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研究生(外文):Yu-Jen Tsai
論文名稱(外文):Evaluation of biodistribution of BTO-6 for boron neutron captures therapy in human hepatoma-bearing SCID mice model
指導教授(外文):Fu-Du Chen
外文關鍵詞:boron neutron capture therapyrelative biological effectivenesshepatocellular carcinomaIP injection
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硼捉中子捕獲治療(Boron Neutron Capture Therapy, BNCT)目前在世界各國早已有不錯的研究成果,研究方向大多為惡性腦瘤及黑色素細胞瘤。國內硼捉中子捕獲治療研究小組將清華大學水池式反應爐(Tsing-Hua Open pool Reactor, THOR)照射孔改建為硼捉中子捕獲治療研究用,同時亦進行許多不同之物理、劑量及生物實驗,並針對國人好發的肝癌來進行各種不同的藥物測試及實驗。
本研究目的分為兩大部分。第一是THOR反應爐產生的超熱中子束的綜合生物效應,我們利用C3H小鼠骨髓細胞捐贈移植動物模式,分別以Cs-137加馬射線及超熱中子射束照射,最後將其活存結果利用多靶單擊模組(multi-target single-hit model)來探討相對生物效應值(relative biological effectiveness)。第二,使用清華大學羅建苗教授實驗室所合成之BTO-6 [3-(4-boronophenyl) cyclobutanone]含硼藥物,來進行人類肝癌細胞的研究。我們使用HepG2人類肝癌細胞,分別進行藥物毒性測試、吸收測試及滯留程度的實驗;此外將HepG2人類肝癌細胞以皮下注射SCID/NOD小鼠的方式來建立腫瘤模式,利用侵入性及非侵入性方式獲得以腹腔注射遞送路徑下其BTO-6含硼藥物之生物分布變化,以獲取最適化的熱中子治療時間點。
在BTO-6含硼藥物部分根據我們實驗結果我們有以下幾點討論, (1)細胞在BTO-6藥物濃度30 ppm環境下,經過24小時後對於藥物吸收可達最高點, (2)BTO-6含硼藥物半致死劑量為28 ppm,(3)BTO-6藥物在4°C環境下,在細胞內滯留時間可達兩小時,(4)BTO-6藥物注入小鼠體內後在體內可能是以腎臟為代謝途徑,(5) BTO-6藥物注入小鼠體內後,腫瘤內藥物濃度維持恆定可達六個小時以上,(6)腫瘤、血液、肝臟內藥物濃度是沒有明顯的差異。
The researches of boron neutron capture therapy (BNCT) are well established and have good results in many countries all over the world. But the research aims are mostly focused on malignant brain tumors and melanoma. In Taiwan, the BNCT research group rebuilds the irradiated port of Tsing-Hua open pool reactor (THOR) for BNCT purpose. And there are many experiments of physics, dosimetry and biology in progress. And also the efficacy of different drugs will be tested and measured in hepatocellular carcinoma that is prevalent in Taiwan.
This study was divided in two major parts. The first part is the study of biological effect of epithermal neutron beam at THOR. We used C3H mice bone marrow transplantation model to evaluate the relative biological effectiveness (RBE) with the epithermal neutron beam and the gamma ray from Cesium-137.The surviving results were evaluated by multi-target single-hit model.
The other part of this study used Boron compound BTO-6 which was synthesized by Professor Lo Jen-Mau’s laboratory as a boron delivery agent. The human hepatoma cell line HepG2 was tested for drug toxicity, uptake and retention test. We also established the animal tumor model by inoculating the HepG2 cells in SCID/NOD mice subcutaneously for in vivo biodistribution of BTO-6. The biodistribution of BTO-6 in mice was determined by gamma camera as dynamic scan which is non-invasively method and inductively coupled plasma-mass spectroscopy (ICP-MS) and gamma counter are invasively method.
The results showed that the relative biological effectiveness value of THOR epithermal neutron beam without any boron agent is 2 by using C3H mice bone marrow cells. The cellular uptake of BTO-6 reached maximum concentration after 24 hours. The IC50 of BTO-6 is 28 ppm. BTO-6 retention in cells would be remained 2 hours under 4°C circumstance. The BTO-6 was probably metabolized from kidneys in mice. Although the BTO-6 persisted in tumor at least 6 hours after IP injection, the concentration of BTO-6 in tumor, blood and liver after IP injection were not significantly different.
Because the BTO-6 concentration in tumor, blood and liver were not significant different and also it was too low to treat HCC. We had a conclusion that BTO-6 might not suitable for HCC treatment. We may try intra-tumoral injection method to improve the tumor-blood and tumor-normal tissue ratio.
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