Abstract 5350: Targeting Heparan Sulfated Proteoglycans by branched peptides for selective cancer imaging and therapy (2015)

Abstract Purpose of this study is evaluating the effect produced by targeting Heparan Sulfated Proteoglycan (HSPG) by specific branched peptides, on cancer cell adhesion, migration and drug-resistance. In previous papers we reported on synthesis and biological activity of tetra-branched peptides (NT4) containing the sequence of human neurotensin (NT), coupled to different tracers or drugs. Differently to monomeric NT, NT4 peptides bind with high selectivity to cells and tissues from different human cancers like colorectal cancer, pancreas adenocarcinoma and urinary bladder cancer and can efficiently and selectively deliver drugs (1-3) or liposomes (4,5) for cancer cell imaging or therapy, in vitro and vivo. By using NT4 conjugated to methotrexate (MTX) or 5FdU we obtained significant reduction of tumor growth in mice (1,2). We demonstrated that the branched structure provides NT4 with the ability to bind membrane sulfated glycosaminoglycans as well as different membrane endocytic receptors like LRP1 and LRP6 (6). This switch in target binding is responsible for the high and broad cancer selectivity of NT4 branched peptides, when compared to native NT. Considering the role of HSPG in cancer cell interaction with the extracellular matrix, we have here analyzed the effect of NT4 on cancer cell adhesion and migration on different supports. Moreover, since binding and internalization of NT4 peptides is mediated by specific NT4 receptors on cancer cell membrane, which may allow by-passing drug resistance produced by drug membrane transporters, we have also tested the ability of drug-armed NT4 to by-pass drug resistance in cancer cell lines. We found that 1- NT4 branched peptide inhibits adhesion and migration of different cancer cell lines on different supports and 2- MTX-conjugated NT4 allows by-passing drug resistance in MTX-resistant human breast cancer cells. The ability of NT4 peptides to allow by-passing drug resistance and to interfere with cancer cell adhesion and migration, when associated to their already demonstrated high and broad cancer selectivity, reinforce their potential role as selective and efficient cancer theranostics. Moreover, due to their specific binding to sulfated glycans, NT4 peptides can be used as probes for clarifying the role of these glycans in different aspects of tumor progression. References. 1. Falciani C. et al. Mol Cancer Ther 2007, 6, 2441-8. 2. Falciani C. et al. Curr Cancer Drug Targets 2010, 10, 695-04. 3. Falciani et al. ChemMedChem 2010, 5, 567-74. 4. Falciani C. et al. ChemMedChem 2011, 4, 678-85. 5. Falciani C. et al. J Pept Sci 2013, 19, 198-204. 6. Falciani C. et al. J Med Chem 2013, 56, 5009-18. Citation Format: Jlenia Brunetti, Lorenzo Depau, Chiara Falciani, Elisabetta Mandarini, Giulia Riolo, Giulia Roscia, Alessandro Pini, Luisa Bracci. Targeting Heparan Sulfated Proteoglycans by branched peptides for selective cancer imaging and therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5350. doi:10.1158/1538-7445.AM2015-5350