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

TL;DR

A new liposomal method safely delivers a potent chemotherapy drug by using a hydrophilic prodrug that activates inside cells.

Contribution

A novel liposomal formulation using SN38-G derivatives enables efficient and stable delivery of hydrophobic chemotherapeutics.

Findings

SN38-G derivatives were successfully loaded into liposomes with over 60% drug-to-phospholipid ratio.

The liposomes retained the drug for 15 days in simulated body fluids.

SN38-G liposomes activated intracellularly via lysosomal enzymes, inducing cytotoxicity.

Abstract

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-Gmet and SN38-Geth compatible with liposomal core encapsulation. By employing
an internally alkaline pH, core-loaded SN38-Gmet and SN38-Geth 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.

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