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Impairing proliferation of glioblastoma multiforme with CD44+ selective conjugated polymer nanoparticles
Dorota Lubanska1, Sami Alrashed1, Gage T Mason2
1Department of Biomedical Sciences, University of Windsor, 401 Sunset Ave., Windsor, ON, N9B 3P4, Canada.
Abstract:
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.
Insights
Novel nanoparticles target brain cancer stem cells. Hyaluronic acid-conjugated polymer nanoparticles (CPNs) cross the blood-brain barrier, selectively targeting CD44-positive tumor-initiating cells (TICs) to reduce their stemness and proliferation.
Area of Science:
- Nanomedicine
- Oncology
- Biotechnology
Background:
- Glioblastoma (GBM) is an aggressive brain cancer.
- Treatment resistance is linked to tumor-initiating cells (TICs) and poor drug delivery.
- Targeting TICs is crucial for effective GBM therapy.
Purpose of the Study:
- To develop and evaluate novel conjugated polymer nanoparticles (CPNs) for targeting brain cancer stem cells.
- To assess the ability of Hyaluronic Acid-conjugated CPNs (HA-CPNs) to cross the blood-brain barrier and target CD44-positive TICs.
- To investigate the therapeutic effects of HA-CPNs on TIC stemness, invasiveness, and proliferation.
Main Methods:
- Synthesis of spherical diketopyrrolopyrrole-based CPNs functionalized with Hyaluronic Acid (HA).
- Demonstration of blood-brain barrier permeability in vitro.
- Assessment of selective HA-CPN uptake in CD44-positive GBM-patient derived cultures.
- Evaluation of HA-CPN effects on CD44 receptor signaling, stemness, invasiveness, and proliferation in vitro and in a zebrafish xenograft model.
Main Results:
- CPNs with an average diameter of 109 nm were successfully synthesized.
- HA-CPNs demonstrated blood-brain barrier permeability.
- Selective uptake of HA-CPNs by CD44-positive TICs was observed, dependent on concentration and cell cycle phase.
- HA-CPN uptake downregulated CD44 receptor signaling, reducing TIC stemness, invasiveness, and proliferation.
- These effects were confirmed in both in vitro cultures and a patient-derived xenograft zebrafish model.
Conclusions:
- HA-CPNs represent a novel therapeutic strategy for targeting CD44-positive TICs in glioblastoma.
- Surface moiety-driven targeting via HA offers a selective approach to overcome treatment resistance.
- This CPN-based system shows potential for improved glioblastoma treatment by targeting key cancer stem cell populations.
