Subr V, Sivák L, Koziolová E, Braunová A, Pechar M, Strohalm J, Kabešová M, Ríhová B, Ulbrich K, Kovář M
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic v.v.i. , Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
Biomacromolecules. 2014 Aug 11;15(8):3030-43. doi: 10.1021/bm500649q. Epub 2014 Jul 10.
The effects of novel polymeric therapeutics based on water-soluble N-(2-hydroxypropyl)methacrylamide copolymers (P(HPMA)) bearing the anticancer drug doxorubicin (Dox), an inhibitor of ABC transporters, or both, on the viability and the proliferation of the murine monocytic leukemia cell line P388 (parental cell line) and its doxorubicin-resistant subline P388/MDR were studied in vitro. The inhibitor derivatives 5-methyl-4-oxohexanoyl reversin 121 (MeOHe-R121) and 5-methyl-4-oxohexanoyl ritonavir ester (MeOHe-RIT), showing the highest inhibitory activities, were conjugated to the P(HPMA) via the biodegradable pH-sensitive hydrazone bond, and the ability of these conjugates to block the ATP driven P-glycoprotein (P-gp) efflux pump was tested. The P(HPMA) conjugate P-Ahx-NH-N═MeOHe-R121 showed a dose-dependent increase in the ability to sensitize the P388/MDR cells to Dox from 1.5 to 24 μM, and achieved an approximately 50-fold increase in sensitization at 24 μM. The P(HPMA) conjugate P-Ahx-NH-N═MeOHe-RIT showed moderate activity at 6 μM (∼10 times higher sensitization) and increased sensitization by 50-fold at 12 μM. The cytostatic activity of the P(HPMA) conjugate P-Ahx-NH-N═MeOHe-R121(Dox) containing Dox and the P-gp inhibitor MeOHe-R121, both bound via hydrazone bonds to the P(HPMA) carrier, was almost 30 times higher than that of the conjugate P-Ahx-NH-N═Dox toward the P388/MDR cells in vitro. A similar result was observed for P-Ahx-NH-N═MeOHe-RIT(Dox), which exhibited almost 10 times higher cytostatic activity than P-Ahx-NH-N═Dox.
研究了基于负载抗癌药物阿霉素（Dox）、ABC转运蛋白抑制剂或二者兼具的水溶性N-（2-羟丙基）甲基丙烯酰胺共聚物（P（HPMA））的新型聚合物疗法，对小鼠单核细胞白血病细胞系P388（亲代细胞系）及其阿霉素耐药亚系P388/MDR的活力和增殖的体外影响。将显示出最高抑制活性的抑制剂衍生物5-甲基-4-氧代己酰瑞维菌素121（MeOHe-R121）和5-甲基-4-氧代己酰利托那韦酯（MeOHe-RIT），通过可生物降解的pH敏感腙键与P（HPMA）偶联，并测试了这些偶联物阻断ATP驱动的P-糖蛋白（P-gp）外排泵的能力。P（HPMA）偶联物P-Ahx-NH-N═MeOHe-R121对P388/MDR细胞对Dox的致敏能力呈剂量依赖性增加，从1.5 μM增加到24 μM，并在24 μM时实现了约50倍的致敏增加。P（HPMA）偶联物P-Ahx-NH-N═MeOHe-RIT在6 μM时显示出中等活性（致敏性高约10倍），在12 μM时致敏性增加50倍。含有Dox和P-gp抑制剂MeOHe-R121且二者均通过腙键与P（HPMA）载体结合的P（HPMA）偶联物P-Ahx-NH-N═MeOHe-R121（Dox），其对P388/MDR细胞的体外细胞生长抑制活性几乎比偶联物P-Ahx-NH-N═Dox高30倍。对于P-Ahx-NH-N═MeOHe-RIT（Dox）也观察到了类似结果，其细胞生长抑制活性比P-Ahx-NH-N═Dox高近10倍。
