Safe and Efficient Intracellular Release of SN38 via Lysosomal-Responsive SN38-G Loaded Liposomes

Liposomal formulations remain mostly suited for amphiphilic drugs of mild potency. This high selectivity challenges the formulation of potent chemotherapeutics that are preponderantly hydrophobic. Spontaneous accumulation of certain hydrophobic drugs within the lipid bilayer of liposomes leads to aggregation, destabilization, and inadequate drug retention. Here, we depict an alternative approach to load such hydrophobic drugs using SN38, the active form of CPT-11 (Irinotecan, Camptosar), through SN38 glucuronide (SN38-G), its hydrophilic glucuronide prodrug derivative. SN38-G was esterified in acidic methanol or ethanol to produce amphiphilic derivatives SN38-G^met and SN38-G^eth compatible with liposomal core encapsulation. By employing an internally alkaline pH, core-loaded SN38-G^met and SN38-G^eth underwent spontaneous hydrolysis, reverting into the hydrophilic SN38-G. This internal conversion resulted in sustained drug retention through lipid-bilayer containment of hydrophilic compounds. Loading above 60% drug-to-phospholipid molar ratio was attained, together with sustained retention over 15 days at 37 °C in simulated body fluids. Our in vitro assay demonstrated that SN38-G liposomes were activated to SN38 through a lysosomal beta-glucuronidase-dependent manner, inducing cytotoxicity. This delivery method could be applied to various potent and hydrophobic drugs with challenging delivery requirements.