A prominent intrinsic marker of tumor hypoxia is make carbonic anhydrase to an attractive molecule for targeting approaches

The fact that CAIX represents an endogenous marker for cellular hypoxia with predictive potential and that it is easily accessible through its extracellular domain. A further interesting feature is its strong overexpression in renal cell carcinoma. Monoclonal antibodies with high affinity to human carbonic anhydrase IX have already been generated and tested for diagnosis as well as for treatment. Peptides are an attractive alternative to antibodies. They possess favourable pharmacokinetic properties through their small size, such as rapid clearance from blood, while lacking the immunogenic potential of antibodies. Furthermore, peptides are easy and cheap to synthesize. Therefore, there is increasing interest in the development of new peptide ligands with specific BAY-60-7550 targeting abilities. A very promising tool for the identification of new specific binders is the phage display technology. The method has found wide application for the identification of new receptors and natural ligands, mapping and mimicking epitopes or isolating specific antigens that bind to bioactive compounds. Phage display was also successfully applied for the selection of novel peptides that target organs, tumors or cell types. In this study we applied the phage display technology for the identification of a new peptide ligand binding specifically to human carbonic anhydrase IX. Panning was performed using the recombinant extracellular domain of CAIX as target structure. The identified peptide CaIX-P1 was synthesized and its binding properties were evaluated in vitro on various cell lines. Furthermore, in vivo organ distribution studies in tumor bearing mice were performed and the stability of the peptide in human serum was investigated. Tumor hypoxia is known to be one of the key factors for malignant tumor aggression and progression, representing an independent negative prognostic factor for therapy outcome. Various experimental and clinical studies have confirmed the major role of hypoxia in treatment failure of both radiation therapy and chemotherapy with an up to 3-fold resistance to radiation therapy. Oxygen deficiency leads to a reduced production of cytotoxic reactive species and promotes via accumulation of HIF-1a the upregulation of a variety of genes, such as glycolysis-associated genes or the vascular endothelial growth factor, which not only induces angiogenesis but also protects the endothelial cells from irradiation. The leading role of tumor hypoxia for therapy outcome and disease prognosis reveals the necessity for the development of hypoxia targeting and imaging assays. In the past years several tracers have been developed for hypoxia imaging using positron emission tomography . Among them fluorine-18labeled fluoromisonidazole has been extensively evaluated in both preclinical and clinical trials demonstrating a significantly higher retention of the tracer in hypoxic than in normoxic tumors and a correlation between uptake and treatment response.

Leave a Reply

Your email address will not be published. Required fields are marked *