Lubanska D, Alrashed S, Mason GT, Nadeem F, Awada A, DiPasquale M, Sorge A, Malik A, Kojic M, Soliman MAR, deCarvalho AC, Shamisa A, Kulkarni S, Marquardt D, Porter LA, and Rondeau-Gagné S. Impairing proliferation of glioblastoma multiforme with CD44+ selective conjugated polymer nanoparticles. Sci Rep 2022; 12(1):12078.
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.
Medical Subject Headings
Animals; Cell Line, Tumor; Cell Proliferation; Glioblastoma; Humans; Hyaluronan Receptors; Hyaluronic Acid; Nanoparticles; Polymers; Zebrafish