Encapsulation\nand Delivery of the Kinase Inhibitor\nPIK-75 by Organic Core High-Density Lipoprotein-Like Nanoparticles\nTargeting Scavenger Receptor Class B Type 1

PIK-75 (F7) is a\npotent multikinase inhibitor that targets p110α,\nDNA-PK, and p38γ. PIK-75 has shown potential as a therapy in\npreclinical cancer models, but it has not been used in the clinic,\nat least in part, due to limited solubility. We therefore developed\na nanoparticle to encapsulate PIK-75 and enable targeted cellular\ndelivery. Scavenger receptor class B type 1 (SR-B1) is often overexpressed\nin cancer compared with normal cells, which enables targeting by synthetic\nlipid nanoparticles with some features of native high-density lipoprotein\n(HDL), the natural ligand of SR-B1. We investigated the use of organic\ncore (oc) molecular platforms to synthesize HDL-like nanoparticles\n(oc-HDL NP). Employing an oc, we successfully formulated PIK-75 into\noc-HDL NPs. The PIK-75 loaded oc-HDL NP (PIK-75 oc-HDL NP), comprising\n∼20 PIK-75 molecules/NP, has similar size, surface charge,\nand surface composition as oc-HDL NP and natural human HDL. Using\nprostate cancer (PCa) and cutaneous T-cell lymphoma (CTCL) models\nknown to be sensitive to inhibitors of p110α and p38γ,\nrespectively, we found that PIK-75 oc-HDL NPs specifically targeted\nSR-B1 to deliver PIK-75 and potently induced cell death <i>in\nvitro</i> in PCa and CTCL and <i>in vivo</i> in a murine\nPCa model. Additionally, we found that PIK-75 oc-HDL NP, but not free\nPIK-75 or oc-HDL NP alone, reduced the IC<sub>50</sub> in the NCI-60\ncell line panel and additional pancreatic cancer cell lines. These\ndata demonstrate the first example of drug-loaded oc-HDL NP that actively\ntarget SR-B1 and kill cancer cells in vitro and in vivo, encouraging\nfurther development and translation to human patients.