Codelivery of Doxorubicin and Verapamil for Treating Multidrug Resistant Cancer Cells.

Abstract

Patients undergoing chemotherapy can develop resistance not only to the administered drug, but also to many other unrelated types of drugs, a phenomenon known as multidrug resistance. One of the most common mechanisms of multidrug resistance is an elevated expression of drug efflux pumps. Codelivery of an efflux pump inhibitor with a chemotherapeutic can increase the killing of multidrug-resistant cancer cells. Our hypothesis was that delivering doxorubicin directly to the cytosol of multidrug resistant cancer cells via a folate-targeted liposome loaded with a perfluoropentane emulsion droplet and doxorubicin (folated eLipoDox), along with the delivery of verapamil to block the efflux pumps will prove to be more effective in killing multidrug resistant cancer cells compared to conventional drug delivery. Multidrug-resistant KB-V1 cells and doxorubicin-sensitive KB-3-1 cells were treated with 500 µM verapamil and 6.5 µM doxorubicin for 2 hours. Cell viability was measured 48 hours later via an MTT assay. Doxorubicin-sensitive KB-3-1 cells had a cell viability of 29% when treated with verapamil and folated eLipoDox, whereas multidrug-resistant KB-V1 cells had a cell viability of 25% (p=0.38). The co-delivery of verapamil and folated eLipoDox produced the greatest toxicity to KB-V1 and KB- 3-1 cells. We conclude that the cytosolic delivery of doxorubicin via folated eLipoDox combined with the blocking of export pumps via verapamil can overcome the multidrug resistance of KB-V1 cells and even significantly reduce the viability of doxorubicin-sensitive KB-3-1 cells.