Enzymatic non-covalent synthesis of supramolecular assemblies as a general platform for bioorthogonal prodrugs activation to combat drug resistance
Enzymatic non-covalent synthesis of supramolecular assemblies as a general platform for bioorthogonal prodrugs activation to combat drug resistance
复制标题
超分子组装体的酶促非共价合成作为生物正交前药激活以对抗耐药性的通用平台
DOI：
10.1016/j.biomaterials.2021.121119
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发表时间：
2021
期刊：
影响因子：
14
通讯作者：
Gao Yuan
中科院分区：
文献类型：
--
作者：
Yao Qingxin;Gao Shuo;Wu Chengling;Lin Ting;Gao Yuan
多药耐药（MDR）是抗癌失败的主要原因之一。除了MDR通路的阻断外，开发更有效的药物也是迫切需要的，但主要由于安全性和有效性之间的不平衡而被推迟。生物正交前药活化策略的最新发展显示出平衡安全性和有效性的巨大潜力，而最近的研究仅关注少数药物实体，如多柔比星和单甲基奥瑞他汀E，留下大量毒素未确定。在这里，我们列举了典型的分子实体，从食品和药物管理局（FDA）批准的药物到加热的抗体药物缀合物（ADC）弹头和单孢霉烯毒素，以证明生物正交笼和特异性活化可以作为一种通用设计，以增加生物活性分子的治疗指数。这些前药可以被生物正交活化剂按需有效地活化，其分布由癌细胞特异性酶促非共价合成的超分子自组装体调节。前体药物的激活不仅在很宽的剂量比范围内增强了协同治疗效果，而且还允许方便地切换药物身份，以成功地在体内对抗MDR肿瘤。一般来说，这种策略可以作为一个通用的平台，它可以很容易地适用于扩大各种生物活性分子的治疗窗口。我们设想，时空控制的生物正交前体药物活化将促进抗癌药物的发现。
Multi-drug resistance (MDR) is one of the leading causes of the anticancer failures. Besides the blockage of the MDR pathways, the development of more potent drugs is with urgent needs, but has been postponed mainly due to an imbalance between safety and efficacy. The recent development of the bioorthogonal prodrug activation strategy has shown immense potential to balance safety and efficacy, while recent studies only focused on few drug entities such as doxorubicin and monomethyl auristatin E, leaving the vast collection of toxins undetermined. Here we have enumerated typical molecular entities ranging from food and drug administration (FDA) approved drugs to a heated antibody drug conjugates (ADC) warhead and a trichothecene toxin to demonstrate that the bioorthogonal caging and specific activation could serve as a general design to increase the therapeutic index of bioactive molecules. These prodrugs can be efficiently activated on-demand by the bioorthogonal activators whose distribution was regulated by the cancer cell specific enzymatic non-covalent synthesis of supramolecular self-assemblies. The prodrug activation not only enhanced the synergistic therapeutic effect within a broad range of dose ratios but also allowed the convenient switching of drug identities to successfully combat MDR tumorin vivo. In general, this strategy might serve as a general platform, which can be readily applicable to enlarge the therapeutic window for various bioactive molecules. We envision that the spatiotemporal controlled bioorthogonal prodrug activation would facilitate the discovery of anticancer drugs.