A molecular anchor for mitoxantrone: improving binding affinity to albumin for enhanced antitumor efficacy and safety

The risk-benefit profile of mitoxantrone (MTO) in clinical settings is substantially limited by dose-limiting toxicities and a constrained therapeutic index. Human serum albumin (HSA) is an attractive carrier for chemotherapeutics, but its weak affinity for MTO hampers formulation stability and efficacy. To address this challenge, we developed an HSA-binding moiety engineering strategy by conjugating fatty alcohols (FAs, C₈, C₁₂, C₁₆) to MTO through disulfide linkages, thereby introducing a high-affinity "molecular anchor" for HSA while ensuring tumor-selective drug release. These conjugates were formulated with HSA at varying mass ratios to optimize the nanoparticle assembly. Structure-activity analysis revealed that elongating FA chains significantly improved albumin affinity, nanoparticle stability, and therapeutic efficacy. The lead candidate, MTO-C₁₆, exhibited optimal performance, forming stable HSA nanoparticles with enhanced pharmacokinetics, tumor accumulation, and antitumor potency. At an MTO-equivalent dose of 5 mg/kg, MTO-C₁₆@HSA nanoparticles achieved robust tumor suppression with minimal off-target toxicity. This study introduces a versatile approach to enhance the therapeutic outcome of MTO and offers a broadly applicable platform for chemotherapeutics facing similar clinical challenges.