Article
Targeting glioblastoma using a novel peptide specific to a deglycosylated isoform of brevican
Gezielte Glioblastomtherapie und -PET-Bildgebung mit einem neuen Peptid spezifisch für eine deglykosylierte Isoform von Brevican
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Published: | June 4, 2021 |
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Objective: Glioblastoma (GBM) is the most common and deadliest form of brain tumor and treatment options available today have limited success. Brevican (Bcan), a central nervous system (CNS)-specific extracellular matrix protein, is upregulated in high-grade glioma cells, including GBM. A Bcan isoform lacking most glycosylation, dg-Bcan, is found only in GBM tissues and therefore represents a viable target for tumor specific targeted therapy.Our objective was to explore dg-Bcan as a molecular target for GBM by identifying a dg-Bcan specific peptide.
Methods: A microfluidic chip for magnetic-activated sorting was used to screen a one bead one compound (OBOC) library containing a vast number of different D-peptides (theoretical diversity more than > 10^16 different unique peptides). Candidate peptides were then screened in vitro for affinity and specificity to dg-Bcan as well as cell uptake in patient derived GBM cells. The most promising candidate (BTP-7) was further evaluated in vivo, radiolabeled with 18F and used as a PET imaging agent in a GBM orthotopic xenograft mouse model. The potential of BTP-7 based targeted therapy was evaluated by functionalizing BTP-7 with camptothecin and testing its efficacy in vitro and in vivo.
Results: BTP-7 binds to dg-Bcan with high affinity and specificity (KD= 0.26 μM). BTP-7 is preferentially internalized by dg-Bcan-expressing patient derived glioma cells and can cross the blood-brain barrier (BBB) in vitro and in mice. Radiolabeled 18F-BTP-7 enabled PET imaging of orthotopic xenograft tumors in mice (n = 3/3). Conjugation of BTP-7 to camptothecin via a cleavable linker led to significantly increased DNA damage in intracranial GBM-6 tumors (p < 0.0001) and prolonged survival in tumor-bearing mice in comparison to vehicle and a scrambled control compound (Scr) (median survival in days = 73 (BTP-7) vs. 67 (Scr) vs. 46 (vehicle), p < 0.01 / p < 0.001); n = 7 mice per group).
Conclusion: dg-Bcan is an attractive molecular target for GBM, and BTP-7 represents a promising lead candidate for further development into novel imaging agents and targeted therapeutics.