title: Poly(caprolactone)-modified Pluronic P105 micelles for reversal of paclitaxcel-resistance in SKOV-3 tumors.
abstract: Three poly(caprolactone)-modified Pluronic P105 polymers (P105/PCLs) were synthesized using commercially available ε-caprolactone monomers and Pluronic P105 copolymers. The chemical structures, compositions and molecular weights of the P105/PCLs were confirmed by FT-IR, (1)H NMR and GPC measurements. Three paclitaxel (PTX)-loaded P105/PCL polymeric micelles were then prepared, and they showed average diameters in the range of 30-150 nm, drug-loading coefficients of 0.15%-5.43%, and encapsulation ratios of 2.1%-76.53%. The in vitro cytotoxicity assay demonstrated that three PTX-loaded P105/PCL micelles were able to sensitize the resistant SKOV-3/PTX tumor cells. The PTX-loaded P105/PCL(50) micelle was then selected for an in vivo antitumor efficacy study. The tumor volumes in nude mice bearing s.c. resistant SKOV-3/PTX carcinoma treated with this micellar PTX were significantly less than the control group treated with Taxol. It was demonstrated that three PCL-modified P105 monomers and micelles inhibited P-gP efflux activity in the resistant SKOV-3/PTX cells via at least three intracellular events: 1) inhibition of ATPase of P-gP, 2) decrease of membrane microviscosity and 3) a loss of mitochondrial membrane potential and subsequent decrease of ATP levels at the concentration of monomers (0.001%) and/or micelles (0.01-1.0%). Considering other favorable characteristics, such as sustained PTX release in vitro, long-circulating time in vivo and increased PTX concentration in the tissues of ovaries and uterus in mice, the PCL-modified Pluronic P105 polymeric micelle system could have important clinical implications for delivery of paclitaxel and treatment of the resistant ovarian tumors.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 200032, China. yongzhong00@126.com
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Junguo
authors.initials: J
authors.lastname: Hao
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Li
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xianyi
authors.initials: X
authors.lastname: Sha
authors.forename: Limei
authors.initials: L
authors.lastname: Han
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Fang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008823:Micelles; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D020442:Poloxamer / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D020442:Poloxamer; C016240:polycaprolactone; C519610:pluronic P105; D017239:Paclitaxel