Structure-biodistribution relationships of chemically and physically modified albumin: a systematic approach to organ-specific drug delivery.

Human serum albumin (HSA) undergoes post-translational modifications that alter its receptor recognition and biodistribution. While HSA receptors such as gp18, gp30, cubilin, and megalin regulate HSA distribution, the relationship between HSA structural changes and organ-specific targeting remains poorly understood. In this study, we systematically prepared five types of modified HSA (acid-treated, base-treated, oxidized, fatty acid-modified, and heat-treated) and characterized their structural alterations using circular dichroism, fluorescence spectroscopy, and site-specific fluorescent probe-binding assays. Comprehensive radar chart analysis revealed that structural changes could be classified into three distinct categories based on their conformational profiles. Biodistribution studies in normal mice demonstrated treatment-specific organ accumulation patterns: heat-treated HSA showed 2-fold increased liver and spleen accumulation; oxidized and fatty acid-modified HSA exhibited 2-fold increased liver and kidney accumulation; while acid-treated and base-treated HSA showed minimal changes compared to untreated HSA. Notably, in tumor-bearing mice, acid-treated HSA which exhibited structural similarity to Abraxane-derived HSA demonstrated 2.5-fold higher tumor accumulation than untreated HSA and comparable or superior tumor targeting versus Abraxane. These findings establish a systematic framework correlating albumin structural modifications with biodistribution patterns and suggest that acid-treated HSA warrants further investigation as a tumor-targeting drug carrier. The mechanism underlying enhanced tumor accumulation requires elucidation in future receptor-specific studies.