| Multidrug resistance(MDR)in tumor cells is a significant obstacle for successful cancer chemotherapy.Overexpression of drug efflux transporters such as P-glycoprotein(P-gp)is a key factor contributing to the development of tumor drug resistance.Elacridar,a P-gp inhibitor,has been reported to be able to reverse completely the resistance caused by P-gp.In comparison to the early generation of chemosensitizers(e.g.cyclosporin-A,verapamil),which are not optimized for MDR reversal,Elacridar has a higher potency for P-gp and a lower cellular toxicity.For optimal synergy,the drug and inhibitor combination may need to be temporally colocalized in the tumor cells.Herein,we investigated the simultaneous and targeted delivery of anticancer drug,Doxorubicin(DOX),along with Elacridar,using FA/Cy7-PEG-PCL MCs to overcome tumor drug resistance.The FA/Cy7-MCs(Dox/Ela)exhibited an average size of around 35 nm and smooth sphere morphology illustrated by DLS and TEM.In vitro studies,compared with DOX-loaded MCs and free DOX,FA/Cy7-MCs(Dox/Ela)resulted in an increased accumulation of DOX in drug-resistant tumor cells,and a higher cytotoxicity.Enhanced therapeutic efficacy of dual agent MCs could be ascribe to increased accumulation of DOX in drug-resistant tumor cells.We suggest that the synergistic effect of folate receptor-mediated internalization and Elacridar-mediated overcoming MDR could be beneficial in treatment of MDR solid tumors by targeting delivery of micellar DOX into tumor cells.More importantly,in vivo results illustrated that FA/Cy7-MCs(Dox/Ela)not only displayed better tumor accumulation and tumor targeting,and more efficiently inhibited the growth of tumor in MCF-7/ADR tumor-bearing mice,but also induced significantly less pathological damage to the cardiac tissue in comparison with free DOX.As a result,the difunctional micelle systems is a very promising approach to overcome multi-drug resistance and tumor imaging. |
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