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dc.contributor.authorKang, Jeong Yeon
dc.description.abstractAnthracyclines are potent anticancer agents, but cardiotoxicity mediated by free radical generation limits their clinical use. These studies evaluated the anticancer activity of phenyl-2-aminoethyl selenide (PAESe) and its potential to reduce doxorubicin (DOX)-induced cardiotoxicity. Growth inhibitory effects of PAESe with DOX, and vincristine, clinically used anticancer agents, and tert-butylhydroperoxide (TBHP), a known oxidant, was determined on the growth of human prostate carcinoma (PC-3) and breast cancer (BT-474) cells. PAESe did not alter the growth of PC-3 and BT-474 cells, however, concomitant use of PAESe decreased the oxidative-mediated cytotoxicity of TBHP, but had limited effect on vincristine or DOX activity. Further, PAESe decreased the formation of intracellular reactive oxygen species from TBHP and DOX. In tumor xenograft mouse model, PAESe did not alter DOX antitumor activity and showed evidence of direct antitumor activity relative to controls. DOX treatment decreased mice body weight significantly, whereas concomitant administration of PAESe and DOX was similar to controls. Most importantly, PAESe decreased DOX-mediated infiltration of neutrophil and macrophages into the myocardium. These data suggest PAESe had in vivo antitumor activity and in combination with DOX decreased early signs of cardiotoxicity while preserving its antitumor activity. Furthermore, sterically stabilized PAESe liposome (SSL-PAESe) was formulated and the pharmacokinetic properties of SSL-PAESe were evaluated and compared with those of free PAESe to determine the effect of encapsulation using newly developed high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS) analytical method with electrospray ionization. Significant alterations in pharmacokinetic properties were observed; Circulation half-life of SSL-PAESe was increased significantly compared to free PAESe. A significant decrease in the rate of elimination and total systemic clearance and an increase in AUC were observed in animals receiving SSL-PAESe compared to free PAESe. The antitumor effect of SSL-PAESe was established by determining tumor growth inhibition, body weight, and survival using a tumor xenograft mice model. These results might be associated with increased exposure of drug in the body to improve efficacy (antitumor activity) with encapsulation in long-circulating liposomes. We demonstrated that PAESe encapsulation in SSL provides a potential to be developed as a clinical therapeutic product for improving cancer treatment
dc.subjectPhenylaminoethyl selenides
dc.subjectMass Spectrometry
dc.titleAntitumor and cardioprotective effects of antioxidant phenylaminoethyl selenide in liposomes
dc.description.departmentPharmaceutical and Biomedical Sciences
dc.description.advisorJason Zastre
dc.description.committeeJason Zastre
dc.description.committeeCatherine White
dc.description.committeeRobert Phillips
dc.description.committeeShelley Hooks
dc.description.committeeRobert Arnold

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