Sodium cholesterol sulfate mediated mitoxantrone prodrug electrostatic nanocomplexes: achieving the therapeutic efficacy and safety of mitoxantrone

Forming electrostatic nanocomplexes (ENCs) with counter-ions can improve the delivery efficiency of chemotherapy drugs. However, water-soluble chemotherapy drugs like mitoxantrone (MTO), have limited affinity for counter-ions, posing challenges in the creation of stable ENCs. Herein, MTO was connected to fatty alcohols of varying chain lengths (C8, C12, C16) via disulfide bonds, forming hydrophobic prodrugs. We found that conjugating MTO to fatty alcohols significantly improved its affinity for the counter-ion sodium cholesterol sulfate (SCS). Among the designed prodrugs, conjugated to fatty alcohols with longer carbon chain lengths exhibited heightened affinity for SCS, resulting in the formation of more stable ENCs. However, extending the carbon chain also slowed the rate of drug release. Overall, compared with MTO solution, these ENCs demonstrated comparable therapeutic efficacy while causing minimal damage to healthy tissues, especially for MTO-SS-C16 ENCs. Our research provides new insights for constructing stable and safe ENCs for hydrophilic drugs like MTO.