Chen Ran, Yang Jiakun, Mao Yumin, Zhao Xiaofei, Cheng Ru, Deng Chao, Zhong Zhiyuan
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.
Biomacromolecules. 2023 Nov 13;24(11):5371-5380. doi: 10.1021/acs.biomac.3c00830. Epub 2023 Oct 6.
Multiple myeloma (MM) is the second most common hematological malignancy. For relapsed and refractory MM, a proteasome inhibitor, carfilzomib (CFZ), has become one of the few clinical options. CFZ suffers, nevertheless, metabolic instability and poor bioavailability and may induce severe cardiovascular and renal adverse events. Here, we report that daratumumab (Dar)-decorated polypeptide micelles (Dar-PMs) mediate the targeted delivery of CFZ to CD38-positive MM, effectively boosting its anti-MM efficacy. CFZ-loaded Dar-PMs (Dar-PMs-CFZ) exhibited an average diameter of ca. 80 nm and Dar density-dependent cell endocytosis and anti-MM activity, in which over 6-fold greater inhibitory effect to LP-1 and MM.1S MM cells than nontargeted PMs-CFZ control was achieved at a Dar density of 3.2 (Dar-PMs-CFZ). Interestingly, Dar-PMs-CFZ markedly enhanced the growth inhibition of orthotopic LP-1 MM in mice and significantly extended the median survival time compared with PMs-CFZ and free CFZ (95 days vs 60 and 54 days, respectively). In line with its high MM targetability and anti-MM efficacy, Dar-PMs-CFZ revealed little toxic effects and effectively prevented osteolytic lesions. The antibody-targeted nanodelivery of a proteasome inhibitor appears to be an appealing strategy to treat multiple myeloma.
多发性骨髓瘤（MM）是第二常见的血液系统恶性肿瘤。对于复发难治性MM，蛋白酶体抑制剂卡非佐米（CFZ）已成为少数临床选择之一。然而，CFZ存在代谢不稳定和生物利用度差的问题，并且可能引发严重的心血管和肾脏不良事件。在此，我们报告了达雷妥尤单抗（Dar）修饰的多肽胶束（Dar-PMs）介导CFZ靶向递送至CD38阳性的MM细胞，有效增强其抗MM疗效。负载CFZ的Dar-PMs（Dar-PMs-CFZ）平均直径约为80 nm，并且具有Dar密度依赖性的细胞内吞作用和抗MM活性，其中在Dar密度为3.2时（Dar-PMs-CFZ），对LP-1和MM.1S MM细胞的抑制作用比非靶向的PMs-CFZ对照高6倍以上。有趣的是，与PMs-CFZ和游离CFZ相比，Dar-PMs-CFZ显著增强了小鼠原位LP-1 MM的生长抑制作用，并显著延长了中位生存时间（分别为95天 vs 60天和54天）。与其高MM靶向性和抗MM疗效一致，Dar-PMs-CFZ显示出几乎没有毒性作用，并有效预防了溶骨性病变。蛋白酶体抑制剂的抗体靶向纳米递送似乎是治疗多发性骨髓瘤的一种有吸引力的策略。
