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.