title: Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors: Shaoping
authors: S
authors: Yin
authors: Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors: Jue
authors: J
authors: Huai
authors: Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors: Xi
authors: X
authors: Chen
authors: Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 210009, China.
authors: Yong
authors: Y
authors: Yang
authors: Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 201203, China.
authors: Xinxin
authors: X
authors: Zhang
authors: Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 201203, China.
authors: Yong
authors: Y
authors: Gan
authors: Center of Pharmacokinetics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Guangji
authors: G
authors: Wang
authors: College of Pharmacy, University of Manitoba, Winnipeg, MB R3E 0T5, Canada.
authors: Xiaochen
authors: X
authors: Gu
authors: Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: lijuancpu@163.com.
authors: Juan
authors: J
authors: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis*; D004058:Diffusion; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D061986:MCF-7 Cells; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D058726:Nanoconjugates / Q000737:chemistry / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D053769:Nanocapsules; D058726:Nanoconjugates; D011108:Polymers; D006820:Hyaluronic Acid; D017239:Paclitaxel
keywords: CD44; Cancer-targeted therapy; HA-ss-PTX conjugates; Intracellular release; Redox-response