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

Jonathan S. Rink, Adam Y. Lin, Andrea E. Calvert, David Kwon, Alexandra Moxley, Stephen E. Henrich, Aliakbar Mohammadlou, Xu Hannah Zhang, Xiwei Wu, Christiane Querfeld, Donald J.Vander Griend, Hongwei Holly Yin, David A. Horne, Son Binh T. Nguyen, Steven T. Rosen, Leo I. Gordon*, Colby Shad Thaxton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 IC50 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.

Original languageEnglish (US)
Pages (from-to)363-373
Number of pages11
JournalACS Applied Materials and Interfaces
Volume17
Issue number1
DOIs
StatePublished - Jan 8 2025

Funding

This work was supported by SPORE in Prostate Cancer at the Robert H Lurie Comprehensive Cancer Center, Northwestern University (P50CA180995). We thank the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, IL for the use of the Flow Cytometry Core Facility, which provided access to the BD Fortessa II cytometer. The Lurie Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30CA060553. The Thaxton group is thankful for a grant from the V Foundation. The Gordon group was supported in part by grants from the Schroeder, Sweig and Shannahan Foundations. The Rosen group was supported by an NIH NCI R01 award (1R01CA233922-01) and an LLS grant (ID 6576-19).

Keywords

  • PIK-75
  • cancer
  • drug encapsulation
  • lipid nanoparticle
  • scavenger receptor class B type 1
  • targeted delivery

ASJC Scopus subject areas

  • General Materials Science

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