Acid-sensitive prodrugs; a promising approach for site-specific and targeted drug release

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. [Display omitted] •Pathogenic conditions with non-physiological pHs can be exploited to develop acid-sensitive prodrugs.•Strategies in medicinal chemistry are discussed for the design of acid-sensitive prodrugs.•Commercially available acid-sensitive prodrugs including small molecules and antibody-drug conjugates are summarized.•Acid-sensitive prodrugs in clinical trials, such as Aldoxorubicin, IMMU-110, NC-6300, ProLindac, and DK049 are highlighted.•Acid-sensitive prodrugs with anticancer, anti-inflammatory, and antibacterial agents are thoroughly reviewed.