22: Albumin-ruthenium catalyst for selective delivery of cytotoxic drug to cancer cells via bioorthogonal uncaging

Abstract: Cancer is one of the leading cause of deaths in the United States and the most prevalent cause of mortality among individuals under the age of 85. Despite numerous therapeutic options, most of them lack actual applicability due to their narrow therapeutic window. Targeted drug delivery approach such as antibody-drug conjugates (ADC) represents a promising approach for improving therapeutic selectivity while reducing systemic toxicity. Despite the several FDA approved ADCs, they still possess shortcomings such as premature payload deployment, lack of bystander cell killing and substantial development cost. This study focuses on Albumin-Ruthenium Catalyst (ARC) platform designed to address pitfalls of ADC by leveraging albumin as the protein-based carrier, incorporating a non-cleavable covalent linker, and employing a ruthenium catalyst for selective bio-orthogonal uncaging of the cytotoxic drug. Unlike ADCs, which rely on stoichiometric payload delivery and can suffer from premature drug release, the catalytic ARC platform enables localized and repeated activation of prodrugs while reducing systemic toxicity. Mechanistic studies demonstrated that ARC retains robust catalytic activity under hypoxic conditions characteristic of solid tumors, while undergoing degradation in oxygen-rich environments. This difference in stability emphasizes its potential for selective drug uncaging within tumor tissues. Importantly, ARC exhibits stability in the presence of biologically relevant ascorbic acid and fatty acids, underscoring its compatibility with physiological conditions. Cell-based assays confirm that ARC efficiently releases therapeutically relevant concentrations of a cytotoxic drug while maintaining minimal intrinsic toxicity, thereby supporting its safety and therapeutic efficacy. Moreover, ARC shows affinity for SPARC (Secreted Protein Acidic and Rich in Cysteine), a protein overexpressed in many tumor types without compromising the catalytic activity, indicating that ARC remains functionally active upon tumor localization. Mechanistic insights from in vitro studies suggest that the tumor microenvironment plays a key role in enhancing selective drug delivery through the ARC platform.