Research Project
8905124
? DESCRIPTION (provided by applicant): Although antitumor agents have resulted in significant survival benefits for cancer patients, several agents have serious cardiovascular toxic side effects. Anthracyclines are commonly used antineoplastic drugs with demonstrated clinical utility. However, their effectiveness is limited by well-established dose-dependent risk of acute and chronic cardiotoxicity and congestive heart failure. In current clinical practice several methods are used to noninvasively monitor left ventricle ejection fraction (LVEF) and to assess the impairment of cardiac function by chemotherapy. Unfortunately, regardless of methodology, a decrease in LVEF is a relatively late manifestation of progressive subclinical myocardial damage and abnormal observations are made when cardiac damage has already occurred. Despite routine monitoring of LVEF some patients still develop severe LV dysfunction. Therefore, a non-invasive method for detection of myocardial injury before irreversible left ventricular dysfunction has occurred would be of great clinical significance, providing the opportunity for timely intervention. Our long-term goal is to develop an SPECT imaging probe that will detect cancer treatment-induced cardiotoxicity earlier than methods detecting left ventricle dysfunction. To address this significant unmet medical need, we propose a Phase I proof-of-concept study to show our that novel, innovative molecular probe, 99mTc-Duramycin, which has been demonstrated to image apoptotic/necrotic cells in vivo, will be able to detect doxorubicin (Dox) - induced cardiotoxicity in a rat model. Duramycin is a 19-amino acid peptide that binds to phosphatidylethanolamine (PE) with relatively high affinity and provides an innovative tool for the targeting of PE molecules exposed on target cells and tissues. Duramycin is characterized by multiple thioether crosslinking and uncommon amino acids derived from posttranslational modifications. The overall structure of Duramycin assumes a compact cyclic configuration, with a single binding pocket that specifically interacts with the glycerophosphoethanolamine head group of PE. Two aims are proposed to achieve our proof-of-concept study. Specific Aim 1 is directed towards establishing the ability of 99mTc-Duramycin to image Dox-induced cardiotoxicity in an acute rat model. Specific Aim 2 is directed towards demonstrating the ability of 99mTc-Duramycin imaging to detect Dox-induced cardiotoxicity at an earlier time point than the onset of LV dysfunction in a chronic Dox-induced cardiotoxicity rat model. In summary, this phase I SBIR project is intended to confirm the hypothesis that 99mTc-Duramycin will detect Dox-induced cardiotoxicity by in vivo SPECT imaging prior to the onset of left ventricle dysfunction as measured by echocardiography.
