title: Novel oral administrated paclitaxel micelles with enhanced bioavailability and antitumor efficacy for resistant breast cancer.
abstract: Paclitaxel (PTX) is a widely used antineoplastic drug in clinic. Due to poor aqueous solubility, it is administrated by intravenous infusion of cremophor EL containing formulation with serious adverse effects. The low oral bioavailability is a great challenge for oral formulation development. In addition, P-gp mediated multidrug resistance limit its clinical use in various resistant cancers. In this study, a novel super-antiresistant PTX micelle formulation for oral administration was developed. A P-gp inhibitor, bromotetrandrine (W198) was co-encapsulated in the micelle. The micelles were composed of Solutol HS 15 and d-a-tocopheryl polyethylene glycol succinate to avoid Cremophor EL induced toxicity. The micelles were round with a mean particle size of ∼13nm and an encapsulation efficiency of ∼90%. A series of in vitro evaluations were performed in non-resistant MCF-7 cells and resistant MCF-7/Adr cells. The super-antiresistant PTX micelles showed higher cell uptake efficiency, significantly increased cytotoxicity and antimitotic effect in drug resistant MCF-7/Adr cells when compared with Taxol and other PTX micelle formulations. Compared with Taxol, the super-antiresistant PTX micelles significantly improved bioavailability after oral administration in rats, and inhibited tumor growth in multidrug resistance xenografted MCF-7/Adr nude mice. In summary, the noval super-antiresistant PTX micelles showed a great potential for oral delivery of PTX against resistant breast cancer.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Luo
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Hanmei
authors.initials: H
authors.lastname: Li
authors.affiliation: Beijing Institute for Drug Control, Beijing 100035, China. Electronic address: dingrui1001@aliyun.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Ding
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address: gongtaoy@126.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D044182:Benzylisoquinolines / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy*; D018938:Caco-2 Cells; D002453:Cell Cycle; D019008:Drug Resistance, Neoplasm; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D044182:Benzylisoquinolines; D008823:Micelles; C514835:bromotetrandrine; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol
keywords: Micelles; Multidrug resistance; Oral bioavailability; P-glycoprotein inhibitor; Paclitaxel; Permeability