| ECG and serum CK-MB (creatinine kinase) or cardiac troponin analyses are the routine tests for the diagnosis of myocardial necrosis. Borderline CK-MB elevations and uninterpretable ECGs are common emergency room encounters. Elevation of troponin levels do not occur until about 6 hours after the onset of chest pain. Additional complications occur in patients who are brought to the hospital days after the onset of chest pain. These in vitro laboratory tests can not distinguish between new and old infarcts besides they do not provide information on infarct size as is the case with non-Q wave myocardial infarction where infarct size is usually small. Endomyocardial biopsy is not performed for diagnosis of myocardial infarction due to the invasiveness of the procedure. Coronary angiography has been widely used for evaluating the anatomical features of coronary arteries. This technique can establish the severity of coronary stenosis and wall motion abnormality but it is an invasive method. Additionally, out of the 1.5 million cases reported for acute myocardial infarction, 1/3rd of the cases are usually misdiagnosed by the above mentioned traditional methods. For such cases, noninvasive imaging tests coupled with very low non-target back ground activity would be preferable. In addition, diagnosis of cardiomyopathies such as myocarditis, doxorubicin cardiotoxicity and heart transplant rejection require endomyocardial biopsy as the Gold Standard for diagnosis.;Doxorubicin has been used extensively for the treatment of hematological cancers, cancers of breast, lung and bone, and soft tissue sarcomas. However, cumulative dose dependent cardiotoxicity has been a major hurdle where doxorubicin is the primary choice as an anti-tumor drug.;The overall aim of this thesis project is to prepare different bispecific antibody complexes and the polymers coupled with radionuclides in order to achieve early and specific detection of irreversible myocardial injury and also demonstrate that doxorubicin cardiotoxicity can be reduced using covalently linked doxorubicin-polymers prodrugs by gamma imaging.;To accomplish this aim, bispecific antibody complex consisting of intact monoclonal anti-myosin antibody covalently linked via thioether bond to anti-DTPA antibody will be used. Bispecific antibody complexes such as Fab' linked to Fab will be used for molecular imaging.;A highly sensitive approach has been developed for the diagnosis of doxorubicin induced cardiotoxicity. In addition, the polymer-prodrug conjugates where doxorubicin was covalently conjugated to polyglutamic acid polymers were shown to be less cardiotoxic in vitro and in vivo. Furthermore, cardiotoxicity was minimal with D-Dox-PGA treatment even at cummulative equivalent doxorubicin dose of 4 times the MTD (7.5 mg/kg) of Dox. |
