School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
Recent Pat Anticancer Drug Discov. 2021;16(4):479-497. doi: 10.2174/1574892816666210509001139.
The design of anti-cancer therapies with high anti-tumour efficacy and reduced toxicity continues to be challenging. Anti-cancer prodrug and antibody-drug-conjugate (ADC) strategies that can specifically and efficiently deliver cytotoxic compounds to cancer cells have been used to overcome some of the challenges. The key to the success of many of these strategies is a self-immolative linker, which after activation can release the drug payload. Various types of triggerable self-immolative linkers are used in prodrugs and ADCs to improve their efficacy and safety.
Numerous patents have reported the significance of self-immolative linkers in prodrugs and ADCs in cancer treatment. Based on the recent patent literature, we summarise methods for designing the site-specific activation of non-toxic prodrugs and ADCs in order to improve selectivity for killing cancer cells.
In this review, an integrated view of the potential use of prodrugs and ADCs in cancer treatment are provided. This review presents recent patents and related publications over the past ten years uptill 2020.
The recent patent literature has been summarised for a wide variety of self-immolative PABC linkers, which are cleaved by factors including responding to the difference between the extracellular and intracellular environments (pH, ROS, glutathione) through over-expressed enzymes (cathepsin, plasmin, β-glucuronidase) or bioorthogonal activation. The mechanism for self-immolation involves the linker undergoing a 1,4- or 1,6-elimination (via electron cascade) or intramolecular cyclisation to release cytotoxic drug at the targeted site.
This review provides the commonly used strategies from recent patent literature in the development of prodrugs based on targeted cancer therapy and antibody-drug conjugates, which show promise in therapeutic applications.
设计具有高抗肿瘤疗效和降低毒性的抗癌疗法仍然具有挑战性。抗癌前药和抗体药物偶联物（ADC）策略可以特异性和有效地将细胞毒性化合物递送到癌细胞，已被用于克服一些挑战。这些策略中的许多成功的关键是自毁性连接物，其在激活后可以释放药物有效载荷。各种类型的触发自毁性连接物用于前药和 ADC 中，以提高它们的疗效和安全性。
许多专利报告了自毁性连接物在前药和 ADC 中在癌症治疗中的重要性。基于最近的专利文献，我们总结了设计非毒性前药和 ADC 的位点特异性激活方法，以提高对杀伤癌细胞的选择性。
在这篇综述中，提供了前药和 ADC 在癌症治疗中的潜在用途的综合观点。本综述介绍了过去十年中至 2020 年的最新专利和相关出版物。
最近的专利文献已经为各种各样的自毁性 PABC 连接物进行了总结，这些连接物通过响应细胞外和细胞内环境（pH、ROS、谷胱甘肽）之间的差异而被激活，包括通过过表达的酶（组织蛋白酶、纤溶酶、β-葡糖苷酸酶）或生物正交激活来激活。自毁的机制涉及连接物通过 1,4-或 1,6-消除（通过电子级联）或分子内环化在靶向部位释放细胞毒性药物。
本综述提供了最近专利文献中基于靶向癌症治疗和抗体药物偶联物的前药开发中常用的策略，这些策略在治疗应用中显示出前景。
