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: Yongzhong Wang, Junguo Hao, Yajuan Li, Zhiwen Zhang, Xianyi Sha, Limei Han, Xiaoling Fang
• Journal: Biomaterials (Biomaterials) Vol. 33 Issue 18 Pg. 4741-51 (Jun 2012) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 22445254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Drug Carriers
• Micelles
• Polyesters
• Poloxamer
• polycaprolactone
• pluronic P105
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, chemistry, therapeutic use)
• Cell Line, Tumor
• Drug Carriers (chemistry)
• Drug Resistance, Neoplasm
• Female
• Humans
• Mice
• Micelles
• Ovarian Neoplasms (drug therapy)
• Paclitaxel (administration & dosage, chemistry, therapeutic use)
• Poloxamer (chemistry)
• Polyesters (chemistry)
• Xenograft Model Antitumor Assays