Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid

doi:10.1016/j.actbio.2015.08.029

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	Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid
	Yin, Shaoping 4; Huai, Jue 4; Chen, Xi 4; Yang, Yong 5; Zhang, Xinxin1 ; Gan, Yong1 ; Wang, Guangji 3; Gu, Xiaochen 2; Li, Juan 4
刊名	ACTA BIOMATERIALIA
	2015-10-15
卷号	26 页码:274-285
关键词	Redox-response HA-ss-PTX conjugates Cancer-targeted therapy Intracellular release CD44
ISSN号	1742-7061
DOI	10.1016/j.actbio.2015.08.029
文献子类	Article
英文摘要	Polymer drug conjugates have demonstrated application potentials in optimizing chemotherapeutics. In this study a new bioconjugate, HA-ss-PTX, was designed and synthesized with cooperative dual characteristics of active tumor targeting and selective intracellular drug release. Paclitaxel (PTX) was covalently attached to hyaluronic acid (HA) with various sizes (MW 9.5, 35, 770 kDa); a cross-linker containing disulfide bond was also used to shield drug leakage in blood circulation and to achieve rapid drug release in tumor cells in response to glutathione. Incorporation of HA to the conjugate enhanced the capabilities of drug loading, intracellular endocytosis and tumor targeting of micelles in comparison to mPEG. HA molecular weight showed significant effect on properties and antitumor efficacy of the synthesized conjugates. Intracellular uptake of HA-ss-PTX toward MCF-7 cells was mediated by CD44-caveolae-mediated endocytosis. Compared to Taxol and mPEG-ss-PTX, HA9.5-ss-PTX demonstrated improved tumor growth inhibition in vivo with a TIR of 83.27 +/- 5.20%. It was concluded that HA9.5-ss-PTX achieved rapid intracellular release of PTX and enhanced its therapeutic efficacy, thus providing a platform for specific drug targeting and controlled intracellular release in chemotherapeutics. Statement of Significance Polymer drug conjugates, promising nanomedicines, still face some technical challenges including a lack of specific targeting and rapid intracellular drug release at the target site. In this manuscript we designed and constructed a novel bioconjugate HA-ss-PTX, which possessed coordinated dual characteristics of active tumor targeting and selective intracellular drug release. Redox-responsive disulfide bond was introduced to the conjugate to shield drug leakage in blood circulation and to achieve rapid drug release at tumor site in response to reductant like glutathione. Paclitaxel was selected as a model drug to be covalently attached to hyaluronic acid (HA) with various sizes to elucidate the structure activity relationship and to address whether HA could substitute PEG as a carrier for polymeric conjugates. Based on a series of in vitro and in vivo experiments, HA-ss-PTX performed well in drug loading, cellular internalization, tumor targeting by entering tumor cells via CD44-caveolae-mediated endocytosis and rapidly release drug at target in the presence of GSH. One of the key issues in clinical oncology is to enhance drug delivery efficacy while minimizing side effects. The study indicated that this new polymeric conjugate system would be useful in delivering anticancer agents to improve therapeutic efficacy and to minimize adverse effects, thus providing a platform for specific drug targeting and controlled intracellular release in chemotherapeutics. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
资助项目	National Natural Science Foundation of China[81373363] ; National Major Scientific and Technological Special Project for "Significant New Drugs Development" during the Twelfth Five-year Plan Period[2015ZX09501001] ; Fundamental Research Funds for the Central Universities[PT2014YX0085] ; Huahai Pharmaceutical Postgraduate Innovation Fund[CX14B-001HH] ; Advantages of Disciplines in Colleges and Universities in Jiangsu Province Construction Grant Program[00000000]
WOS关键词	SELF-ASSEMBLED NANOPARTICLES ; DRUG-DELIVERY ; BLOCK-COPOLYMERS ; GENE DELIVERY ; BREAST-CANCER ; MICELLES ; RELEASE ; CELLS ; MECHANISM ; THERAPY
WOS研究方向	Engineering ; Materials Science
语种	英语
出版者	ELSEVIER SCI LTD
WOS记录号	WOS:000362917200026
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276361]
专题	药物制剂研究中心
通讯作者	Li, Juan
作者单位	1.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Univ Manitoba, Coll Pharm, Winnipeg, MB R3E 0T5, Canada 3.China Pharmaceut Univ, Key Lab Drug Metab & Pharmacokinet, Ctr Pharmacokinet, Nanjing 210009, Jiangsu, Peoples R China; 4.China Pharmaceut Univ, Dept Pharmaceut, Nanjing 210009, Jiangsu, Peoples R China; 5.China Pharmaceut Univ, Ctr New Drug Safety Evaluat & Res, Nanjing 210009, Jiangsu, Peoples R China;
推荐引用方式 GB/T 7714	Yin, Shaoping,Huai, Jue,Chen, Xi,et al. Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid[J]. ACTA BIOMATERIALIA,2015,26:274-285.
APA	Yin, Shaoping.,Huai, Jue.,Chen, Xi.,Yang, Yong.,Zhang, Xinxin.,...&Li, Juan.(2015).Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid.ACTA BIOMATERIALIA,26,274-285.
MLA	Yin, Shaoping,et al."Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid".ACTA BIOMATERIALIA 26(2015):274-285.