Polymeric Nanocarriers Functionalized with Peptides for Improved Glioblastoma Targeting and Blood–Brain Barrier Permeability

We report the synthesis of polymeric conjugates designed to penetrate the blood–brain barrier (BBB) and selectively bind glioblastoma (GBM) cells through reversible addition–fragmentation chain transfer (RAFT) polymerization. The resulting materials were engineered to contain peptide macromonomers for cell-specific targeting and integrated DOTA units to facilitate radiolabeling with copper-64 (⁶⁴Cu), yielding radiolabeled conjugates with greater than 95% radiochemical purity. In biodistribution assessments conducted in mice, C1C2 peptide-conjugated polymers showed significantly improved accumulation in brain tissue, supported by brain perfusion analyses confirming efficient BBB penetration. Additionally, flow cytometry evaluations demonstrated specific affinity of GBM-targeted polymer formulations toward U87 glioblastoma cells. Overall, these polymer–peptide conjugates─particularly the C1C2-functionalized variant─demonstrate notable promise for targeted imaging and therapy of glioblastoma, providing a foundation for future preclinical development.