pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer

• Published in: International journal of nanomedicine Vol. 12; pp. 8631 - 8647
• Main Authors: Huo, Qiang, Zhu, Jianhua, Niu, Yimin, Shi, Huihui, Gong, Yaxiang, Li, Yang, Song, Huihui, Liu, Yang
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2017; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Adenosine triphosphate; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - chemistry; Cancer; Cancer therapies; Charge reversal; Chemotherapy; Disulfiram; Disulfiram - administration & dosage; Disulfiram - chemistry; Dosage and administration; Drug delivery systems; Drug Delivery Systems - methods; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug therapy; Glycoproteins; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Micelles; Multidrug resistance; Multidrug resistant organisms; Nanoparticles; NMR; Nuclear magnetic resonance; Original Research; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - chemistry; pH-response; Pharmacy; Polyethylene Glycols - chemistry; Polylysine - analogs & derivatives; Polylysine - chemistry; Polymer solubility; Polymers - chemistry; Solvents; Vacuum distillation; Beijing China; China; multidrug resistance; paclitaxel; disulfiram; pH response; charge reversal
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S144452

Multidrug resistance (MDR) remains a major challenge for providing effective chemotherapy for many cancer patients. To address this issue, we report an intelligent polymer-based drug co-delivery system which could enhance and accelerate cellular uptake and reverse MDR. The nanodrug delivery systems were constructed by encapsulating disulfiram (DSF), a P-glyco-protein (P-gp) inhibitor, into the hydrophobic core of poly(ethylene glycol)- -poly(l-lysine) (PEG- -PLL) block copolymer micelles, as well as 2,3-dimethylmaleic anhydride (DMA) and paclitaxel (PTX) were grafted on the side chain of l-lysine simultaneously. The surface charge of the drug-loaded micelles represents as negative in plasma (pH 7.4), which is helpful to prolong the circulation time, and in a weak acid environment of tumor tissue (pH 6.5-6.8) it can be reversed to positive, which is in favor of their entering into the cancer cells. In addition, the carrier could release DSF and PTX successively inside cells. The results of in vitro studies show that, compared to the control group, the DSF and PTX co-loaded micelles with charge reversal exhibits more effective cellular uptake and significantly increased cytotoxicity of PTX to MCF-7/ADR cells which may be due to the inhibitory effect of DSF on the efflux function of P-gp. Accordingly, such a smart pH-sensitive nanosystem, in our opinion, possesses significant potential to achieve combinational drug delivery and overcome drug resistance in cancer therapy.