BTP-7, a novel peptide for therapeutic targeting of malignant brain tumors

Background Targeted therapies for malignant brain cancer that are currently available have little clinical activity, highlighting an urgent need for the development of novel precision medicines. Brevican (Bcan), a central nervous system (CNS)-specific extracellular matrix protein is upregulated in glioma cells. A brevican isoform lacking glycosylation, dg-Bcan, is a unique glioma marker and thus represents a valuable target for anti-cancer therapy. In this study, we aimed to find a versatile dg-Bcan specific ligand to facilitate glioma targeting. Methods We screened a D-peptide library to identify dg- B can- T argeting P eptide (BTP) candidates, which were characterized extensively through binding kinetic analyses, cell uptake tests and animal studies. Results The top candidate, BTP-7 binds dg-Bcan with high affinity and specificity, is preferentially internalized by Bcan-expressing glioma cells and can cross the blood-brain barrier in vitro and in mice. Functionalization of camptothecin with BTP-7 led to increased drug delivery to intracranial glioblastoma and cytotoxicity in tumor tissues, as well as prolonged survival in tumor-bearing mice. Conclusion dg-Bcan is an attractive therapeutic target for high-grade gliomas, and BTP-7 represents a promising lead candidate for further development into novel targeted therapeutics. Key points BTP-7 is a high affinity peptide ligand for the dg-Bcan protein and Bcan-expressing cells. BTP-7 targets human intracranial GBM xenografts in mice. Functionalization of a toxic anti-cancer drug with BTP-7 enables targeted delivery of the therapeutic to intracranial GBM in mice Importance of the Study Targeted therapies for malignant brain cancer that are currently available have little clinical activity, highlighting an urgent need for the development of novel precision medicines that can selectively recognize and kill high-grade glioma tissues. A protein called dg-Bcan is an ideal target because it is present only in the extracellular matrix of high-grade glioma cells and is absent from normal brain tissues. Here, we describe the discovery of a novel dg- B can- T argeting P eptide, called BTP-7 that can bind specifically to high-grade glioma cells/tissues, and thus serve as a promising drug delivery vehicle.