Hydroxyl-based acid-hypersensitive acetal ester bond: Design, synthesis and the application potential in nanodrugs

Targeted drug delivery systems exploiting the acidic tumor microenvironment have been thriving, with responsive modifications to the active sites like hydroxyl groups enhancing stability, reducing toxicity, and boosting targeted bioavailability. Yet, the utility of hydroxyl-based acid-sensitive linkages is currently constrained by the intricacy of synthesis, questionable stability, and an inability to discern between physiological pH levels associated with health and disease. Here, we unveiled a novel hydroxyl-based acid-labile linkage, the "acetal ester bond", which not only excelled in its hypersensitive acid responsiveness, but was also facile to synthesize, with exceptionally high yields (>80 %) of final products derived from primary, linear secondary, cyclic secondary, and tertiary alcohols consistently, demonstrating its broad applicability. Further research indicated that the acetal ester bond bearing-paclitaxel conjugate (PTX-COU) with the ability to self-assembly, remained intact in simulated physiological settings, while swiftly hydrolyzed to release PTX in the acidic tumor environment within minutes, contributing to mitigated systemic toxicity and improved bioavailability. In vitro and in vivo experiments demonstrated that PTX-COU outperformed PTX in tumor growth inhibition due to drug accumulation facilitated by acid-responsive target release. This discovery offered a promising solution for pH-triggered drug release, providing new insights and methods for the development of novel targeted drug delivery systems.