Optimizing doxorubicin prodrug albumin nanoparticles through tailored alkyl chain lengths and optimized linker chemistry

Albumin-based nanoparticle (ANP) drug delivery systems have achieved significant clinical success. However, the low affinity between Doxorubicin (DOX) and human serum albumin (HSA) hinders the formation of stable nanoparticles. In our studies, we initially conjugated DOX to disulfide bond-containing fatty alcohols via carboxamide bond to systematically evaluate the impact of carbon chain length (C4, C8, C12, C20) on the binding affinity between DOX and HSA. Notably, when the carbon chain length of fatty alcohols reached eight (C8), DOX exhibited strong binding affinity to HSA. However, these prodrugs exhibited weak cytotoxicity, indicating insufficient DOX release due to the stable carboxamide bond. To address this issue, we further replaced the stable carboxamide bond with relative active carbamate bond (DOX-OCO-C 8 ). Under high glutathione (GSH) conditions in tumor cells, DOX-OCO-C 8 ANPs exhibited accelerated hydrolytic activity and efficient release of DOX. The ANPs significantly improved the pharmacokinetic profile and antitumor efficacy of DOX while reducing systemic toxicity. Our findings suggested optimizing alkyl chain lengths and linker chemistry offers a promising strategy for developing effective and safe DOX prodrug ANPs.