The development of an imaging method capable of measuring the increase in apoptosis early in the course of pro-apoptotic/anti-proliferative pharmacotherapies will accelerate the evaluation of experimental pre- clinical therapies and permit the personalization of established therapies in the clinic. The molecular basis for such an imaging method lies in the fact that as cells proceed along pathways to apoptosis or death, phosphatidylserine (PS), a lipid normally facing the cytoplasm, flips and faces the extracellular milieu. PS is an attractive target for imaging pharmacotherapy because (i) diverse pharmacotherapies have a common propensity to induce apoptosis, (ii) PS is an early and general marker of apoptosis and, (iii) PS can be imaged using annexin V, a protein that binds PS selectively and which has been used as a radiolabeled clinical diagnostic agent. Using fluorescent annexin V's, we have obtained important proof of principle data that the accumulation of fluorescent annexin V (38kDa) reflects the early response to anti-proliferative drug treatment in animal models of diverse diseases (cancer, arthritis). We have also shown that a magneto/optical annexin V (50 nm) can be used to image ischemia induced apoptosis by MRI in vivo. Though Tc-annexin V has been used for imaging chemotherapeutic response, clinical results to date are can be described as limited and mixed. The premise of this proposal is that annexin V based probes can be successfully used to image chemotherapy induced apoptosis, provided a vastly improved understanding of how annexin V binds to tumor and endothelial cells stressed by various chemotherapic agents in vitro is obtained. In addition, key variables regarding annexin V probe behavior in vivo must be understood, including elucidation of the cellular targets of these probes and determination of whether chemotherapy induced changes in tumor blood volume complicate the quantitation of the molecular marker, PS. This proposal will provide essential information regarding the interaction of annexin V probes with cells subjected to chemotherapeutic stress, and allow imaging apoptosis to realize its as yet unrecognized and vast potential. It will provide a basis for the selection pharmotherapeutic regimes based on the expression of a molecular marker upregulated on tumors undergoing treatment, indicating which regimes will be efficacious for specific individuals, and sparing many side-effect prone regimes which provide no benefit. ? ?
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| Blois, Joseph; Smith, Adam; Josephson, Lee (2011) The slow cell death response when screening chemotherapeutic agents. Cancer Chemother Pharmacol 68:795-803 |
| Garanger, Elisabeth; Blois, Joseph; Hilderbrand, Scott A et al. (2010) Divergent oriented synthesis for the design of reagents for protein conjugation. J Comb Chem 12:57-64 |
| Sosnovik, David E; Garanger, Elisabeth; Aikawa, Elena et al. (2009) Molecular MRI of cardiomyocyte apoptosis with simultaneous delayed-enhancement MRI distinguishes apoptotic and necrotic myocytes in vivo: potential for midmyocardial salvage in acute ischemia. Circ Cardiovasc Imaging 2:460-7 |
| Sosnovik, David E; Nahrendorf, Matthias; Panizzi, Peter et al. (2009) Molecular MRI detects low levels of cardiomyocyte apoptosis in a transgenic model of chronic heart failure. Circ Cardiovasc Imaging 2:468-75 |
| Smith, Adam; Blois, Joseph; Yuan, Hushan et al. (2009) The antiproliferative cytostatic effects of a self-activating viridin prodrug. Mol Cancer Ther 8:1666-75 |
| Garanger, Elisabeth; Weissleder, Ralph; Josephson, Lee (2009) A multifunctional single-attachment-point reagent for controlled protein biotinylation. Bioconjug Chem 20:170-3 |
| Yuan, Hushan; Pupo, Monica T; Blois, Joe et al. (2009) A stabilized demethoxyviridin derivative inhibits PI3 kinase. Bioorg Med Chem Lett 19:4223-7 |
| Smith, R Adam; Yuan, Hushan; Weissleder, Ralph et al. (2009) A wortmannin-cetuximab as a double drug. Bioconjug Chem 20:2185-9 |
| Garanger, Elisabeth; Hilderbrand, Scott A; Blois, Joseph T et al. (2009) A DNA-binding Gd chelate for the detection of cell death by MRI. Chem Commun (Camb) :4444-6 |
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