Department of Pharmaceutics and Pharmaceutical Chemistry/Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, USA.
Department of Pharmaceutics and Pharmaceutical Chemistry/Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, USA; Faculty of Pharmacy, Silpakorn University,Nakhon Pathom, Thailand.
J Control Release. 2019 Jan 10;293:84-93. doi: 10.1016/j.jconrel.2018.11.015. Epub 2018 Nov 19.
Chemosensitization strategies have been used to sensitize cancer cells to conventional drugs, but their utility is often obstructed by additional off-target toxicity, limited access to intracellular targets and heterogeneous tumor pathogenesis. To address these challenges, we rationally developed a drug-free human serum albumin (HSA)-based therapeutic (KH-1) that functions extracellularly and exhibits pleiotropic effect on multiple intracellular signaling pathways. It is a two-step touch-trigger system that consists of a pretargeting anchor on surface receptor CD20 (anti-CD20 Fab' conjugated with a morpholino oligonucleotide 1) and a CD20 clustering actuator (HSA grafted with multiple copies of complementary morpholino oligonucleotide 2). The extracellular actuation by surface CD20 crosslinking boosts robust activations of numerous intracellular responses, and promotes cancer cell susceptibility to various anticancer drugs, including docetaxel (microtubule stabilizer), gemcitabine (nucleoside analogue) and GDC-0980 (PI3K/mTOR inhibitor). The broad applicability of KH-1 is demonstrated to result from simultaneous inhibition of survival pathways and augmentation of apoptotic pathways. In addition, KH-1 covalently conjugated with anthracycline anticancer agent, epirubicin, integrates the advantages of both chemosensitization function and improved intracellular drug delivery in a single system and takes effect on the same cell. Therefore, in the present study, we have provided mechanistic demonstration that crosslinking of surface receptors can be leveraged to elicit chemosensitization.
化学增敏策略被用于使癌细胞对常规药物敏感，但它们的效用常常受到额外的非靶毒性、细胞内靶标有限的可达性和异质性肿瘤发病机制的阻碍。为了解决这些挑战，我们合理地开发了一种无药物的人血清白蛋白（HSA）为基础的治疗剂（KH-1），它在细胞外发挥作用，并对多种细胞内信号通路表现出多效性效应。它是一个两步触发性系统，由表面受体 CD20 上的预靶向锚（与莫洛尼寡核苷酸 1 结合的抗 CD20 Fab'）和 CD20 聚类激活剂（与多个互补莫洛尼寡核苷酸 2 嫁接的 HSA）组成。表面 CD20 交联的细胞外激活促进了许多细胞内反应的强烈激活，并增强了癌细胞对各种抗癌药物的敏感性，包括多西他赛（微管稳定剂）、吉西他滨（核苷类似物）和 GDC-0980（PI3K/mTOR 抑制剂）。KH-1 的广泛适用性是由于同时抑制生存途径和增强凋亡途径。此外，KH-1 与蒽环类抗癌药物表柔比星共价结合，在单个系统中整合了化学增敏功能和改善细胞内药物传递的优势，并对同一细胞起作用。因此，在本研究中，我们提供了机制证明，表面受体的交联可以被利用来引发化学增敏。
