Enzyme-Sensitive Lipid Trigger-Mediated Release of Payload from Liposomes

Esterase enzymes are overexpressed in tumor tissues of certain cancer cell types, and it is this property which makes them interesting candidates as a method of inducing cargo release from liposomes. Esterase-responsive liposomes could be developed that could be exploited to selectively deliver drug cargo to tumor tissues upregulating esterase enzyme. For this purpose, a 1,2-dioleoyl-sn-glycero-3- phosphatidylethanolamine (DOPE) lipid was coupled to a trimethyl lock molecule unit bearing an esterase-sensitive moiety. Upon introduction into an esterase-rich environment, the esterase-sensitive labile moiety would degrade. The activation of the trimethyl lock cyclization is expected to drive the restoration of the non-bilayer properties of DOPE, leading to a shift in lipid aggregate shape that disturbs lipid membrane packing properties and thereby drives release of drug cargo. Trimethyl locked-DOPE (TML-DOPE) lipids were developed and incorporated into liposomes at a 30% inclusion. Liposomes were analyzed by fluorescence release assay, including an incremental addition of esterase enzyme to a liposomal sample and a measure of the release from the liposomes over time after the addition of a discrete volume of esterase enzyme. Dynamic Light Scattering (DLS) experiments were also performed to examine liposome size and uniformity. Our results provide preliminary evidence of content release, and further work will focus on optimizing release conditions.