| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 99 === The new drug development is a lengthy, high-risk and high cost process. Moreover, more strict regulation is required for new drug marketing. An important issue for new drug development is to shorten development time and to reduce cost. Recently, molecular imaging has become a new approach in new drug development. One of the molecular imaging approaches is nuclear molecular imaging. Nuclear molecular imaging is a non-invasive diagnosis technology for obtaining the information of physical or pathogenic imaging to monitor the change of physiology or pathology, using high sensitivity and specific radiopharmaceuticals and instruments. Recently, owing to the rapid development of new nuclear medicines and instruments, nuclear molecular imaging technology is becoming more important in clinical medicine and drug discovery. In this study, a new nuclear imaging agent and a new imaging instrument were evaluated.
Firstly, the radioiodinated labeling of ANV-6L15, a kind of KPI-annexin V fusion protein possess high affinity to phosphatidylserine of apoptotic cells was performed and the radiochemical purity and in vitro stability of radioiodinated ANV-6L15 were evaluated. The binding affinity of radioiodinated ANV-6L15 to apoptotic cells was evaluated using erythrocyte ghosts and anti-cancer drug-induced apoptotic cells, compared to that of radioiodinated naïve ANV. The ANV-6L15 was radioiodinated successfully and the radiolabeling yield and radiochemical purity were 40??0% and ＞95%, respectively. It also has a higher binding affinity to phosphatidylserine, which suggested more potential for apoptosis imaging. In addition, it was found that radioiodinated ANV-6L15 possesses a higher binding affinity to phosphatidylserine at physiologic calcium concentration compared to radioiodinated naïve ANV. Biodistribution and animal imaging analyses revealed that 123I-ANV-6L15 was uptaked 40.01 ?b 6.25% and 12.29 ?b 0.22% of injected dose in blood at 2 minutes and 60 minutes after injection, respectively. The rapid blood clearance of 123I-ANV-6L15 benefits the image quality.
Secondly, the feasibility of using planar positron imaging system (PPIS) to monitor chemotherapeutic efficacy in BALB/cJ mice bearing CT-26 tumor implants was evaluated. The efficacy of PPIS was compared to that of microPET, the current standard modality of PET imaging for small animals. PPIS was found to have a similar trend of tumor detection efficacy, compared with microPET. They can both detect the change of tumor growth in vivo. In the CT-26 tumor model without treatment of anti-cancer drug, the correlation coefficient (r2) of tumor/non-tumor ratios and tumor size for PPIS and microPET were 0.72 and 0.63, respectively. In the CT-26 tumor model treated with anti-cancer drug, the correlation coefficient (r2) of tumor/non-tumor ratios and tumor size for PPIS and microPET were 0.81 and 0.98, respectively. These results together indicated that the microPET and PPIS imaging methods were equally useful to monitor tumor response in syngeneic murine models. Due to the greater capacity for imaging with PPIS compared to microPET, using PPIS to determine tumor response for new anti-cancer drug is a new convenient screening system for high throughput imaging of small animal.
In conclusion, these results provided evidence that a new imaging agent, radioiodinated ANV-6L15, and a new positron imaging system, PPIS, have potential to improve and overcome the current drawbacks of nuclear molecular imaging in clinical medicine and drug discovery.
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