Albumin-based nanoparticles encapsulating SN-38 demonstrate superior antitumor efficacy compared to irinotecan.

Efficient formulation of SN-38 for broad-spectrum chemotherapy remains an unmet medical need. The limited solubility of SN-38 in both aqueous and organic solvents poses a major challenge for formulation development. As a result, the predominant strategy, polymer-SN-38 drug conjugates, often involves complex synthetic procedures and low drug loading (1-5% w/w). Such limitations hinder their large-scale production and clinical translation. In this study, we developed an encapsulation strategy that utilizes the reversible lactone-carboxylate equilibrium of SN-38 to simplify the formulation process and achieve enhanced drug loading. The major issue of SN-38 solubility in organic solvents was effectively addressed by sodium hydroxide (NaOH)-induced conversion of the lactone to the carboxylate form. We have demonstrated that SN-38 carboxylate, once encapsulated within human serum albumin-polylactic acid (HSA-PLA) nanoparticles, retains its reversibility and can be converted back to the active lactone form simply by the addition of hydrochloric acid (HCl). The drug loading capacity of SN-38 in the HSA-PLA nanoparticles was increased to 19% w/w.