Engineering lipid-based nanocarriers for PROTAC delivery: evaluating the influence of manufacturing and morphology on...

Proteolysis targeting chimeras (PROTACs) are a promising therapeutic modality used in a significant number of pre-clinical and clinical investigations. The encapsulation of highly lipophilic PROTACs into lipid based drug delivery systems can be used to improve systemic exposure after parenteral administration, and thereby enable efficacy at lower PROTAC doses. Here we describe nanoparticle lipid based drug delivery systems, including liposomes and lipodisks, for intravenous administration to enhance exposure of a bivalent PROTAC molecule for estrogen receptor alpha, G5472. We utilized different manufacturing technologies - microfluidic mixing, flash nanoprecipitation, and thin film hydration plus extrusion - to investigate and optimize the conditions that result in the production of liposomes and lipodisks. When optimized G5472 formulations were administered intravenously in mice and compared to free G5472 at a matched dose of 1 mg/kg, a 3.2x enhancement in apparent G5472 exposure was observed for liposomes and lipodisks compared to free G5472. In addition, the liposome and lipodisk formulations showed a significant reduction in the apparent clearance (3.5x and 3.0x, respectively) and a corresponding increase in the apparent G5472 plasma half life (8.1x and 5.9x, respectively). Surprisingly, nanoparticle size had a greater impact than nanoparticle morphology on the extent of G5472 exposure improvement. These findings illuminate the impact of manufacturing conditions on nanoparticle size and morphology and provide a framework for how to engineer such nanoparticles for the delivery of PROTACs and similar molecules.