Abstract 1366: Computer-modeled novel cancer targeting peptides for therapy and imaging

Abstract

Abstract We have recently developed practical software programs for optimization of cancer targeting peptides, including combinatorial construction of 3D peptide library (Buildpep), binding pocket analyzer (PscanMS) and high accuracy protein-ligand scoring program (HotLig). Based on these programs, a strategy of structure-based optimization of cancer targeting peptides in silico is developed to target human GRP78 which consists of 654 amino acids. The homology modeling of human GRP78 was constructed through aligning amino acid sequence and 3D structure with its homologs. This protein contains two major structural domains, the peptide-binding domain and the ATPase. Based on the results from the molecular modeling, new peptide analogs were designed and examined for optimized binding to the targeted GRP78 through in silico analysis. We had thus delineated the pharmacophore description of binding motif targeting peptide-binding domain of GRP78 as Pro-X1-Leu-X2. Peptides possessing this motif can be applied in cancer-targeted drug delivery system. We have thus designed several new tumor-targeted peptides [P-12, P-13, and P-6]. Their ability to bind target protein was confirmed in subsequent in vitro binding through Biacore analysis. We next examined their capacity to target cancer cells in the in vitro binding with various cancer cells, and in vivo tumor imaging and targeted chemotherapeutic studies. The results indicate that these peptides exhibit promising therapeutic potential by their selective binding to cancer cells, but not normal cells. Notably, these peptide analogs can bind to breast cancer stem cell (CSC) population in xenografts of primary breast cancer suggesting that they can target breast CSC enriched subpopulation. The microSPECT/CT molecular imaging of a primary human breast tumors, BC0244, xenograft with 188Re-liposome-PEG-P12 or P13 peptide showed significantly more uptake of radioactivity as compared to 188Re- liposome-PEG-L-peptide in the BC0244 breast tumors in NOD/SCID mice at 6, 24 and 48 h after intravenous injection, and even greater difference was found as compared to that of 188Re-liposome alone. To further compare P12 labeled liposome with L-peptide labeled liposome for therapeutic efficacy, mice bearing BC0244 xenografts were distributed into 4 groups for treatment with P12-Lipo-Dox, L-peptide-Lipo-Dox, Lipo-Dox, and PBS. The tumor growth of P12-lipo-Dox group was 1.57-fold slower than that of the L-peptide group; both of them showed significant increase in the therapeutic efficiency than Lipo-Dox control. These optimized cancer targeting peptides may be useful for imaging and targeted therapy of cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1366. doi:10.1158/1538-7445.AM2011-1366