Abstract 4467: Receptor targeted delivery of the multi-kinase inhibitor F7/PIK-75 by organic-core templated lipid nanoparticles as cancer therapy
Authors: Jonathan S. Rink, Andrea E. Calvert, David Kwon, Xu Hannah Zhang, Hongwei H. Yin, David Horne, SonBinh T. Nguyen, Adam Y. Lin, Steven T. Rosen, Leo I. Gordon, C Shad Thaxton
Journal: Cancer Research (2025)

Abstract Introduction: PIK-75 is a potent multi-kinase inhibitor, targeting p110α, p38γ and DNA-PKs. We and others have demonstrated that PIK-75 is effective against a diverse range of malignancies, including prostate cancer, cutaneous T-cell lymphomas, acute myeloid leukemia (AML) and pancreatic cancer, among others. However, PIK-75 is hydrophobic and difficult to deliver to target tissues, which has limited clinical development. To address these limitations, we developed a bio-inspired delivery platform for PIK-75 that has some features of natural high-density lipoproteins (HDL). We employed an organic core (oc) template to synthesize HDL-like nanoparticles (ocHDL NP) with size, shape, surface composition and targeting functions similar to mature, spherical, naturally occurring HDLs. The ocHDL NPs target and bind to the high-affinity HDL receptor scavenger receptor class B type 1 (SR-B1). SR-B1 is often over-expressed in cancer, making it an ideal target for drug delivery. Therefore, we hypothesized that ocHDL NPs can deliver PIK-75 via SR-B1 to cancer cells to induce cell death in vitro and in vivo. Methods: PIK-75 ocHDL NPs were synthesized by combining an oc with PIK-75, phospholipids and the HDL-defining apolipoprotein A-I. Following spontaneous self-assembly the PIK-75 ocHDL NP were purified by dialysis. PIK-75 ocHDL NPs were characterized for size, surface charge and drug loading. In vitro efficacy was assessed in prostate cancer cell lines (CWRR1, LnCaP), AML cell lines (HEL, KASUMI-1, BDCM, KG1a), and the NCI-60 panel + 6 pancreatic cancer cell lines. An SR-B1 blocking antibody and small molecule inhibitor of SR-B1 were used to demonstrate SR-B1-mediated delivery of PIK-75 by ocHDL NPs. In vivo efficacy was assessed in a prostate cancer tumor xenograft model. Results: PIK-75 was successfully incorporated into the ocHDL NP platform. Data demonstrate PIK-75 ocHDL NP had 20 ± 1 PIK-75/ NP. PIK-75 ocHDL NPs specifically target SR-B1 and deliver PIK-75 to inhibit its kinase targets, as measured by flow cytometry and western blotting. PIK-75 ocHDL NPs potently induced cell death in all cell lines tested, with average IC50s for prostate cancer (1.58 nM), AML (2.50 nM), pancreatic cancer (10.56 nM) and NCI60 panel (3.09 nM) in the low nanomolar range. PIK-75 ocHDL NPs significantly reduced tumor growth in a murine model of castrate resistant prostate cancer and there were no obvious untoward side effects. Conclusions: ocHDL NPs can be successfully loaded with hydrophobic drug cargo, such as PIK-75, to enable SR-B1 targeting and delivery of PIK-75 to cancer cells. PIK-75 ocHDL NPs potently induced cell death across a wide array of malignancies in vitro, and in an in vivo prostate cancer xenograft model. These results provide proof-of-principle that ocHDL NPs can be successfully leveraged to deliver hydrophobic small molecule drugs in a receptor targeted manner. Citation Format: Jonathan S. Rink, Andrea E. Calvert, David Kwon, Xu Hannah Zhang, Hongwei H. Yin, David Horne, SonBinh T. Nguyen, Adam Y. Lin, Steven T. Rosen, Leo I. Gordon, C Shad Thaxton. Receptor targeted delivery of the multi-kinase inhibitor F7/PIK-75 by organic-core templated lipid nanoparticles as cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4467.