| Summary: | 碩士 === 國立清華大學 === 生醫工程與環境科學系 === 99 === Myeloperoxidase(MPO) plays an important role in formation of atherosclerotic plaques. MPO can activate lipid oxidization and localization in the intima of blood vessel wall, resulting in lipid cores in atherosclerotic plaque. If the lipid core dominates the plaque, the latter would become unstable and easily ruptured, forming thrombi that circulate in the blood. It would be very dangerous to make thrombi obstruct the blood vessels, causing fatal disease such as stroke and myocardial infarction. Hence, early detection of MPO within the blood vessels may be of great importance for clinical management of related vascular diseases.
Method: In this study, a radioactive agent, 111In-bis-5HT-DTPA was synthesized to detect MPO for early diagnosis. The 5HT base agent could oligomerize by itself or with proteins through a specific mechanism mediated by myeloperoxidase. For in vitro study, the agent was incubated with myeloperoxidase and hydrogen peroxide to confirm the aggregation with the enzyme. For animal study, apoE knockout mice were used to generate plaque and atherosclerosis changes for investigation with blood analysis and histopathologic studies. NanoSPECT/CT imaging and biodistribution assay were carried out to ensure the binding (with MPO) of 111In-Bis-5HT-DTPA with MPO in a murine atherosclerotic model.
Results: Bis-5HT-DTPA was synthesized and its structure confirmed by1H-NMR and ESI-MASS. 111In-bis-5HT-DTPA synthesized in this study exhibited ≧ 95% radiochemical purity and high stability in rat plasma. MALDI-TOF spectrum demonstrated that the 5HT base agent could oligomerize by itself. The nanoSPECT/CT imaging study indicated that the accumulation of
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111In-Bis-5HT-DTPA around the heart in apo E knockout mice was apparently more significant than that of the wild type mice. In the biodistribution study, the artery wall uptake of 111In-bis-5HT-DTPA oligomer in the artery wall of apo E knockout mice was about 1.38±0.03-fold higher than that in the wild type mice at 1 hour. The elimination rate of 111In-bis-5HT-DTPA from the blood vessel in apoE KO mice was 0.14±0.09 % ID/g/h, whereas that in the wild type mice was 3.88±0.25 % ID/g/h (P = 0.010, P<0.05).
Conclusion: From the imaging and biodistribution study, the radioactivity signal around the heart in apo E knockout mice is significantly higher than that of the wild type mice. It revealed that 111In-Bis-5HT-DTPA can accumulate1.38±0.03-fold higher in the aorta of apo E knockout mice than in the wild type mice. In summary, this study has described a fundamental radionuclide pharmacokinetic and biodistribution results in apoE knockout mice and possible utilization of oligomerization in 111In-Bis-5HT-DTPA for early detection of myeloperoxidase within the blood vessel wall.
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