In Heon Lee, PharmD
Targeted Delivery of Nanoparticles to Cancer Stem Cells in Glioblastoma
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor, with overall survival of less than two years. Nearly all GBMs eventually recur. One likely cause of recurrence is the presence of cancer stem cells (CSCs), a small subpopulation of cancer cells that are more resistant to radio- and chemotherapy than normal cancer cells. Thus, a new treatment modality that is more specific to CSCs and less toxic to normal cells is urgently needed. CXCR4 is a receptor that is overexpressed on the cell surface in CSCs isolated from GBM tumors. CXCR4 proteins expressed on the cell surface are internalized upon ligand binding. It has been shown that nanoparticles (NPs) carrying a receptor agonist to CXCR4 or other receptors are internalized upon receptor binding, revealing that CXCR4 can function as portals for NP binding and cellular uptake. Interestingly, allosteric ligands, which bind to different sites on receptors than orthosteric ligands, can preserve the function of CXCR4 and minimize adverse effects expected from the use of orthosteric antagonists. The main goal of this project is to develop drug-loaded, CXCR4- targeted, allosteric peptide-conjugated NPs that can utilize the functional selectivity of allosteric peptides for selective drug delivery to cancer cells with less toxicity. This project will investigate the feasibility of CXCR4-targeted delivery of nanocarriers conjugated to allosteric peptides, fabricate and deliver CXCR4-targeted, drug-loaded polymeric NPs into CXCR4-expressing cells, and evaluate the in vitro efficacy of the CXCR4-targeted NPs for the treatment of GBM.
This predoctoral fellowship has given me the financial support that has allowed me to focus on my dissertation research. I sincerely appreciate the PhRMA Foundation for the opportunity to do what I love to do as a pharmaceutical scientist.