fabricated as a drug carrier capable of bone-seeking as well as pathology-responsive charge reversal to ensure effective cellular uptake at the lesion sites. The chimeric peptide CKGHPGGPQAsp8 consists of an osteotropic anionic Asp8, a cathepsin K (CTSK)-cleavable substrate (HPGGPQ) and a cationic residue tethered to the polymer chain. Pep-b-PEG-b-PTMC can spontaneously self-assemble into negatively charged nanomicelles (∼75 nm). As to the model drug of doxorubicin, Pep-b-PEG-b-PTM shows 30.0 ± 1% and 90.1 ± 2% for the loading content and loading efficiency, respectively. High bone binding capability is demonstrated with 66% of Pep-b-PEG-b-PTMC micelles were able to bind to hydroxyl apatite, whereas less than 15% of Pep-free micelles were bound to hydroxyl apatite. The nanomicelles exhibit a negative-to-positive charge conversion from −18.5 ± 1.9 mV to 15.2 ± 1.8 mV upon exposure to CTSK, an enzyme overexpressed in bone metastatic microenvironments. Such a pathology-responsive transition would lead to remarkably enhanced cellular uptake of the nanomicelles upon reaching lesion sites, thus improving the drug efficacy as verified by the in vitro cytotoxicity assay and the in vivo study with the myeloma-bearing 5TGM1 mice model.
Co-reporter:Hua-Fen Wang;Hui-Zhen Jia;Yan-Feng Chu;Xian-Zheng Zhang ;Ren-Xi Zhuo
Macromolecular Bioscience 2014 Volume 14( Issue 4) pp:526-536
Publication Date(Web):
DOI:10.1002/mabi.201300414
This paper reports a drug nanovehicle self-assembled from an amine-functionalized block copolymer poly(6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione)-block-poly(1,3-dioxepan-2-one) (PADMC-b-PTeMC), which is prepared by controlable ring-opening block copolymerization attractively in a “one-shot feeding” pathway. The copolymers display high cell-biocompatibility with no apparent cytotoxicities detected in 293T and HeLa cells. Due to their amphiphilic nature, PADMC-b-PTeMC copolymers can self-assemble into nanosized micelles capable of loading anticancer drugs such as camptothecin (CPT) and doxorubicin (DOX). In particular, the outer PADMC shell endows the PADMC-b-PTeMC nanomicelles with pH-dependent control over the micellar morphology, cell uptake efficiency, and the drug release pattern. Confocal inspection reveals the remarkably enhanced cellular internalization of drug loaded micelles by cancerous HeLa cells at relatively lower pH 5.8 simulating the mildly acid microenvironment in tumors. Along with the acidity-triggered volume expansion of micelles, an accelerated CPT release in vitro occurs. The obtained results adumbrate the possibility of completely biodegradable PADMC-b-PTeMC as pH-sensitive drug carriers for tumor chemotherapy.
Co-reporter:Hui-zhen Jia, Jun-yi Zhu, Xu-li Wang, Han Cheng, Gang Chen, Yi-fang Zhao, Xuan Zeng, Jun Feng, Xian-zheng Zhang, Ren-xi Zhuo
Biomaterials 2014 35(19) pp: 5240-5249
Publication Date(Web):
DOI:10.1016/j.biomaterials.2014.03.029
Co-reporter:Bin Yang;Yin Lv;QingRong Wang;Yun Liu;Hong An
Science China Chemistry 2014 Volume 57( Issue 4) pp:558-567
Publication Date(Web):2014 April
DOI:10.1007/s11426-013-5058-7
Based on specific host-guest interactions between amine-modified β-cyclodextrin (CD-TAEA) and functional adamantane (AD) derivatives, a module-template strategy has been proposed for the construction of low-molecular-weight cationic assemblies for gene transport. This strategy offers great flexibility in terms of the introduction of mono- or multi-functionality by the inclusion of one or more adamantane-based modules with the desired functionalities. As proof of concept, phenylboronic acid (PB) containing adamantane (PB-AD) was used as a model module in the hope of offering enhanced cytosolic delivery in consideration of the special affinity of PB groups with cell membranes. The physicochemical properties of the complexes formed with plasmid DNA, such as particle size, zeta potential and morphology were investigated. Confocal laser scanning microscopy and flow cytometry experiments demonstrated the important contribution of the functional PB-AD module to the considerably enhanced intracellular internalization and uptake by cellular nuclei. Compared to the parent CD-TAEA, PB-AD/CD-TAEA assemblies mediated higher transfection rates, which were even comparable to that of PEI25K. In addition, PB-AD/CD-TAEA displayed much lower cytotoxicity than PEI25K in both 293T and HeLa cell lines. The encouraging results suggest that CD-TAEA can be developed as a powerful template capable of readily accommodating various AD-based modules giving versatile functionalities for improved transfection.
Co-reporter:Jian-gang Ren, Hua-fen Wang, Gang Chen, Wei Zhang, Hui-zhen Jia, Jun Feng and Yi-fang Zhao
Journal of Materials Chemistry A 2013 vol. 1(Issue 20) pp:2601-2611
Publication Date(Web):19 Mar 2013
DOI:10.1039/C3TB20196A
Fast-flow vascular malformations are very difficult to treat by the currently available drug delivery systems due to the particular obstacles associated with rapid blood flow. The goal of the present study is to address such a challenge through a novel chemotherapy approach with the aid of injectable hydrogel. Specifically, a pingyangmycin (PYM)/PECE hydrogel is purposely designed with a programmed synergetic therapy mechanism involving the transient embolotherapy of hydrogel and in situ chemotherapy induced by the locally released drug in a sustained manner. This formulation remained mobile at room temperature whereas rapidly undergoing in vivo sol–gel transition upon injection into the body. The sustained release characteristic of PYM/PECE formulation was revealed both in vitro and in vivo. All the pharmacokinetic characteristics were highly improved including the Tmax, Cmax, t1/2β and AUC(0−t). The exceptional efficacy of PYM/PECE formulation was validated by rapid vascular occlusion in rabbit's fast-flow central auricular arteries whereas respective PYM and PECE treatment failed. The most remarkable features included the precise control over the occlusion site and the irreversible formation of vessel-isolated cell-rich lumps that was believed to benefit the occlusion formation. Intravascular PYM/PECE administration induced neither toxic responses nor histopathological changes in rabbits' major organs. The hydrogel matrix could be completely absorbed in vivo. The present study highlighted the great promise of our design as a safe and extremely effective modality in the treatment of fast-flow vascular malformations.
Co-reporter:Chen-Wei Liu, Feng Xiong, Hui-Zhen Jia, Xu-Li Wang, Han Cheng, Yong-Hua Sun, Xian-Zheng Zhang, Ren-Xi Zhuo, and Jun Feng
Biomacromolecules 2013 Volume 14(Issue 2) pp:
Publication Date(Web):January 3, 2013
DOI:10.1021/bm3015297
In this paper, a facile strategy to develop graphene-based delivery nanosystems for effective drug loading and sustained drug release was proposed and validated. Specifically, biocompatible naphthalene-terminated PEG (NP) and anticancer drugs (curcumin or doxorubicin (DOX)) were simultaneously integrated onto oxidized graphene (GO), leading to self-assembled, nanosized complexes. It was found that the oxidation degree of GO had a significant impact on the drug-loading efficiency and the structural stability of nanosystems. Interestingly, the nanoassemblies resulted in more effective cellular entry of DOX in comparison with free DOX or DOX-loaded PEG-polyester micelles at equivalent DOX dose, as demonstrated by confocal microscopy studies. Moreover, the nanoassemblies not only exhibited a sustained drug release pattern without an initial burst release, but also significantly improved the stability of formulations which were resistant to drug leaking even in the presence of strong surfactants such as aromatic sodium benzenesulfonate (SBen) and aliphatic sodium dodecylsulfonate (SDS). In addition, the nanoassemblies without DOX loading showed negligible in vitro cytotoxicity, whereas DOX-loaded counterparts led to considerable toxicity against HeLa cells. The DOX-mediated cytotoxicity of the graphene-based formulation was around 20 folds lower than that of free DOX, most likely due to the slow DOX release from complexes. A zebrafish model was established to assess the in vivo safety profile of curcumin-loaded nanosystems. The results showed they were able to excrete from the zebrafish body rapidly and had nearly no influence on the zebrafish upgrowth. Those encouraging results may prompt the advance of graphene-based nanotherapeutics for biomedical applications.
Co-reporter:Hui-zhen Jia, Xiao-hua Luo, Han Cheng, Juan Yang, Cao Li, Chen-Wei Liu, Jun Feng, Xian-zheng Zhang and Ren-xi Zhuo
Journal of Materials Chemistry A 2012 vol. 22(Issue 45) pp:24092-24101
Publication Date(Web):24 Sep 2012
DOI:10.1039/C2JM35175G
Different from commonly used alkylation strategies, PEI25K was modified with rigid, highly hydrophobic aromatic moieties to develop superior gene vectors with multiple functions, including structural compatibility with the cell membrane as well as cooperative contribution of electrostatic and hydrophobic interactions to the transfer process. A facile preparation approach was proposed by directly reacting PEI25K with 5-benzyloxyl trimethylene carbonate (BTMC) while omitting reagent activation and catalyst aid. The hydrophobic interactions between PEI-BTMC molecules serves as hydrophobic “locks” to stabilize polyplexes. PEI-BTMC polyplexes were kept good stability in the presence of heparin and DNase. The transfections mediated by PEI-BTMC vectors were better than PEI25K control in different cell lines. Particularly in HeLa cells, such enhancement owing to BTMC attachment can reach even up to 150 times. Experimental data indicated that the highly enhanced transfection mediated by PEI-BTMC was possibly more dependent on the special functions caused by BTMC modification rather than the improved cell-biocompatibility. Confocal laser scanning microscopy (CLSM) studies revealed the considerably higher potency of PEI-BTMC in transporting DNA into HeLa cells in comparison with PEI25K. It is expected that useful information provided in the current study would prompt the advance of PEI-based gene vectors towards practical applications.
Co-reporter:Hua-Fen Wang, Xiao-Hua Luo, Chen-Wei Liu, Jun Feng, Xian-Zheng Zhang, Ren-Xi Zhuo
Acta Biomaterialia 2012 Volume 8(Issue 2) pp:589-598
Publication Date(Web):February 2012
DOI:10.1016/j.actbio.2011.08.030
Abstract
The present paper reports the design and preparation of an amphiphilic triblock co-polymer poly(ε-caprolactone) (PCL)–poly(6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione) (PADMC)–PCL and the use of micelles composed of them as carriers for pH-sensitive drug release. The triblock co-polymers were synthesized via two-step ring-opening polymerization with catalysis by Novozym-435 lipase. By adjusting the feed ratio, three co-polymers with different PCL lengths and the same PADMC length were produced. The block structure of the co-polymers obtained was confirmed by comparative studies on PCL–PADMC–PCLs and the corresponding random poly(ε-caprolactone-random-6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione) (poly(CL-r-ADMC)) by means of nuclear magnetic resonance and differential scanning calorimetry. Cell cytotoxicity tests showed that the co-polymer displayed no apparent cytotoxicity to 293T and HeLa cells. Transmissions electron microscopy indicates that the self-assembled micelles exhibited a well-defined spherical shape with a diameter between ∼30 and 50 nm. The critical aggregation concentration was dependent on the block composition. Due to the presence of ionizable tertiary amine groups in the PADMC block, acid-induced variation in the micellar morphology was evident with respect to micelle size and size distribution. The size–pH curve was characterized by a smooth sigmoid form, and had a dramatic upward shift with decreasing pH from 6.5 to 4.5, which correlated well with the buffer range of hydrophilic PADMC. As a demonstration of the potential of PCL–PADMC–PCL micelles to control drug delivery, acid induced drug release for prednisone acetate-loaded micelles was explored. PCL–PADMC–PCL micelles show good promise as smart drug carriers, sensing the local specific pH decrease around lesion sites.
Co-reporter:Bin Yang, Yun-xia Sun, Wen-jie Yi, Juan Yang, Chen-wei Liu, Han Cheng, Jun Feng, Xian-zheng Zhang, Ren-xi Zhuo
Acta Biomaterialia 2012 Volume 8(Issue 6) pp:2121-2132
Publication Date(Web):July 2012
DOI:10.1016/j.actbio.2012.02.013
Abstract
This paper presents an attempt to design an efficient and biocompatible cationic gene vector via structural optimization that favors the efficient utilization of amine groups for DNA condensation. To this end, a linear-dendritic block copolymer of methoxyl-poly(ethylene glycol)-dendritic polyglycerol-graft-tris(2-aminoethyl)amine (mPEG-DPG-g-TAEA) was prepared with specially designed multiple functions including strong DNA affinity, endosomal buffering and expected serum-tolerance. Based on the transfection in serum-free and serum-conditioned media, the influences of the polymer structures including the degree of polymerization of DPG and TAEA substitution degree were explored. As compared to polyethylenimine (Mw = 5 kDa) (PEI5k) with similar molecular weight and higher amine density, mPEG-DPG-g-TAEA displayed comparably high DNA affinity due to the special linear-dendritic architecture. Consequently, at very low N/P ratio, mPEG-DPG-g-TAEA vectors could mediate efficient in vitro luciferase expression at levels that are comparable with or even superior to the commercially available Lipofectamine™ 2000, while being apparently higher than PEI5k. The designed vectors exhibit considerably higher cell biocompatibility and better resistance against bovine serum albumin adsorption than PEI5k. The stability of the complexes on coincubation with heparin was found to be largely dependent on the polymer structure. As concluded from the comparative transfection study in the absence/presence of chloroquine, it is likely that the polycation itself could produce endosomal buffering. This linear-dendritic vector shows promising potential for the application of gene delivery.
Co-reporter:Hui-zhen Jia, Hua-fen Wang, Chen-wei Liu, Cao Li, Juan Yang, Xiao-ding Xu, Jun Feng, Xian-zheng Zhang and Ren-xi Zhuo
Soft Matter 2012 vol. 8(Issue 26) pp:6906-6912
Publication Date(Web):24 May 2012
DOI:10.1039/C2SM25280E
The present study reported a pH-sensitive hydrogel constructed from a cationic hyperbranched polycarbonate, namely poly(EHDO-co-ADMC), functionalized with many hydroxyl and amine groups. The selective solubility of this hyperbranched polymer permitted the fabrication of corresponding nanoparticles/nanohydrogels of around 169 nm through a simple dialysis method. By using Nile Red dye as a model, the experimental results suggested the structural stability of the nanohydrogel in a neutral pH environment, and adumbrated its potential use as a delivery carrier for poorly water-soluble drugs. The nanohydrogel morphology presented a fast pH-responsive change across a narrow pH range from 7.4 to 6.6. This nanohydrogel shows promising potential in the application of controlled drug delivery.
Co-reporter:Hua-Fen Wang;Hui-Zhen Jia;Jing-Yi Zhu;Yan-Feng Chu;Xian-Zheng Zhang ;Ren-Xi Zhuo
Macromolecular Bioscience 2012 Volume 12( Issue 12) pp:1689-1696
Publication Date(Web):
DOI:10.1002/mabi.201200295
Co-reporter:Fu-Wei Huang, Jin Yang, Jun Feng, Ren-Xi Zhuo and Xian-Zheng Zhang
Journal of Materials Chemistry A 2011 vol. 21(Issue 11) pp:3585-3596
Publication Date(Web):27 Jan 2011
DOI:10.1039/C0JM03618H
In this paper, a highly efficient gene transfer vector with hepatocyte-targeted function, galactosylated poly(L-succinimide)-g-polyethylenimine-g-lactobionic acid (PSI-g-PEI-g-LA), was synthesized by conjugating lactobionic acid (LA) to biodegradable cationic PSI-g-PEI polymers. The physicochemical properties of PSI-g-PEI-g-LA including buffer capability, plasmid DNA (pDNA) binding ability, cytotoxicity, zeta potential and complex size were explored. Dynamic light scattering (DLS) reveals that PSI-g-PEI-g-LA can compactly condense pDNA into nano-sized particles with a hydrodynamic diameter of 95–175 nm. PSI-g-PEI-g-LA exhibits much higher cell-biocompatibility compared to PSI-g-PEI and PEI. The hepatocyte-targeted function was demonstrated by comparative studies on three polymeric vectors including PSI-g-PEI-g-LA, PSI-g-PEI and PEI25k. The transfection efficiency was evaluated in two different cell lines including asialoglyco protein receptor (ASGP-R) bearing HepG2 cells and ASGP-R-lacking HeLa cells. The in vitro transfection tests using different reporter genes indicate that PSI-g-PEI-g-LA displays higher transfection activity in HepG2 cells due to the specific interaction between LA segments and its ASGP-R on HepG2 cells compared with PSI-g-PEI and PEI. In contrast, the three polymers exhibit similar transfection activity in HeLa cells. PSI-g-PEI-g-LA displays better serum-tolerant transfection ability. Based on these analyses, PSI-g-PEI-g-LA was used as the vector to mediate the transfection of a tumor-suppressor gene p53. By means of western blotting analysis, flow cytometry and confocal laser scanning microscopy techniques, considerably high p53 gene expression and consequently strong p53-inducing apoptosis of HepG2 cells are distinctly observed.
Co-reporter:Wei Su, Hua-fen Wang, Jun Feng, Xiao-hua Luo, Xian-zheng Zhang and Ren-xi Zhuo
Journal of Materials Chemistry A 2011 vol. 21(Issue 17) pp:6327-6336
Publication Date(Web):18 Mar 2011
DOI:10.1039/C0JM04245E
The current study aimed at designing cationic and biodegradable biomaterials with improved biological functionality. We report the enzymatic synthesis, characterization and preliminary biological assessment of a series of novel functionalized poly(ester-co-carbonate)s, namely [poly(ADMC-co-CL)]s containing tertiary amine groups in the backbone. The copolymer compositions agreed very well with the feed ratios of co-monomers, indicating the excellent controllability of the preparation method. Static contact angle measurement revealed that the hydrophilicity of copolymers can be tailored and gradually increased with an increasing ADMC content in copolymers. With respect to the weight loss, in vitrodegradation tests demonstrated the occurrence of lipase-dependent degradation. Copolymers with a higher ADMC content degraded far faster as well. Cell proliferation tests suggested that the incorporation of ADMC in copolymers would considerably promote cell adhesion and proliferation on the polymer surface, indicative of good biocompatibility. As a demonstration of a potential application, poly(ADMC–co-CL) microspheres were fabricated in an attempt to construct a controlled delivery system for the drug ibuprofen. The sustained release of ibuprofen loaded in the copolymers was found to have an evident acceleration in acidic conditions, indicating the pH dependence of such release behavior.
Co-reporter:Xiao-hua Luo, Chen-Wei Liu, Ze-yong Li, Si-yong Qin, Jun Feng, Xian-zheng Zhang and Ren-xi Zhuo
Journal of Materials Chemistry A 2011 vol. 21(Issue 39) pp:15305-15315
Publication Date(Web):25 Aug 2011
DOI:10.1039/C1JM12849C
Endosomal escape of DNA polyplexes is one prominent bottleneck involved in the transfection process. Purposely against the low pH level in the endosome compartment, a series of acid-cleavable gene vectors constructed from oligoethyleneimine OEI800 polyconjugates linked with ketalized glycolic acid were designed herein and termed OEI-GKs. Their potential as gene vectors was comparatively evaluated by investigating the properties including DNA binding ability, polyplexes zeta potential, particle size, acid-triggered degradation, buffer capability before and after degradation, cytotoxicity, and transfection efficiency. The resultant data indicate that the transfection efficiency and cell-biocompatibility are dependent on the polymer architecture and molecular weights, which can be tailored by adjusting the charge ratio of OEI800versus the linking agent. OEI-GK(1:1) can be potentially developed as efficient vectors for the gene delivery in terms of their transfection activity even higher than PEI25k as well as the negligible cytotoxicity. Those improved properties are believed to have association with ketal-associated degradation of OEI-GK under acid conditions in the endosome, which lead to not only easy unpacking of DNA from the hydrolyzed polyplexes but also, interestingly, substantially enhanced buffer capability.
Co-reporter:Wei Su;Xiao-hua Luo;Hua-fen Wang;Lei Li;Xian-Zheng Zhang ;Ren-xi Zhuo
Macromolecular Rapid Communications 2011 Volume 32( Issue 4) pp:390-396
Publication Date(Web):
DOI:10.1002/marc.201000600
Co-reporter:Xiao-hua Luo, Fu-wei Huang, Si-yong Qin, Hua-fen Wang, Jun Feng, Xian-zheng Zhang, Ren-xi Zhuo
Biomaterials 2011 32(36) pp: 9925-9939
Publication Date(Web):
DOI:10.1016/j.biomaterials.2011.09.011
Co-reporter:Fu-Wei Huang, Hui-Yuan Wang, Cao Li, Hua-Fen Wang, Yun-Xia Sun, Jun Feng, Xian-Zheng Zhang, Ren-Xi Zhuo
Acta Biomaterialia 2010 Volume 6(Issue 11) pp:4285-4295
Publication Date(Web):November 2010
DOI:10.1016/j.actbio.2010.06.016
Abstract
Novel functional biodegradable gene vectors, poly(l-succinimide)-g-polyethylenimines-g-poly(ethylene glycol) (PSI-g-PEI-g-PEGs) were synthesized by conjugating methoxy poly(ethylene glycol) (mPEG, Mw = 750 Da) to PEI segments (Mw = 800 Da) of PSI-g-PEI. The physicochemical properties of PSI-g-PEI-g-PEGs, including buffering capability, pDNA binding ability, cytotoxicity, zeta potential and the particle size of polymer/pDNA complexes, were explored. The influence of PEGylation was discussed based on a comparative study of PSI-g-PEI-g-PEGs, PSI-g-PEI and PEI25k (Mw = 25 kDa). SEM images revealed that PSI-g-PEI-g-PEG/pDNA particles have a regular shape with the diameter ranging from 70 to 170 nm. PEGylation could suppress the aggregation occurrence between complexes, resulting in a reduction of the polymer/pDNA complex size. PSI-g-PEI-g-PEGs exhibited remarkably lower cytotoxicity compared to PSI-g-PEI and PEI25k. In 293T and HeLa cells, the obtained PSI-g-PEI-g-PEGs showed very high transfection efficiency compared to PEI25k. Fluorescent confocal microscopy demonstrated that PSI-g-PEI-g-PEGs could effectively transport pGL-3 plasmids into the nuclei of HeLa cells. Taking into account the continued high transfection efficacy and decreased toxicity after PEG modification, PSI-g-PEI-g-PEGs show great potential as the non-viral vectors for gene transfection.
Co-reporter:Xiao-hua Luo, Jun Feng, Hua-fen Wang, Wei Su, Xian-zheng Zhang and Ren-xi Zhuo
Polymer Journal 2010 42(9) pp:722-727
Publication Date(Web):August 4, 2010
DOI:10.1038/pj.2010.69
In this study, we developed a metal-free biosynthetic strategy of enzymatic polymerization to fabricate aliphatic poly(pentamethylene carbonate) (PPMC). Novozym-435 lipase showed considerably high catalytic efficiency, and high molecular weights (Mn) of up to 6.0 × 104 g mol−1 were readily achieved through the ring-opening polymerization of cyclobis(pentamethylene carbonate). The reaction parameters, including monomer concentration and lipase concentration, were examined. It seemed that little polymer degradation occurred during the polymerization, which would happen in the case of organometallic catalysis. In vitro enzymatic degradation tests indicate that the carbonate groups may not be sensitive to catalysis from the lipases of porcine pancreas and Candida rugosa (AYS). PPMC was found to possess higher flexibility and tenacity, relative to poly(trimethylene carbonate). Thermogravimetrical analyses suggest that the chemical structure of poly(alkylene carbonate)s exerts a significant influence on their thermal stability and decomposition mechanism.
Co-reporter:Hua-Fen Wang, Wei Su, Chao Zhang, Xiao-hua Luo, and Jun Feng
Biomacromolecules 2010 Volume 11(Issue 10) pp:
Publication Date(Web):September 13, 2010
DOI:10.1021/bm1001476
Degradable polymers with specifically designed functionality have wide applications in biomedical fields. We reported herein the synthesis and characterization of a water-soluble and fast-degradable polycarbonate, functionalized with tertiary amine groups in the backbone. A novel cyclic carbonate monomer, namely, 6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione (ADMC)2, was synthesized and polymerized to provide the title polycarbonate [poly(ADMC)] via Novozym-435 lipase or tin(II) 2-ethylheaxanoate [Sn(Oct)2] catalyzed ring-opening polymerization (ROP). Novozym-435 lipase exhibited high activity toward the ROP in terms of molecular weight (Mn) and monomer conversion, whereas the attempt with Sn(Oct)2 failed. In the presence of molecular sieves-4 Å, the highest Mn value of 1.2 × 104 g/mol was obtained in toluene with an initial monomer concentration of 0.58 M at 75 °C in the presence of 10 wt % of Novozym-435 to the monomer. Parameters that influence the polymerization, including reaction temperature, enzyme concentration, monomer concentration, and solvent composition, were investigated systematically. The resultant data suggested “living” characteristics for this enzyme-catalyzed polymerization, and the “living” feature seemed independent of the lipase concentration. The polymerization conducted in mixed solvents (toluene/isooctane) showed that product Mns were heavily dependent on the solvent composition. Poly(ADMC) was demonstrated to be amorphous by DSC technique. The obtained poly(ADMC) was found to be soluble in most of the organic solvents and interestingly in H2O as well. In vitro hydrolytic degradation of poly(ADMC) as monitored by GPC indicated the degradation was a relatively fast process. HPLC-ESI/MS and 1H NMR analyses demonstrated that N-methyl diethanolamine was the main product after degradation. Poly(ADMC) presented low cytotoxicity toward human cervix carcinoma (HeLa) cells and hepatoblastoma cells (Hep G2), as demonstrated by MTT assay.
Co-reporter:Wei Su, Jun Feng, Hua-Fen Wang, Xian-Zheng Zhang, Ren-Xi Zhuo
Polymer 2010 Volume 51(Issue 5) pp:1010-1015
Publication Date(Web):2 March 2010
DOI:10.1016/j.polymer.2010.01.009
The primary aim of this paper is to explore the influence of the number of CH2 groups per –(CH2)nOCOO– repeat unit (Numc) on the properties of poly(alkylene carbonate)s. A series of poly(alkylene carbonate)s with different Numc, including PTMC (Numc = 3), PTeMC (Numc = 4), PPMC (Numc = 5), PHMC (Numc = 6) and PDMC (Numc = 10) were investigated for that purpose by DSC and XRD techniques. The method of Sn(Oct)2-catalyzed ring-opening polymerization was developed to prepare poly(pentamethylene carbonate)s (PPMC), which presented a controllable feature. Regarding crystallization rate and Tm of poly(alkylene carbonate)s, an interesting odd–even effect was first reported related to the Numc. The order of crystallizing ability of poly(alkylene carbonate) was: PTMC (Numc = 3) < PPMC(Numc = 5) < PTeMC (Numc = 4) < PHMC (Numc = 6) < PDMC (Numc = 10). Poly(alkylene carbonate)s characterized with even Numc appeared to readily crystallize relative to that with odd Numc.
Co-reporter:Jun Feng, Wei Su, Hua-fen Wang, Fu-wei Huang, Xian-zheng Zhang and Ren-xi Zhuo
ACS Applied Materials & Interfaces 2009 Volume 1(Issue 12) pp:2729
Publication Date(Web):November 25, 2009
DOI:10.1021/am900452c
AB type diblock methoxy poly(ethylene glycol)-b-poly(tetramethylene carbonate) (mPEG-PTeMC) copolymers were designed for the first time and used as carriers for the sustained release of the hydrophobic drug ibuprofen. In this paper, we developed a facile ring-opening polymerization (ROP) method to prepare mPEG-PTeMC copolymers under the catalysis of Novozym-435 lipase. Attractively, the polymerization has been successfully performed at 30 °C, close to room temperature. The data show that the copolymer compositions agree well with the feed ratio of TeMC to mPEG, indicating the controllable feature of the polymerization. The copolymer structures were characterized by 1H NMR, IR, SEC, and DSC measurements. mPEG-PTeMC exhibits no apparent in vitro cytotoxicity toward human embryonic kidney transformed 293T cells. Those amphiphilic copolymers can readily self-assemble into nanosized micelles (about 150 nm) in aqueous solution. Their critical micelle concentrations are in the range of (1.6−9.3) × 10−7 mol/L, determined by fluorescence spectroscopy. The micelles present high stability in PBS solution, with no obvious change in micelle diameters over 5 days. Ibuprofen can be loaded effectively in mPEG-PTeMC micelles, and its sustained release behavior is observed. Transmission electron microscopy shows that the well-dispersed spherical micelles are around 25 nm in diameter, while the diameter is 30 nm after loading ibuprofen. The release rate increases when the chain length of the PTeMC block decreases. These properties show that the micelles self-assembled from mPEG-PTeMC copolymers would have great potential as carriers for the effective encapsulation as well as sustained release of hydrophobic drugs.Keywords: cytotoxicity; drug release; micelle; nanoparticle; polycarbonate; polyethylene oxide
Co-reporter:Fu-Wei Huang;Jun Nie;Si-Xue Cheng;Xian-Zheng Zhang;Ren-Xi Zhuo
Macromolecular Bioscience 2009 Volume 9( Issue 12) pp:1176-1184
Publication Date(Web):
DOI:10.1002/mabi.200900187
Co-reporter:Jun Feng, Hua-fen Wang, Xian-zheng Zhang, Ren-xi Zhuo
European Polymer Journal 2009 Volume 45(Issue 2) pp:523-529
Publication Date(Web):February 2009
DOI:10.1016/j.eurpolymj.2008.11.006
In this study, 26-membered macrocyclic carbonate, cyclobis(decamethylene carbonate) [(DMC)2] was attempted to undergo ring-opening polymerization by lipase catalysis in toluene. Novozym-435 exhibited even higher catalytic activity towards (DMC)2 polymerization compared with SnOCt2 while high molecular weight (Mn) of 5.4 × 104 and yield of 99% was still achieved at ultra-low enzyme/substrate (E/S) weight ratio of 1/200. 1H NMR spectra demonstrated the existence of terminal hydroxyl group. Solid phase polymerization in the absence of toluene unexpectedly took place at the temperature lower than (DMC)2’s melting point of 110 °C. Compared with solvent-free case, the addition of toluene solvent resulted in marked increase in reaction rate. As to the polymerization during 48 h with the E/S weight ratio of 1/100, a region existed at around toluene/carbonate (vol/wt, ml/g) ratio of 1∼2 where the polymerizations gave optimal results in terms of both higher molecular weight and monomer conversion. It was found that much higher molecular weight polymers may be obtained by decreasing enzyme concentrations. Plots of ln{[M]0:[M]t} versus reaction time were in linear agreement, indicating no chain termination, and monomer consumption follows a first-order rate law. The Novozym-435 catalyzed polymerization of (DMC)2 in toluene presented pseudo-living characteristic. Compared with 6-membered trimethylene carbonate, much lower reaction activity of large-sized (DMC)2 is observed, which is opposite to the result concerning the enzymatic polymerization of lactones with different ring-size.
Co-reporter:Fen Qiu, Jun Feng, De-Qun Wu, Xian-Zheng Zhang, Ren-Xi Zhuo
European Polymer Journal 2009 Volume 45(Issue 4) pp:1024-1031
Publication Date(Web):April 2009
DOI:10.1016/j.eurpolymj.2008.12.025
A series of amphiphilic copolymers, dextran-graft-methoxypolyethylene glycol/poly(ε-caprolactone) (Dex-g-mPEG/PCL) were synthesized by grafting both PCL and mPEG chains to dextran, and subsequently the micellar self-assembly behavior of resultant copolymers was investigated. PCL was designed by using Fmoc-protected valine other than organometallic catalyst as the initiator to ring-opening polymerize ε-caprolactone (CL) in view of the safety demand as well as the extra application potential resulting from –NH2 group introduced after Fmoc deprotection. All the copolymers were characterized by 1H NMR, FT-IR and GPC measurements. The prepared copolymers are capable of self-assembling into nanosized spherical micelles in aqueous solution with the diameter of around 100–200 nm determined by TEM image and DLS measurement. The critical micellar concentration (CMC) of the graft copolymers is in the range of 10–100 mg/L determined by the fluorescence robe technique using pyrene. The result also indicated that the CMC of self-assembled micelles could be adjusted by controlling the degree of substitution of mPEG and PCL, and these micelles may find great potential as drug carriers in biomedical fields.
Co-reporter:Jing-Yi Zhu, Xuan Zeng, Si-Yong Qin, Shuang-Shuang Wan, Hui-Zhen Jia, Ren-Xi Zhuo, Jun Feng, Xian-Zheng Zhang
Biomaterials (March 2016) Volume 83() pp:79-92
Publication Date(Web):March 2016
DOI:10.1016/j.biomaterials.2016.01.003
Co-reporter:Jing-Yi Zhu, Xuan Zeng, Si-Yong Qin, Shuang-Shuang Wan, Hui-Zhen Jia, Ren-Xi Zhuo, Jun Feng, Xian-Zheng Zhang
Biomaterials (March 2016) Volume 83() pp:79-92
Publication Date(Web):March 2016
DOI:10.1016/j.biomaterials.2016.01.003
In principle, not only efficient but rapid transfection is required since it can maximize the bioavailability of vector-carried gene prior to the cellular excretion. However, the “rapid” goal has been paid few attentions so far in the research field of vector-aided transfection. As a pioneering attempt, the present study designed a lysosome-targeting acidity-responsive nanoassembly as gene vectors, which proved the amazing potency to mediate the “Superfast” transnuclear gene transport and gene transfection with high efficiency in vitro and in vivo. The nanoassembly was constructed on the pH-reversible covalent boronic acid-diol coupling between 1,3-diol-rich oligoethylenimine (OEI-EHDO) and phenylboronic acid modified cholesterol (Chol-PBA). The rapid and efficient nuclei-tropic delivery and transfection was demonstrated to highly rely on the lysosome-acidity induced assembly destruction followed by the easy liberation of gene payloads inside cells. The nanoassembly-mediated transfection at 8 h can afford the outcome even comparable to that achieved at 48 h by the golden standard of PEI25k, and the transfection efficiency can still remain at a high level during 48 h. In contrast, time-dependent efficiency enhancement was identified for the transfections using PEI25k and OEI-EHDO as delivery vectors. Moreover, owing to the hydroxyl-rich surface, this delivery nanosystem presented strong tolerance to the serum-induced transfection inhibition that frequently occurred for the polycationic gene vectors such as PEI25k. The in vitro and in vivo results manifested the low toxicity of this bio-decomposable nanoassembly.
Co-reporter:Hui-Zhen Jia, Wei Zhang, Xu-Li Wang, Bin Yang, Wei-Hai Chen, Si Chen, Gang Chen, Yi-Fang Zhao, Ren-Xi Zhuo, Jun Feng and Xian-Zheng Zhang
Biomaterials Science (2013-Present) 2015 - vol. 3(Issue 7) pp:NaN1077-1077
Publication Date(Web):2014/12/18
DOI:10.1039/C4BM00382A
This study plans to develop a nanoparticle technology that can assemble different polymeric “building blocks” with various desired functionalities into one nanosystem in a pH-dependent manner. For this purpose, polymeric building blocks were specifically designed with hyperbranched architectures, and orthogonal pH-reversible phenylboronic acid-diols were taken as “joints” to integrate them together. To verify the idea, a corona-core dual-polymer nanoassembly was prepared as the vehicle for lysosomotropic gene/drug co-delivery. Phenylboronic acid modified hyperbranched oligoethylenimine (OEI-PBA) was arranged to cluster around the hydrophobic core composed of hyperbranched polyglycerol, just by mixing two polymers in an appropriate ratio at neutral conditions. Compared with the parent OEI-PBA, this nanoassembly demonstrated better capture of plasmid DNA, highly enhanced activity for cellular transport and gene transfection (up to 100 fold), the ability to further load hydrophobic drugs, lysosome acidity-targeting pH-dependent release of both carried cargoes, and improved cell-biocompatibility. To evaluate its potential for combinational gene/drug therapy, in vitro experiments using the therapeutic p53 gene and antitumor doxorubicin as models were carried out. This intracellular co-delivery led to apparently synergetic anti-cancer effects in cultured cancer cells. This dynamic paradigm shows interesting features including easy manipulation, reversible conjugation, lysosome-targeting pH-responsiveness, high co-delivery efficiency, and functional expandability by further accommodating other building blocks.
Co-reporter:Xuli Wang, Ye Yang, Huizhen Jia, Wanjian Jia, Scott Miller, Beth Bowman, Jun Feng and Fenghuang Zhan
Biomaterials Science (2013-Present) 2014 - vol. 2(Issue 7) pp:NaN971-971
Publication Date(Web):2014/04/14
DOI:10.1039/C4BM00020J
To improve bone metastasis chemotherapy, a peptide-conjugated diblock copolymer consisting of a chimeric peptide, poly(ethylene glycol) and poly(trimethylene carbonate) (Pep-b-PEG-b-PTMC) is fabricated as a drug carrier capable of bone-seeking as well as pathology-responsive charge reversal to ensure effective cellular uptake at the lesion sites. The chimeric peptide CKGHPGGPQAsp8 consists of an osteotropic anionic Asp8, a cathepsin K (CTSK)-cleavable substrate (HPGGPQ) and a cationic residue tethered to the polymer chain. Pep-b-PEG-b-PTMC can spontaneously self-assemble into negatively charged nanomicelles (∼75 nm). As to the model drug of doxorubicin, Pep-b-PEG-b-PTM shows 30.0 ± 1% and 90.1 ± 2% for the loading content and loading efficiency, respectively. High bone binding capability is demonstrated with 66% of Pep-b-PEG-b-PTMC micelles were able to bind to hydroxyl apatite, whereas less than 15% of Pep-free micelles were bound to hydroxyl apatite. The nanomicelles exhibit a negative-to-positive charge conversion from −18.5 ± 1.9 mV to 15.2 ± 1.8 mV upon exposure to CTSK, an enzyme overexpressed in bone metastatic microenvironments. Such a pathology-responsive transition would lead to remarkably enhanced cellular uptake of the nanomicelles upon reaching lesion sites, thus improving the drug efficacy as verified by the in vitro cytotoxicity assay and the in vivo study with the myeloma-bearing 5TGM1 mice model.
Co-reporter:Jian-gang Ren, Hua-fen Wang, Gang Chen, Wei Zhang, Hui-zhen Jia, Jun Feng and Yi-fang Zhao
Journal of Materials Chemistry A 2013 - vol. 1(Issue 20) pp:NaN2611-2611
Publication Date(Web):2013/03/19
DOI:10.1039/C3TB20196A
Fast-flow vascular malformations are very difficult to treat by the currently available drug delivery systems due to the particular obstacles associated with rapid blood flow. The goal of the present study is to address such a challenge through a novel chemotherapy approach with the aid of injectable hydrogel. Specifically, a pingyangmycin (PYM)/PECE hydrogel is purposely designed with a programmed synergetic therapy mechanism involving the transient embolotherapy of hydrogel and in situ chemotherapy induced by the locally released drug in a sustained manner. This formulation remained mobile at room temperature whereas rapidly undergoing in vivo sol–gel transition upon injection into the body. The sustained release characteristic of PYM/PECE formulation was revealed both in vitro and in vivo. All the pharmacokinetic characteristics were highly improved including the Tmax, Cmax, t1/2β and AUC(0−t). The exceptional efficacy of PYM/PECE formulation was validated by rapid vascular occlusion in rabbit's fast-flow central auricular arteries whereas respective PYM and PECE treatment failed. The most remarkable features included the precise control over the occlusion site and the irreversible formation of vessel-isolated cell-rich lumps that was believed to benefit the occlusion formation. Intravascular PYM/PECE administration induced neither toxic responses nor histopathological changes in rabbits' major organs. The hydrogel matrix could be completely absorbed in vivo. The present study highlighted the great promise of our design as a safe and extremely effective modality in the treatment of fast-flow vascular malformations.
Co-reporter:Fu-Wei Huang, Jin Yang, Jun Feng, Ren-Xi Zhuo and Xian-Zheng Zhang
Journal of Materials Chemistry A 2011 - vol. 21(Issue 11) pp:NaN3596-3596
Publication Date(Web):2011/01/27
DOI:10.1039/C0JM03618H
In this paper, a highly efficient gene transfer vector with hepatocyte-targeted function, galactosylated poly(L-succinimide)-g-polyethylenimine-g-lactobionic acid (PSI-g-PEI-g-LA), was synthesized by conjugating lactobionic acid (LA) to biodegradable cationic PSI-g-PEI polymers. The physicochemical properties of PSI-g-PEI-g-LA including buffer capability, plasmid DNA (pDNA) binding ability, cytotoxicity, zeta potential and complex size were explored. Dynamic light scattering (DLS) reveals that PSI-g-PEI-g-LA can compactly condense pDNA into nano-sized particles with a hydrodynamic diameter of 95–175 nm. PSI-g-PEI-g-LA exhibits much higher cell-biocompatibility compared to PSI-g-PEI and PEI. The hepatocyte-targeted function was demonstrated by comparative studies on three polymeric vectors including PSI-g-PEI-g-LA, PSI-g-PEI and PEI25k. The transfection efficiency was evaluated in two different cell lines including asialoglyco protein receptor (ASGP-R) bearing HepG2 cells and ASGP-R-lacking HeLa cells. The in vitro transfection tests using different reporter genes indicate that PSI-g-PEI-g-LA displays higher transfection activity in HepG2 cells due to the specific interaction between LA segments and its ASGP-R on HepG2 cells compared with PSI-g-PEI and PEI. In contrast, the three polymers exhibit similar transfection activity in HeLa cells. PSI-g-PEI-g-LA displays better serum-tolerant transfection ability. Based on these analyses, PSI-g-PEI-g-LA was used as the vector to mediate the transfection of a tumor-suppressor gene p53. By means of western blotting analysis, flow cytometry and confocal laser scanning microscopy techniques, considerably high p53 gene expression and consequently strong p53-inducing apoptosis of HepG2 cells are distinctly observed.
Co-reporter:Hui-zhen Jia, Xiao-hua Luo, Han Cheng, Juan Yang, Cao Li, Chen-Wei Liu, Jun Feng, Xian-zheng Zhang and Ren-xi Zhuo
Journal of Materials Chemistry A 2012 - vol. 22(Issue 45) pp:NaN24101-24101
Publication Date(Web):2012/09/24
DOI:10.1039/C2JM35175G
Different from commonly used alkylation strategies, PEI25K was modified with rigid, highly hydrophobic aromatic moieties to develop superior gene vectors with multiple functions, including structural compatibility with the cell membrane as well as cooperative contribution of electrostatic and hydrophobic interactions to the transfer process. A facile preparation approach was proposed by directly reacting PEI25K with 5-benzyloxyl trimethylene carbonate (BTMC) while omitting reagent activation and catalyst aid. The hydrophobic interactions between PEI-BTMC molecules serves as hydrophobic “locks” to stabilize polyplexes. PEI-BTMC polyplexes were kept good stability in the presence of heparin and DNase. The transfections mediated by PEI-BTMC vectors were better than PEI25K control in different cell lines. Particularly in HeLa cells, such enhancement owing to BTMC attachment can reach even up to 150 times. Experimental data indicated that the highly enhanced transfection mediated by PEI-BTMC was possibly more dependent on the special functions caused by BTMC modification rather than the improved cell-biocompatibility. Confocal laser scanning microscopy (CLSM) studies revealed the considerably higher potency of PEI-BTMC in transporting DNA into HeLa cells in comparison with PEI25K. It is expected that useful information provided in the current study would prompt the advance of PEI-based gene vectors towards practical applications.
Co-reporter:Wei Su, Hua-fen Wang, Jun Feng, Xiao-hua Luo, Xian-zheng Zhang and Ren-xi Zhuo
Journal of Materials Chemistry A 2011 - vol. 21(Issue 17) pp:NaN6336-6336
Publication Date(Web):2011/03/18
DOI:10.1039/C0JM04245E
The current study aimed at designing cationic and biodegradable biomaterials with improved biological functionality. We report the enzymatic synthesis, characterization and preliminary biological assessment of a series of novel functionalized poly(ester-co-carbonate)s, namely [poly(ADMC-co-CL)]s containing tertiary amine groups in the backbone. The copolymer compositions agreed very well with the feed ratios of co-monomers, indicating the excellent controllability of the preparation method. Static contact angle measurement revealed that the hydrophilicity of copolymers can be tailored and gradually increased with an increasing ADMC content in copolymers. With respect to the weight loss, in vitrodegradation tests demonstrated the occurrence of lipase-dependent degradation. Copolymers with a higher ADMC content degraded far faster as well. Cell proliferation tests suggested that the incorporation of ADMC in copolymers would considerably promote cell adhesion and proliferation on the polymer surface, indicative of good biocompatibility. As a demonstration of a potential application, poly(ADMC–co-CL) microspheres were fabricated in an attempt to construct a controlled delivery system for the drug ibuprofen. The sustained release of ibuprofen loaded in the copolymers was found to have an evident acceleration in acidic conditions, indicating the pH dependence of such release behavior.
Co-reporter:Xiao-hua Luo, Chen-Wei Liu, Ze-yong Li, Si-yong Qin, Jun Feng, Xian-zheng Zhang and Ren-xi Zhuo
Journal of Materials Chemistry A 2011 - vol. 21(Issue 39) pp:NaN15315-15315
Publication Date(Web):2011/08/25
DOI:10.1039/C1JM12849C
Endosomal escape of DNA polyplexes is one prominent bottleneck involved in the transfection process. Purposely against the low pH level in the endosome compartment, a series of acid-cleavable gene vectors constructed from oligoethyleneimine OEI800 polyconjugates linked with ketalized glycolic acid were designed herein and termed OEI-GKs. Their potential as gene vectors was comparatively evaluated by investigating the properties including DNA binding ability, polyplexes zeta potential, particle size, acid-triggered degradation, buffer capability before and after degradation, cytotoxicity, and transfection efficiency. The resultant data indicate that the transfection efficiency and cell-biocompatibility are dependent on the polymer architecture and molecular weights, which can be tailored by adjusting the charge ratio of OEI800versus the linking agent. OEI-GK(1:1) can be potentially developed as efficient vectors for the gene delivery in terms of their transfection activity even higher than PEI25k as well as the negligible cytotoxicity. Those improved properties are believed to have association with ketal-associated degradation of OEI-GK under acid conditions in the endosome, which lead to not only easy unpacking of DNA from the hydrolyzed polyplexes but also, interestingly, substantially enhanced buffer capability.
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