title: Co-delivery of docetaxel and verapamil by reduction-sensitive PEG-PLGA-SS-DTX conjugate micelles to reverse the multi-drug resistance of breast cancer.
abstract: 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.
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China; School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
authors.forename: Wenxiu
authors.initials: W
authors.lastname: He
authors.affiliation: Qingdao Tumor Hospital, No.127 Siliu South Road, Qingdao, 266042, PR China.
authors.forename: Shengfeng
authors.initials: S
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
authors.forename: Dujuan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Key Lab of Colloid & Interface Chemistry, Shandong University, Ministry of Education, 250100, PR China.
authors.forename: Zhonghao
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China. Electronic address: yuxialuan@sdu.edu.cn.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Luan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002470:Cell Survival; D000077143:Docetaxel; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013388:Succinimides / Q000737:chemistry*; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry*; D014700:Verapamil / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008823:Micelles; D011091:Polyesters; D013388:Succinimides; D043823:Taxoids; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D000077143:Docetaxel; D011092:Polyethylene Glycols; C050761:polyethylene glycol bis(succinimidyl succinate); D014700:Verapamil
keywords: Co-delivery; DTX; MDR; PP-SS-DTX; Reduction sensitive; VRP