Abstract
Abstract Multi-drug resistance against chemotherapeutic agents is a major problem in the treatment of cancer. It is primarily mediated by over-expression of P-glycoprotein (P-gp) encoded by the MDR-1 gene by the tumor cells. Most of the promising anticancer drugs such as doxorubicin, docetaxel, paclitaxel, and mitoxantrone are P-gp substrates. Thus, various ways for overcoming the multi-drug resistance, e.g. combination of an anticancer drug and a P-gp inhibitor or the formulation of nanoparticles in conjunction with anticancer drugs as well as the P-gp inhibitor, have been studied. Anticancer drug-loaded nanoparticles, such as paclitaxel-loaded polymer nanoparticles, are excellent candidates to overcome multi-drug resistance due to their enhanced therapeutic efficacy induced by increased cellular accumulation and sustained intracellular drug delivery. In this work, we developed an ampholytic copolymer that can encapsulate paclitaxel, and the resulting nanoparticles were found to have good water-solubility. In addition, in contrast to native paclitaxel, the paclitaxel-loaded nanoparticles were able to reverse multi-drug resistance in MCF7/ADR and MT-3/ADR cell lines, resulting in drug sensitivities comparable to the parental MCF7 and MT3 cell lines. P-gp expression was confirmed in both ADR cell lines by Western blotting, and its functionality was verified using a rhodamine accumulation and efflux assay. The nanoparticles were taken up by endocytosis in both cell lines and their enhanced therapeutic efficacy is probably due to the different mode of entry into the cell that may avoid the P-gp efflux pump. As a consequence higher concentrations of paclitaxel reach the nucleus and induce cell killing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1726. doi:10.1158/1538-7445.AM2011-1726
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