Intrinsic or acquired multidrug resistance (MDR) is a major problem in the treatment of cancer. The expression of the P-glycoprotein is one of the characteristics of resistant tumor cells and leads to reduced intracellular accumulation of anticancer drugs. The goal of our project is the development of dual acting prodrugs which consist of an anticancer agent, a P-glycoprotein specific MDR-modulator and a targeting moiety. In this way, an inhibitor of the P-glycoprotein as well as an anticancer agent are transported simultaneously to tumor tissue and tumor cells thus preventing the efflux of the anticancer drug from resistant cancer cells with a concomitant increase in tumor cell death.

As a carrier endogenous albumin is used due to uptake of this protein in solid tumors. In situ coupling to albumin is achieved by intravenous application of a maleimide bearing prodrug that binds to the cysteine-34 position of circulating albumin. This targeting approach has been assessed preclinically as well as clinically with an acid-sensitive prodrug of doxorubicin [1].

For realizing dual acting prodrugs, 6-maleimidocaproic acid was functionalized with glutamic acid in order to couple an anticancer agent as well an inhibitor of the P-glycoprotein. In a second step an inhibitor of the third generation, i.e., OC144-093, as well as the anticancer agent camptothecin were bound to the bifunctional linker through a cathepsin B cleavable substrate (Val-Cit). The novel prodrug bound rapidly and selectively to endogenous albumin and was cleaved by cathepsin B.

[1] F. Kratz, A. Warnecke, K. Scheuermann, C. Stockmar, J. Schwab, P. Lazar, P. Drückes, N. Esser, J. Drevs, D. Rognan, C. Bissantz, C. Hinderling, G. Folkers, I. Fichtner, C. Unger (2002): Probing the Cysteine-34 Position of Endogenous Serum Albumin with Thiol-binding Doxorubicin Derivatives: Improved Efficacy of an Acid-sensitive Doxorubicin Derivative with Specific Albumin-binding Properties Compared to the Parent Compound, J.Med.Chem. 45, 5523-5533.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA