Environment-Sensitive Polymeric Micelles Encapsulating SN-38 Potently Suppress Growth of Neuroblastoma Cells Exhibiting Intrinsic and Acquired Drug Resistance.
Environment-Sensitive Polymeric Micelles Encapsulating SN-38 Potently Suppress Growth of Neuroblastoma Cells Exhibiting Intrinsic and Acquired Drug Resistance.
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封装 SN-38 的环境敏感聚合物胶束可有效抑制表现出内在和获得性耐药性的神经母细胞瘤细胞的生长。
DOI：
10.1021/acsptsci.0c00182
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发表时间：
2021
影响因子：
--
通讯作者：
Chorny,Michael
中科院分区：
文献类型：
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作者：
Polunin,Yehor;Alferiev,IvanS;Brodeur,GarrettM;Voronov,Andriy;Chorny,Michael
传统的治疗方法不能提供持久的控制侵略性恶性肿瘤由于固有的或获得性耐药性的特点，高风险的疾病。SN-38是一种有效的喜树碱类似物，特异性靶向DNA拓扑异构酶I切割复合物，在临床前研究中显示出对侵袭性实体瘤的前景。然而，其临床应用受到在药学上可接受的媒介物中溶解度不足以及化学和代谢稳定性差的限制。由两亲可逆聚合物（AIP）配制的胶束可以通过同时使水不溶性分子货物增溶和通过保护化学不稳定剂免于失活来解决这些问题。此外，通过与细胞膜接触触发的AIP的反转和载体-药物复合物的破坏使得可以将治疗有效载荷递送到细胞内部而不损害其生物活性。在本研究中，我们表征了SN-38的新型基于AIP的胶束制剂，并评估了其对诊断时或强化放化疗后复发时产生的神经母细胞瘤（NB）细胞的生长抑制作用。使用由聚（乙二醇）和聚四氢呋喃（PEG 600-PTHF 650）的交替嵌段组成的AIP制备具有均匀<100 nm尺寸的胶体稳定的载药胶束组装体。以低纳摩尔范围（10-50 nM）应用的胶束药物完全抑制了化学未处理NB细胞的生长，即使在短暂（10分钟）暴露后也是如此。此外，延长暴露至24小时导致胶束制剂对NB细胞生长的深刻和持久的抑制作用，表现出获得性p53功能丧失。这些结果表明，胶束介导的SN-38递送可能为治疗不同阶段的高风险疾病提供一种新的有效策略，包括对常规治疗反应不良的疾病。
Conventional treatment approaches fail to provide durable control over aggressive malignancies due to intrinsic or acquired drug resistance characteristic of high-risk disease. SN-38, a potent camptothecin analog specifically targeting DNA topoisomerase I cleavage complexes, has shown promise in preclinical studies against aggressive solid tumors. However, its clinical utility is limited by inadequate solubility in pharmaceutically acceptable vehicles and by poor chemical and metabolic stability. Micelles formulated from amphiphilic invertible polymers (AIPs) can address these issues by concomitantly enabling solubilization of water-insoluble molecular cargoes and by protecting chemically labile agents from inactivation. Furthermore, the inversion of the AIP and disruption of the carrier–drug complexes triggered by contact with cell membranes makes it possible to deliver the therapeutic payload into the cell interior without compromising its biological activity. In the present study, we characterized a novel AIP-based micellar formulation of SN-38 and evaluated its growth inhibitory effect on neuroblastoma (NB) cells derived either at diagnosis or at relapse after intensive chemoradiotherapy. Colloidally stable, drug-loaded micellar assemblies with a uniform <100 nm size were prepared using an AIP consisting of alternating blocks of poly(ethylene glycol) and polytetrahydrofuran (PEG600-PTHF650). The micellar drug applied in a low nanomolar range (10–50 nM) completely suppressed the growth of chemo-naïve NB cells even after a brief (10 min) exposure. Furthermore, extending the exposure to 24 h resulted in a profound and lasting inhibitory effect of the micellar formulation on the growth of NB cells exhibiting an acquired loss of p53 function. These results suggest that micelle-mediated delivery of SN-38 can potentially offer a new and effective strategy for treating different phases of high-risk disease, including those showing poor response to conventional therapies.