Radiolabeled DOTA-Angiopep-2 peptide achieves 12-fold increased brain-to-blood ratio in mice, targeting the BBB.

Effective treatment for brain tumors, particularly glioblastoma, is severely hampered by the blood-brain barrier (BBB), which restricts the entry of most therapeutic and diagnostic agents into the central nervous system. Current standard-of-care often struggles with inadequate drug concentrations at the tumor site, leading to poor outcomes. Peptide-based drug delivery systems, leveraging specific transport mechanisms, offer a promising strategy to overcome this challenge. Angiopep-2 is a well-characterized peptide vector known for its ability to cross the BBB, making it an attractive candidate for developing novel radioconjugates to enhance brain delivery.

Researchers synthesized DOTA-Angiopep-2 via solid-phase peptide synthesis, then radiolabeled it with Lutetium-177 (177Lu) and Terbium-161 (161Tb), both relevant for therapy and SPECT imaging. Cytotoxicity was assessed in T98 glioblastoma cells to confirm peptide tolerability. Radiochemical stability was evaluated at room temperature and in human serum. Finally, in vivo biodistribution studies were conducted in healthy CFW mice to quantify brain-associated radioactivity and brain-to-blood ratios at various time points after intravenous injection, serving as a preclinical platform evaluation.

Cytotoxicity assays in T98 glioblastoma cells demonstrated that Angiopep-2 was well-tolerated, maintaining approximately 100% cell viability at 20 μM and showing only a moderate decline up to 100 μM. The radiolabeling process achieved high yields, consistently greater than 95%, with excellent radiochemical stability observed at room temperature for up to 10 days. Moderate stability was maintained in the presence of human serum. Biodistribution studies in healthy CFW mice revealed a brain-associated radioactivity of 0.24% ± 0.05% IA/g at 5 min p.i. (post-injection).