本研究是以VX2腫瘤細胞誘發多發病灶肝腫瘤兔模式，探討以硼酸為含硼藥物對肝腫瘤硼中子捕獲治療(Boron neutron capture therapy, BNCT)之藥物動力學及療效評估。本研究使用含99% 10B之硼酸為硼藥物，以硼酸靜脈注射急性毒性試驗，決定適當使用的施藥濃度，硼酸經靜脈注射劑量達800 mg/kg bw，對兔子不會造成明顯毒性，故選擇以施打300 mg/kg bw硼酸(等同於50 mg 10B/kg bw)進行肝腫瘤BNCT研究。荷肝腫瘤兔經靜脈注射50 mg 10B/kg bw硼酸進行藥物動力學及生物體分布試驗，以決定最佳中子照射時段，肝腫瘤兔於硼酸注射後30分鐘在清華開放式水池反應器進行中子照射。療效評估前試驗結果顯示腫瘤施以物理劑量達5.84Gy具有明顯反應。根據MCNP模擬結果，利用開口直徑為5.5公分之collimator進行照射，以提供腫瘤較高之治療劑量及對正常組織有較佳之保護效果。一次BNCT治療組之腫瘤於BNCT治療所接受之物理劑量範圍為7.99-16.66Gy，一次治療後可觀察到腫瘤生長受到抑制，但多數腫瘤於治療後之29-36天復發。二次BNCT治療組之腫瘤於第一次BNCT治療所接受之物理劑量範圍為7.00-16.24Gy，治療後動物體重下降，但於7-14天回復；第一次治療後21天(即為第二次治療前1天)，經超音波及電腦斷層掃描顯示腫瘤明顯縮小，且腫瘤周圍血流亦明顯減少。一次治療後之22天進行第二次治療，所接受之物理劑量範圍為6.71-10.48Gy。經第二次治療後，體重僅輕微下降，且腫瘤會持續縮小，於二次治療後18天，腫瘤周圍已偵測不到血流，利用超音波掃描與電腦斷層掃描觀察所獲得的腫瘤反應一致，具有明顯療效。荷肝腫瘤兔於一次BNCT治療後142天(等同於二次治療後120天)犧牲進行組織病理切片檢查，切片上顯示已無存活之腫瘤細胞，證實腫瘤完全治癒。而中子照射組及腫瘤控制組則於腫瘤接種後30-60天，因腫瘤過大而進行人道犧牲。此外，並利用自動放射顯影技術探討荷腫瘤肝葉之硼原子微分布，結果顯示，相較於正常組織，硼酸在腫瘤及其血管有較高之蓄聚，可以見到正常肝組織的α軌跡密度較低。經治療後5天，正常組織區之肝細胞及血管未見有明顯傷害，而腫瘤團塊內則可見大量的細胞壞死，腫瘤周圍動脈則可見多發性、中度之動脈炎，動脈之內皮細胞明顯受到破壞。本研究證實以硼酸為含硼藥物進行肝腫瘤之硼中子捕獲治療，在正常肝組織無明顯可見傷害的情況下，可選擇性破壞腫瘤及其血管，以提供肝腫瘤有效的治療。

The aim of this investigation is to evaluate the pharmacokinetics and therapeutic efficacy of boric acid (BA)-mediated boron neutron capture therapy (BNCT) for liver tumor in the VX2 multifocal liver tumor-bearing rabbit model. 10B-enriched BA (99% 10B) was used as the boron drug in this study. The acute toxicity study was performed to determine the appropriate concentration of BA, the result revealed that BA via an intravenous administration of up to a dose of 800 mg/kg body weight (bw) did not obviously cause acute toxicity in rabbits, 300 mg/kg bw of BA (equal to 50 mg 10B/kg bw) are selected for subsequent uses. Tumor-bearing rabbits were injected with 50 mg 10B/kg bw of BA from a marginal ear vein, the pharmacokinetic and biodistribution analyses were carried out to assess the optimal time interval for neutron irradiation. The tumor bearing rabbits were irradiated with neutrons at the Tsing Hua Open Pool Reactor (THOR) 30 minutes following the BA injection. Potential threshold dose for obvious tumor response were established at 5.84 Gy by the preliminary study. The results of MCNP simulation revealed that the collimator with aperture is 5.5 cm in diameter which can provide a higher dose to tumor and a better protection for neighboring normal tissue was optimal for neutron irradiation. The physical dose administered with single fraction BA-mediated BNCT was ranged from 7.99 to 16.66Gy, the inhibition of tumor growth was observed after the BNCT treatment. Nevertheless, tumor recurrence was observed from 29 to 36 days following the BNCT treatment. In the two-fraction BNCT treated group, the physical dose delivered to tumors with first and second fractions were ranged from 7.00 to 16.24Gy and 6.71 to 10.48Gy, respectively. Although body weight loss was detected in rabbits that had undergone BNCT, this weight was recovered within seven to fourteen days. An obvious reduction in tumor size and in the blood flow around the tumor were detected by ultrasound scanning and computed tomography (CT) scan 21 days after the first fraction of BNCT treatment (that was relative to 1 day before the second BNCT). The second fraction BNCT treatment was performed on the 22th day after first BNCT treatment. The rabbits that underwent the second fraction BNCT exhibited slight weight loss within 7 days. The size of the tumors continued to decrease thereafter and the blood flow around the tumor was undetectable 18 days after the second BNCT. The therapeutic response that was detected by ultrasound scanning, described above, was consistent with the results of the CT scan. Rabbits were sacrificed on the 142th day following the first fraction of BNCT treatment, no histopathologic evidence of residual tumor was seen in the tumor-bearing liver of treated rabbits. The multifocal liver tumors in rabbit VX2 tumor model were completely cured by 2 fractions of BA-mediated BNCT. Owing to tumor overgrowth, rabbits in the neutron treated alone group and the tumor control group were sacrificed humanely 30-60 days after tumor inoculation. Furthermore, neutron capture autoradiography was used to investigate the microdistribution of boron in the tumor-bearing liver, the result showed that BA was specific retained in the tumor and the tumor vessels. A low-density and uniform of alpha tracks was observed in normal liver tissue, in contrast, a high-density of alpha tracks and regional differences in track density were seen in tumor. Histopathological observations of a VX2 tumor-bearing liver of the rabbit five days after BNCT revealed no obvious damage to the hepatocytes or vessels in the normal liver regions, whereas, massive tumor cell necrosis was found in the tumor masses. Multiple, moderate, arteritis was expressed as endothelial cell degeneration and edema with inflammatory cell infiltration in the artery in the VX2 tumor, while no histological abnormalities in the normal artery. BA-mediated BNCT can deliver curative radiation dose to tumors and the tumor vessels while sparing the normal liver tissue. Therefore, this method has the potential to provide a better way for liver tumor therapy.

摘要 I
ABSTRACT II
致謝 IV
目錄 VI
表目錄 VIII
圖目錄 IX
第一章 文獻探討 1
第二章 材料與方法 11
第三章 結果 21
第四章 討論 56
第五章 結論 72
第六章 圖表 75
第七章 參考文獻 145

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