title: [Preparation, characterization of paclitaxel-loaded Pluronic P105 polymeric micelles and in vitro reversal of multidrug resistant tumor].
abstract: Drug delivery system (DDS) is a novel approach to overcome multidrug resistance (MDR) in tumors nowadays. This work was designed to investigate a new micellar delivery system for in vitro reversal of resistant ovarian tumor cells, based on a nonionic triblock copolymer Pluronic P105 and paclitaxel (PTX). The PTX-loaded polymeric micelles (P105/PTX) were prepared by thin film-hydration methods. Based on the results of single factor experiments, the P105/PTX micelle formulation was optimized by employing the central composite design-response surface methodology. The physico-chemical properties of the P105/PTX micelles were characterized, including micelle size, drug loading coefficient, in vitro release behavior, etc. The cytotoxicity of the P105/PTX micelles was assessed against human ovarian tumor cell line, SKOV-3/PTX, by a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay. In order to understand the possible mechanism of Pluronic effects in resistant tumor cells, cellular uptake study of micellar PTX or Rhodamine-123 (R-123) was also carried out. The results showed that the micelle size was about 24 nm with drug loading coefficient of 1.1% and PTX concentration of 700 microg x mL(-1). The cumulative release amount of PTX from the P105/PTX micelles was only 45.4% in 6 h (P < 0.05) and 79.6% in 24 h, whereas Taxol injection in 6 h released 95.2% PTX. The IC50 values of the P105/PTX micelles and Taxol injection against SKOV-3/PTX were 1.14 and 5.11 microg x mL(-1), and resistance reversion index (RRI) was 9.65 and 2.15, respectively. The micellar PTX or R-123 exhibited a significant increase in cellular uptake in resistant SKOV-3/PTX cells compared with free PTX or R-123. These results indicated that PTX could effectively be solubilized by Pluronic P105 block copolymers via thin film-hydration process and formulation optimization, producing nano-scale polymeric micelles with sustained release property in vitro. The P105/PTX micelles were effectively able to reverse resistance to PTX in SKOV-3/PTX tumor cells compared with Taxol injection or free PTX solution, and the enhanced cytotoxicity in the resistant SKOV-3/PTX cell was related to the improved cellular uptake of PTX by Pluronic P105 copolymers.
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 200032, China.
authors.forename: Yong-Zhong
authors.initials: YZ
authors.lastname: Wang
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Fang
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Li
authors.forename: Zhi-Wen
authors.initials: ZW
authors.lastname: Zhang
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Han
authors.forename: Xian-Yi
authors.initials: XY
authors.lastname: Sha
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004337:Drug Carriers; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005079:Excipients / Q000737:chemistry; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008823:Micelles; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D005079:Excipients; D008823:Micelles; D020442:Poloxamer; C519610:pluronic P105; D017239:Paclitaxel