title: Co-delivery of hydrophobic paclitaxel and hydrophilic AURKA specific siRNA by redox-sensitive micelles for effective treatment of breast cancer.
abstract: In this study, a novel redox-sensitive micellar system constructed from a hyaluronic acid-based amphiphilic conjugate (HA-ss-(OA-g-bPEI), HSOP) was successfully developed for tumor-targeted co-delivery of paclitaxel (PTX) and AURKA specific siRNA (si-AURKA). HSOP exhibited excellent loading capacities for both PTX and siRNA with adjustable dosing ratios and desirable redox-sensitivity independently verified by morphological changes of micelles alongside in vitro release of both drugs in different reducing environments. Moreover, flow cytometry and confocal microscopy analysis confirmed that HSOP micelles were capable of simultaneously delivering PTX and siRNA into MDA-MB-231 breast cancer cells via HA-receptor mediated endocytosis followed by rapid transport of cargoes into the cytosol. Successful delivery and transport amplified the synergistic effects between the drugs while leading to substantially greater antitumor efficacy when compared with single drug-loaded micelles and non-sensitive co-loaded micelles. In vivo investigation demonstrated that HSOP micelles could effectively accumulate in tumor sites and possessed the greatest antitumor efficacy over non-sensitive co-delivery control and redox-sensitive single-drug controls. These findings indicated that redox-sensitive HSOP co-delivery system holds great promise for combined drug/gene treatment for targeted cancer therapy.
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Tingjie
authors.initials: T
authors.lastname: Yin
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: cpu_zhoujp@163.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: huomeirongcpu@163.com.
authors.forename: Meirong
authors.initials: M
authors.lastname: Huo
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry; D064096:Aurora Kinase A / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis*; D004058:Diffusion; D004338:Drug Combinations; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D008823:Micelles; D053769:Nanocapsules; D058726:Nanoconjugates; D034741:RNA, Small Interfering; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D017239:Paclitaxel
keywords: Co-delivery; Micelles; Paclitaxel; Redox-sensitive; Synergistic effect; siRNA