A possibility to overcome P-glycoprotein (PGP)-mediated multidrug resistance by antibody-targeted drugs conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carrier

N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing doxorubicin (DOX) and different targeting moieties were developed with the aim of speci fic chemotherapy. Two of them, HPMA-conjugated DOX and galactosamine-target ed DOX, are in phase II clinical trials in the U.K. We studied the effect o f conjugates with different targeting moieties (anti-CD71, antithymocyte gl obulin, anti-CD4, transferrin) on human or mouse multidrug resistance (MDR) cell lines (CEM/VLB, P388-MDR). It was shown that targeting decreases the level of MDR for DOX and the level of MDR depends on the targeting moiety u sed. The combination of these conjugates with chemosensitisers (cyclosporin A, D, G) restored almost completely the sensitivity of MDR cell lines to t hat of parental sublines. These results suggest that different intracellula r trafficking of these conjugates (in membrane-limited organelles) in contr ast to free diffusion for low molecular weight compounds might partially ov ercome P-glycoprotein (Pgp)-mediated MDR. We also report here the developme nt of biodegradable HPMA hydrogels suitable for prolonged release of the cy tostatic drug and chemosensitiser as a potential approach to overcome MDR m ediated by Pgp. (C) 1999 Elsevier Science Ltd. All rights reserved.