Journal
SCIENTIFIC REPORTS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-022-15244-0
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Funding
- Seeds4Hope grant from the Windsor Cancer Centre Foundation
- NSERC [RGPIN-2022-04428]
- CIHR [406811]
- Canada Foundation for Innovation (CFI)
- Ontario Research Fund
- University of Windsor
- National Science Foundation [DMR-2010792]
- National Institute of Standards and Technology, U.S. Department of Commerce
- National Institute of Standards and Technology [DMR-2010792]
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This study investigates the selective targeting of tumor initiating cells (TICs) in brain cancer by synthesizing conjugated polymer nanoparticles (CPNs) and studying their permeability through the blood-brain barrier and selective uptake by CD44 positive GBM-patient derived cultures. The findings show that uptake of CPNs can regulate the levels and signaling activity of the CD44 receptor, reducing stemness, invasive properties, and proliferation of the CD44-TIC populations.
Glioblastoma is one of the most aggressive types of cancer with success of therapy being hampered by the existence of treatment resistant populations of stem-like Tumour Initiating Cells (TICs) and poor blood-brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole-based Conjugated Polymer Nanoparticles (CPNs) with an average diameter of 109 nm. CPNs were designed to include fluorescein-conjugated Hyaluronic Acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood-brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake of HA-CPNs in CD44 positive GBM-patient derived cultures. Interestingly, we found that uptake alone regulated the levels and signaling activity of the CD44 receptor, decreasing stemness, invasive properties and proliferation of the CD44-TIC populations in vitro and in a patient-derived xenograft zebrafish model. This work proposes a novel, CPN- based, and surface moiety-driven selective way of targeting of TIC populations in brain cancer.
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