Abstract 368: Development of a highly potent and non-invasive optical imaging agent for glioblastoma

Abstract

Abstract Using the “one-bead one-compound” (OBOC) combinatorial library approach, we have previously identified a peptide ligand LXY1, cyclic c-d-G-L-G-Hyp-N-c, that targets the α3β1 integrin of U87MG glioblastoma cells. Very recently, we have further optimized LXY1 using the OBOC focused library approach, and subsequently traditional medicinal chemistry. Three focused OBOC peptide libraries have been designed by fixing the motif c-d-G_G_ _c, randomizing the other positions with a large number of D- and other unnatural amino acids, and extending with 1-2 random amino acids at the N-terminus and/or C-terminus of LXY1. The bead libraries have been screened against U87MG cells using an on-bead cell binding assay. Three out of the twelve positive ligands have an additional L-amino acid at the C-terminus of LXY1. However, none of the positive beads has an extension of additional residues at the N-terminus. A series of new ligands has been designed based on the screening results, and extensive structure-activity relationship (SAR) studies have been performed. Several ligands have shown more potent in vitro binding to U87MG cells, and better in vivo tumor uptake than LXY1. Among them, LXY30 [cyclic c-d-G-Phe(3,5-diF)-G-Hyp-N-c-R] is the most promising ligand. Optical imaging of LXY30, using LXY30-biotin/streptavidin-Cy5.5 conjugate, in both subcutaneous and orthotopic U87MG glioblastoma mouse models, will be presented. LXY30 could be used as an efficient vehicle for the delivery of imaging probes and therapeutic agents against glioblastoma and other tumors with a high expression of the α3β1 integrin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 368. doi:1538-7445.AM2012-368