Department of Pharmacognosy, Semmelweis University, 1085, Budapest, Hungary.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Eur J Med Chem. 2024 Oct 5;276:116699. doi: 10.1016/j.ejmech.2024.116699. Epub 2024 Jul 20.
Drugs administered through conventional formulations are devoid of targeting and often spread to various undesired sites, leading to sub-lethal concentrations at the site of action and the emergence of undesired effects. Hence, therapeutic agents should be delivered in a controlled manner at target sites. Currently, stimuli-based drug delivery systems have demonstrated a remarkable potential for the site-specific delivery of therapeutic moieties. pH is one of the widely exploited stimuli for drug delivery as several pathogenic conditions such as tumor cells, infectious and inflammatory sites are characterized by a low pH environment. This review article aims to demonstrate various strategies employed in the design of acid-sensitive prodrugs, providing an overview of commercially available acid-sensitive prodrugs. Furthermore, we have compiled the progress made for the development of new acid-sensitive prodrugs currently undergoing clinical trials. These prodrugs include albumin-binding prodrugs (Aldoxorubicin and DK049), polymeric micelle (NC-6300), polymer conjugates (ProLindac™), and an immunoconjugate (IMMU-110). The article encompasses a broad spectrum of studies focused on the development of acid-sensitive prodrugs for anticancer, antibacterial, and anti-inflammatory agents. Finally, the challenges associated with the acid-sensitive prodrug strategy are discussed, along with future directions.
通过常规制剂给予的药物缺乏靶向性，并且常常扩散到各种不需要的部位，导致在作用部位的亚致死浓度和出现不需要的作用。因此，治疗剂应该以受控的方式递送到靶部位。目前，基于刺激的药物递送系统已经表现出在治疗部位特异性递送治疗剂的显著潜力。pH 值是用于药物递送的广泛利用的刺激之一，因为几种病理条件，如肿瘤细胞、感染和炎症部位，其特征是低 pH 值环境。本文旨在展示设计酸敏感前药所采用的各种策略，概述商业上可用的酸敏感前药。此外，我们还汇编了目前正在进行临床试验的新型酸敏感前药的开发进展。这些前药包括白蛋白结合前药（Aldoxorubicin 和 DK049）、聚合物胶束（NC-6300）、聚合物缀合物（ProLindac™）和免疫缀合物（IMMU-110）。本文涵盖了广泛的研究，重点是开发用于抗癌、抗菌和抗炎剂的酸敏感前药。最后，讨论了与酸敏感前药策略相关的挑战以及未来的方向。
