Affinity-driven epirubicin prodrug albumin nanoassemblies for cancer therapy

The clinical utility of epirubicin (EPI) is limited by its rapid clearance, insufficient tumor accumulation, and severe systemic toxicity. Although albumin-based nanocarriers offer a potential solution, their development is hindered by the inherently weak affinity between EPI and albumin. Here, we reported an affinity-driven prodrug-albumin nanoassembly via a modular design. Specifically, EPI was conjugated to myristic acid (C14) via a pH-sensitive hydrazone linkage to form EPI-C14, which co-assembled with bovine serum albumin (BSA) into stable nanoassemblies (EPI-C14@BSA NPs) with high drug loading and binding efficiency at an optimized ratio. Fatty acid modification markedly enhanced drug-albumin affinity, leading to improved pharmacokinetics compared with free EPI. Upon reaching the tumor site, EPI-C14@BSA NPs responsively released EPI in the acidic microenvironment, inducing potent cytotoxic effects. Benefiting from improved systemic exposure and tumor-selective drug activation, EPI-C14@BSA NPs exhibited superior antitumor efficacy in a 4T1 tumor-bearing mouse model at a high dose, while effectively mitigating body weight loss and systemic toxicity associated with free EPI, thereby achieving a favorable balance between efficacy and safety. This work presented a rational prodrug strategy to enhance drug-carrier affinity, offering a promising approach to expand the utility of albumin-based nanoplatforms for chemotherapy.