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 specific chemotherapy. Two of them, HPMA-conjugated DOX and galactosamine-targeted DOX, are in phase II clinical trials in the U.K. We studied the effect of conjugates with different targeting moieties (anti-CD71, antithymocyte globulin, 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 used. The combination of these conjugates with chemosensitisers (cyclosporin A, D, G) restored almost completely the sensitivity of MDR cell lines to that of parental sublines. These results suggest that different intracellular trafficking of these conjugates (in membrane-limited organelles) in contrast to free diffusion for low molecular weight compounds might partially overcome P-glycoprotein (Pgp)-mediated MDR. We also report here the development of biodegradable HPMA hydrogels suitable for prolonged release of the cytostatic drug and chemosensitiser as a potential approach to overcome MDR mediated by Pgp.
St'astný
M
M
Department of Immunology and Gnotobiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Strohalm
J
J
Plocová
D
D
Ulbrich
K
K
Ríhová
B
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016572:Cyclosporine / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D008689:Methacrylates / Q000008:administration & dosage*; D051379:Mice; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000922:Immunotoxins; D008689:Methacrylates; D004317:Doxorubicin; D016572:Cyclosporine; C032802:hydroxypropyl methacrylate