Co-delivery of docetaxel and verapamil by reduction-sensitive PEG-PLGA-SS-DTX conjugate micelles to reverse the multi-drug resistance of breast cancer

• Published in: Colloids and surfaces, B, Biointerfaces Vol. 151; pp. 119 - 127
• Main Authors: Guo, Yuanyuan, He, Wenxiu, Yang, Shengfeng, Zhao, Dujuan, Li, Zhonghao, Luan, Yuxia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2017
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell Survival; Co-delivery; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; DTX; Female; Humans; Inhibitory Concentration 50; MCF-7 Cells; MDR; Micelles; Microscopy, Electron, Transmission; Polyesters - chemistry; Polyethylene Glycols - chemistry; PP-SS-DTX; Rats; Rats, Wistar; Reduction sensitive; Solubility; Succinimides - chemistry; Taxoids - administration & dosage; Taxoids - chemistry; Verapamil - administration & dosage; Verapamil - chemistry; VRP; DTX; PP-SS-DTX; MDR; Co-delivery; VRP; Reduction sensitive
• ISSN: 0927-7765; 1873-4367
• DOI: 10.1016/j.colsurfb.2016.12.012

[Display omitted] •The micelles showed sustained, reduction sensitive and programmed release profile.•The micelles could completely restrain the efflux activity of p-gp and reverse MDR.•The micelles prolonged the in vivo circulation and enhanced the drug accumulation. The clinical usage of docetaxel (DTX) has been blocked in the clinic because of its poor solubility and tumour multi-drug resistance (MDR). The dominating mechanism of MDR is the over-expression of p-gp on tumour cells. Traditional nano-medicines, such as nanoparticles and micelles, have been used to physically entrap DTX to improve their solubility, while the drug loading content was very low and the tumour resistance was neglected. In this study, the synthesized reduction-sensitive mPEG-PLGA-SS-DTX conjugate was utilized to load the p-gp inhibitor veraparmil (VRP) to prepare DTX and VRP co-delivered mPEG-PLGA-SS-DTX/VRP (PP-SS-DTX/VRP) multi-functional micelles to reverse MDR and enhance the anti-tumour effect of DTX. The micelles had a high drug loading content and showed an obvious reduction-sensitive release property for both DTX and VRP. In addition, an in vitro anti-tumour assay revealed that the micelles markedly inhibited the efflux activity of p-gp and accelerated cell apoptosis, resulting in the improvement of anti-tumour activity and reversal of MDR. The PP-SS-DTX micelles markedly enhanced the in vivo circulation time and increased the drug accumulation in tumour tissues. Therefore, the PP-SS-DTX/VRP micelle is a desirable drug delivery system for multi-drug resistance therapy of DTX and is very promising for clinical usage.