摘要
本研究之目的在於建立肝腫瘤之動物模式，評估施予硼藥物後硼中子捕獲治療之療效與生物效應。實驗中分為細胞實驗與動物實驗兩部分，使用之含硼藥物為硼酸及PBAD-lipiodol，先以細胞實驗測試藥物之毒性，做為選擇含硼藥物濃度之依據，再以動物實驗評估治療之效果。
細胞實驗中，以大鼠正常肝細胞(Clone 9)及人類肝腫瘤細胞(HepG2)測試攝取硼濃度之能力以及藥物對細胞之毒性，結果顯示以含有25 μg 10B/mL硼酸濃度之培養液處理細胞應較為合適。之後並以25 mg 10B/kg bw之硼酸水溶液為含硼藥物進行荷肝腫瘤動物BNCT治療。於動物實驗中，根據藥物於血中之代謝能力以及藥物於生物體中之分佈，決定所有荷肝腫瘤動物於藥物注射後之30分鐘接受BNCT 照射，照射時間在打藥後30至80分鐘間。於治療過程中並將BNCT的治療劑量分為四組，以肝腫瘤所接受之劑量為主，G1組為11.2 Gy，G2組為9.7 Gy，G3組為8 Gy及G4組為5.6 Gy，以了解經BNCT治療之腫瘤消退是否具有劑量依存性。動物經BNCT治療後並追蹤觀察80 天，期間以超音波做為腫瘤影像追蹤之工具，並以血清生化值監測動物體之生理狀況。結果顯示，經BNCT治療之大鼠肝腫瘤於治療後第8天，各組照射劑量者之腫瘤，在超音波追蹤下皆有顯著地減小，其腫瘤邊緣之增生血管分佈亦有明顯的減少，治療後之80天腫瘤大小皆減小90％以上，僅存之團塊在病理切片檢查下診斷為疤痕組織並不見有腫瘤細胞的存在。接受各劑量BNCT照射後4天之老鼠可見明顯的輻射傷害，如腹瀉、淋巴流失等現象，然而於BNCT照射完30天及80天後，便不見上述之傷害，惟睪丸細胞之萎縮病變未見恢復。另外，亦有使用肝動脈注射評估PBAD-lipiodol於腫瘤組織與肝臟組織內之分佈，經油紅染色法染色後，可見腫瘤內累積之脂球明顯高於正常組織數倍，只是PBAD-lipiodol於腫瘤內之分佈並不均勻。因此，若以兩藥物合併做為BNCT治療之含硼藥物，或許便可增加腫瘤中之硼濃度，提高腫瘤與正常組織間之硼濃度比。

Abstract
In this research, a rat model for hepatocellular carcinoma (HCC) was set up, and the boric acid (BA) and PBAD-lipiodol were used as the boron drugs. The pharmacokinetics, radiobiological effects and therapeutic efficacy of boric acid for boron neutron capture therapy (BNCT) for hepatocellular carcinoma were evaluated.
The in vitro and in vivo experiments and the boron drug synthesis were included in this study. HepG2 cells and Clone 9 cells were incubated in culture media containing different concentrations of BA for the cytotoxicity test and uptake evaluation. Concerned with the cytotoxicity of BA and the cellular uptake, we decided to use 25 mg 10B/kg bw BA to treat the tumor bearing rats. BA was injected from the tail vein of rats to assess the biodistribution and pharmacokinetics, and to determine optimal time interval for neutron irradiation. Boron concentration was analyzed by the ICP-AES. The tumor bearing rats were irradiated with neutron after 30 minutes of boron drug injection and were given four level prescription doses to evaluate the radiobiological effects and therapeutic efficiency of BNCT. Ultrasound imaging was used to monitor the changes of tumor size, and doppler imaging was used for the detection of blood flow change after BNCT treatment.
The tumor size and blood flow were decreased after BNCT. However, at the fourth day after BNCT treatment, rats showed some radiation damages, such as diarrhea and lymphocyte diffuse, but these damages were disappearing late. Rats were sacrificed at different intervals after BNCT, and tumor mass was controlled in the good status at the 30th days, and was disappeared at the 80th days. Because the rats were too small to obtain in an applicative shielding, the testis was fall in the beam port. Thus, the testes showed a dose-dependent atrophy after BNCT treatment. In this study, we also used hepatic artery injection to assess the PBAD-lipiodol distribution in the rat liver. The accumulation of PBAD-lipiodol in the tumor region was higher than that in normal liver tissue, but with a non-uniform distribution.
We suggested that it might be a good choice to combined boric acid and PBAD-lipiodol in BNCT for hepatoma, which might be able to increase the boron concentration in tumor region.
Key words：Boron neutron capture therapy (BNCT), Hepatocellular carcinoma (HCC), Boric acid (BA), PBAD-lipiodol

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