PS2 - 178 Brevican-Specific Peptides for the Development of Next-Generation Targeted Theranostics for High Grade Gliomas. (18th October 2016)

• Record Type: Journal Article
• Authors: Cho, C.F.; Kasai, K.; Wolfe, J.; Hornburg, K.; Bononi, F.; Luyt, L.; Pentelute, B.; Viapiano, M.; Chiocca, E.A.; Lawler, S.
• Is Part Of: Canadian journal of neurological sciences. Volume 43(2016)Supplement 4
• Page Start: S14
• Page End: S14
• Publication Date: 2016-10-18
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Electronic journals; 616.8
• DOI: 10.1017/cjn.2016.369
• Languages: English
• ISSNs: 0317-1671

Abstract

Abstract : High-grade gliomas are deadly cancers, and current standard-of-care has demonstrated limited success. The ability to specifically target glioma cells can allow for the development of improved theranostic agents leading to better detection methods, as well as safer anti-cancer therapies. Brevican (Bcan), a CNS-specific protein is upregulated in glioma cells and correlates with tumor progression. Particularly, a Bcan isoform lacking normal glycosylation, called B/bDg is a unique glioma marker and is not expressed in non-cancerous tissues. Therefore, B/bDg represents a valuable target for anti-cancer strategies. We describe here the discovery of novel high-affinity B/bDg-targeted peptides using rapid combinatorial library screening approaches and a microfluidic sorting device of our own design. Briefly, a one-bead-one-compound (OBOC) peptide library was screened against small magnetic particles decorated with B/bDg. Positive "hit" beads labeled with magnetic particles were isolated using an inexpensive but yet, accurate and high-throughput in-house microfluidic magnetic-activated sorter. These hits were exposed to cells expressing B/bDg, and beads with the highest cell association were isolated and sequenced. Seven novel peptides were identified. Cell uptake analyses and blocking studies revealed that 5 of these peptides displayed specific uptake in B/bDg-overexpressing cells. These candidates displayed nano-/micromolar binding affinity for recombinant B/bDg protein. Further analyses of these candidates using confocal microscopy revealed increased peptide binding/uptake in patient-derived glioma stem cells (GSCs) compared with primary human astrocytes. We plan to incorporate these onto multi-functional BBB-penetrating nanoparticles loaded with imaging agents or a drug payload to translate them into highly selective and efficacious brain cancer theranostic agents.