Ao Lin, Reichel Derek, Hu Di, Jeong Hyunyoung, Kim Kyung Bo, Bae Younsoo, Lee Wooin
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.A., D.R., K.B.K., Y.B.); Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (D.H., H.J.); and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.).
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.A., D.R., K.B.K., Y.B.); Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (D.H., H.J.); and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (W.L.)
J Pharmacol Exp Ther. 2015 Nov;355(2):168-73. doi: 10.1124/jpet.115.226993. Epub 2015 Aug 26.
Carfilzomib (CFZ) is a second-generation proteasome inhibitor drug approved for the treatment of multiple myeloma. Contrary to its excellent antimyeloma activity, CFZ has shown only limited efficacy in patients with solid malignancies. This lack of efficacy has been attributed in part to rapid degradation of CFZ in the body, possibly hindering the ability of CFZ to access the proteasome target in solid tumors. We hypothesized that polymer micelles, a currently Food and Drug Administration-approved nanoparticle drug delivery formulation, may protect CFZ from metabolic degradation and thus expand the clinical utility of the drug as an anticancer agent. To test our hypothesis, we prepared CFZ-entrapped polymer micelle particles with various compositions and drug release profiles and examined the extent of the CFZ metabolism in vitro using mouse liver homogenates. We also assessed the cytotoxic activities of the CFZ-entrapped micelle formulations in human cancer cell lines derived from B lymphocytes (RPMI-8226) and the lung (H460). Our data indicated that polymer micelle-based formulations can improve metabolic stability and cytotoxic effects of CFZ compared with free CFZ in human cancer cell lines tested. Taken together, these results suggest that polymer micelles may have potential as a delivery system for CFZ with an extended therapeutic utility for nonhematologic malignancies in the future.
卡非佐米（CFZ）是一种已被批准用于治疗多发性骨髓瘤的第二代蛋白酶体抑制剂药物。与它出色的抗骨髓瘤活性相反，CFZ在实体恶性肿瘤患者中仅显示出有限的疗效。这种疗效不佳部分归因于CFZ在体内的快速降解，这可能会阻碍CFZ作用于实体肿瘤中的蛋白酶体靶点。我们推测，聚合物胶束作为一种目前已获美国食品药品监督管理局批准的纳米颗粒药物递送制剂，可能会保护CFZ不被代谢降解，从而扩大该药物作为抗癌剂的临床应用。为了验证我们的假设，我们制备了具有不同组成和药物释放曲线的包裹CFZ的聚合物胶束颗粒，并使用小鼠肝脏匀浆在体外检测CFZ的代谢程度。我们还评估了包裹CFZ的胶束制剂对源自B淋巴细胞（RPMI - 8226）和肺（H460）的人癌细胞系的细胞毒性活性。我们的数据表明，与游离CFZ相比，基于聚合物胶束的制剂在测试的人癌细胞系中可提高CFZ的代谢稳定性和细胞毒性作用。综上所述，这些结果表明聚合物胶束作为CFZ的递送系统可能具有潜力，未来对非血液系统恶性肿瘤具有扩展的治疗效用。
