A fatty acid modification strategy to improve the binding affinity of Epirubicin to human serum albumin for efficient cancer therapy

Human serum albumin (HSA) is regarded as an ideal carrier for chemo-drug delivery due to its superior advantages. However, for drugs like Epirubicin (EPI), which exhibit poor binding affinity to HSA, efficient delivery remains challenging. Herein, we proposed a fatty acid modification strategy to improve the binding affinity of EPI to HSA for efficient cancer therapy. Briefly, fatty acids (FAs) with varying chain lengths (C 14 , C 18 , and C 22 ) were connected to EPI via pH-sensitive hydrazone bond to create EPI prodrugs (EPI-FAs). These EPI-FAs were then co-assembled with HSA at different mass ratios to screen the optimal formulations. We found that the chain length significantly impacted the binding affinity and assembly performance of EPI-FAs with HSA, as well as the subsequent in vivo fate and anti-tumor efficacy. Notably, EPI-C 18 exhibited high binding affinity and superior assembly performance with HSA, resulting in improved pharmacokinetic behavior with an AUC 0 – 24 h of 38.72 times higher than the EPI Solution. Moreover, the nanocomplex of EPI-C 18 and HSA showed potent anti-tumor activity with minimal toxicity (even at a high dose of 10 mg/kg equal to EPI). This work would offer innovative insights and theoretical basis for the design of albumin-based nano-formulation.