Ionizable small molecule drug-incorporated lipid nanoparticles for treatment of breast cancer

David Cescon – Associate Professor, University Health Network; Eric Donders – Ph.D., University of Toronto; Molly Shoichet – Professor, University of Toronto; Kai Slaughter – Ph.D., University of Toronto

Introduction:

Co-delivery of small molecule drugs and RNA therapeutics in a single nanoparticle can align pharmacokinetics, ensure spatiotemporal co-localization at the tumor site, and enhance synergy against drug-resistant cancers. Ionizable fulvestrant analogs have recently enabled drug-rich, siRNA-loaded nanoparticles with efficient endosomal escape and potent gene silencing. Building on this platform, we hypothesized that combining fulvestrant with ionizable lipids would generate a novel “ionizable drug-lipid” nanoparticle with superior endosomal escape and siRNA-mediated gene silencing relative to conventional LNPs, leading to more effective therapeutic outcomes in breast cancer.