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Enzymatic non-covalent synthesis of supramolecular assemblies as a general platform for bioorthogonal prodrugs activation to combat drug resistance
Biomaterials ( IF 14.0 ) Pub Date : 2021-09-02 , DOI: 10.1016/j.biomaterials.2021.121119
Qingxin Yao 1 , Shuo Gao 2 , Chengling Wu 3 , Ting Lin 2 , Yuan Gao 1
Affiliation  

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 tumor in 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.



中文翻译:

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

多药耐药(MDR)是抗癌失败的主要原因之一。除了阻断 MDR 途径外,更迫切需要开发更有效的药物,但主要由于安全性和有效性之间的不平衡而被推迟。生物正交前药激活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,例如多柔比星和单甲基 auristatin E,而未确定大量毒素。生物活性分子。这些前药可以通过生物正交激活剂按需有效激活,其分布受超分子自组装的癌细胞特异性酶促非共价合成调节。前药激活不仅在广泛的剂量比范围内增强了协同治疗效果,而且还允许方便地转换药物身份以在体内成功对抗 MDR 肿瘤。总的来说,这种策略可以作为一个通用平台,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药激活将促进抗癌药物的发现。

更新日期:2021-09-04
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