title: Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel.
abstract: A targeted intracellular delivery system of paclitaxel (PTX) was successfully developed based on redox-sensitive hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates. The conjugates self-assembled into nano-size micelles in aqueous media and exhibited excellent drug-loading capacities (34.1%) and entrapment efficiency (93.2%) for PTX. HA-ss-DOCA micelles were sufficiently stable at simulated normal physiologic condition but fast disassembled in the presence of 20 mm reducing agent, glutathione. In vitro drug release studies showed that the PTX-loaded HA-ss-DOCA micelles accomplished rapid drug release under reducing condition. Intracellular release of fluorescent probe nile red indicated that HA-ss-DOCA micelles provide an effective approach for rapid transport of cargo into the cytoplasm. Enhanced cytotoxicity of PTX-loaded HA-ss-DOCA micelles further confirmed that the sensitive micelles are more potent for intracellular drug delivery as compared to the insensitive control. Based on flow cytometry and confocal microscopic analyses, observations revealed that HA-ss-DOCA micelles were taken up to human breast adenocarcinoma cells (MDA-MB-231) via HA-receptor mediated endocytosis. In vivo investigation of micelles in tumor-bearing mice confirmed that HA-ss-DOCA micelles possessed much higher tumor targeting capacity than the insensitive control. These results suggest that redox-sensitive HA-ss-DOCA micelles hold great potential as targeted intracellular delivery carriers of lipophilic anticancer drugs.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Meirong
authors.initials: M
authors.lastname: Huo
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.forename: Jumah M
authors.initials: JM
authors.lastname: Mohammad
authors.forename: Yinlong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qinnv
authors.initials: Q
authors.lastname: Zhu
authors.forename: Ayman Y
authors.initials: AY
authors.lastname: Waddad
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003840:Deoxycholic Acid / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D008422:Materials Testing; D051379:Mice; D008823:Micelles; D018625:Microscopy, Atomic Force; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D010078:Oxazines / Q000737:chemistry; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D005456:Fluorescent Dyes; D008823:Micelles; D010078:Oxazines; D003840:Deoxycholic Acid; D006820:Hyaluronic Acid; D005978:Glutathione; C044808:nile red; D017239:Paclitaxel