Encapsulation and Delivery of the Kinase Inhibitor PIK-75 by Organic Core High-Density Lipoprotein-Like Nanoparticles Targeting Scavenger Receptor Class B Type 1.

PIK-75 (F7) is a potent multikinase inhibitor that targets p110α, DNA-PK, and p38γ. PIK-75 has shown potential as a therapy in preclinical cancer models, but it has not been used in the clinic, at least in part, due to limited solubility. We therefore developed a nanoparticle to encapsulate PIK-75 and enable targeted cellular delivery. Scavenger receptor class B type 1 (SR-B1) is often overexpressed in cancer compared with normal cells, which enables targeting by synthetic lipid nanoparticles with some features of native high-density lipoprotein (HDL), the natural ligand of SR-B1. We investigated the use of organic core (oc) molecular platforms to synthesize HDL-like nanoparticles (oc-HDL NP). Employing an oc, we successfully formulated PIK-75 into oc-HDL NPs. The PIK-75 loaded oc-HDL NP (PIK-75 oc-HDL NP), comprising ∼20 PIK-75 molecules/NP, has similar size, surface charge, and surface composition as oc-HDL NP and natural human HDL. Using prostate cancer (PCa) and cutaneous T-cell lymphoma (CTCL) models known to be sensitive to inhibitors of p110α and p38γ, respectively, we found that PIK-75 oc-HDL NPs specifically targeted SR-B1 to deliver PIK-75 and potently induced cell death in vitro in PCa and CTCL and in vivo in a murine PCa model. Additionally, we found that PIK-75 oc-HDL NP, but not free PIK-75 or oc-HDL NP alone, reduced the IC(50) in the NCI-60 cell line panel and additional pancreatic cancer cell lines. These data demonstrate the first example of drug-loaded oc-HDL NP that actively target SR-B1 and kill cancer cells in vitro and in vivo, encouraging further development and translation to human patients.