Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada.
Sci Rep. 2021 May 27;11(1):11103. doi: 10.1038/s41598-021-90585-w.
The heat shock protein 90 inhibitor, luminespib, has demonstrated potent preclinical activity against numerous cancers. However, clinical translation has been impeded by dose-limiting toxicities that have necessitated dosing schedules which have reduced therapeutic efficacy. As such, luminespib is a prime candidate for reformulation using advanced drug delivery strategies that improve tumor delivery efficiency and limit off-target side effects. Specifically, thermosensitive liposomes are proposed as a drug delivery strategy capable of delivering high concentrations of drug to the tumor in combination with other chemotherapeutic molecules. Indeed, this work establishes that luminespib exhibits synergistic activity in lung cancer in combination with standard of care drugs such as cisplatin and vinorelbine. While our research team has previously developed thermosensitive liposomes containing cisplatin or vinorelbine, this work presents the first liposomal formulation of luminespib. The physico-chemical properties and heat-triggered release of the formulation were characterized. Cytotoxicity assays were used to determine the optimal drug ratios for treatment of luminespib in combination with cisplatin or vinorelbine in non-small cell lung cancer cells. The formulation and drug combination work presented in this paper offer the potential for resuscitation of the clinical prospects of a promising anticancer agent.
热休克蛋白 90 抑制剂，Luminespib，在针对多种癌症的临床前研究中显示出强大的活性。然而，由于剂量限制毒性，需要调整剂量方案，这降低了治疗效果，从而阻碍了其临床转化。因此，Luminespib 是使用先进药物输送策略进行重新配方的主要候选药物，这些策略可以提高肿瘤输送效率并限制脱靶副作用。具体来说，热敏脂质体被提议作为一种药物输送策略，能够将高浓度的药物与其他化疗分子一起递送到肿瘤中。事实上，这项工作表明，Luminespib 与顺铂和长春瑞滨等标准护理药物联合使用时，在肺癌中具有协同作用。虽然我们的研究团队之前已经开发了含有顺铂或长春瑞滨的热敏脂质体，但这项工作首次提出了 Luminespib 的脂质体制剂。对制剂的理化性质和热触发释放进行了表征。细胞毒性测定用于确定用于治疗非小细胞肺癌细胞中与顺铂或长春瑞滨联合使用的 Luminespib 的最佳药物比例。本文提出的制剂和药物组合工作为恢复有前途的抗癌药物的临床前景提供了潜力。
