Biosignature and Vector Development Core

Washington University, Saint Louis MO

Investigators

Linked publications & trials

Abstract

CORE C3: Biosiqnature and Vector Development Core Introduction Molecular imaging agents are extending the potential of noninvasive medical diagnosis from basic gross anatomical descriptions to complicated phenotypic characterizations based upon the recognition of unique cellsurface biochemical signatures. "Molecular imaging" is now a prominent feature of most clinically relevant imaging modalities, which affords the opportunity for targeted diagnostic studies but also for image-monitored site-specific therapeutic delivery, much like the "magic bullet" envisioned by Paul Erhlich 100 years ago. As we have demonstrated, integrin-targeted perfluorocarbon nanoparticles can combine molecular imaging with local drug delivery, i.e. rational targeted therapy, and provide prognostic information about the expected response to treatment1-4. Common to all tumors are the demands for oxygenation, nutritive energy supplies, and development of a vasculature. Cell-matrix interactions, fundamental to tumor invasion and metastasis, as well as angiogenesis, are closely associated with cell membrane adhesion molecules referred to as integrins. The integrins are heterodimeric, transmembrane glycoproteins resulting from the combination of 19 alpha and 8 beta subunits. In addition to their adhesive functions, integrins are involved in the transduction of information along classical signaling pathways and are presumed to influence cellular proliferation and apoptosis of cancer and activated endothelial cells. As described in several programs of this SCCNE, antagonists of alphavbeta3-integrin and a5b1 integrin maybe coupled to nanoparticle surfaces and utilized for high affinity, high-specificity targeting of the neovasculature. Indeed, the role of alphavbeta3-integrin is well documented in melanoma and breast cancer metastasis, but varies temporally within and across tumor types. Whereas, less aggressive tumors have low expression or only transient expression of anb3-integrin, alambdab1-integrin is more frequently expressed by low malignant potential tumors in addition to aggressive carcinomas, e.g., in ovarian cancers6. Endothelial proliferations of glioblastomas may be phenotypically characterized into three subtypes 6:1) solid-glomeruloid ICAM-1, alpha2beta1,alpha3beta1,alpha5beta1 negative;2) channeled-branching ICAM-1 negative, and alpha2beta1,alpha3beta1,alpha5beta1 positive;or 3) channeled-telangiectatic ICAM-1 ,alpha2beta1,alpha3beta1,alpha5beta1 positive. The variable expression of these molecules probably reflect different steps in the maturation of endothelium and further illustrates the need to develop arrays of targeted agents to properly segment and treat the heterogeneous population of tumor neovasculature. For ligand-targeted therapies to work efficiently, patients must be administered the appropriate individualized agent (or mixture of agents). The Siteman Center for Nanotechnology Excellence will establish this core for the development and characterization of targeting ligands to be used with current and future nanotechnology platforms within the center and more broadly at other centers. The approach tripartite combines the state-of-the art technologies of: 1) peptide phage display, 2) recombinant antibody production, and 3) bioinformatics to address the unmet need for unique tumor binding ligands.