放射增敏劑於癌症放射治療之應用

Radiosensitizer in Cancer Radiation Therapy

陳苓諭(Jenny Ling-Yu Chen)

指導教授 ： 謝銘鈞

國立臺灣大學/工學院/醫學工程學研究所/博士(2018年)

https://doi.org/10.6342/NTU201800095

摘要

放射治療在癌症治療的領域是非常重要的，約七成癌症病人需接受放射治療。大多數腫瘤都存在一定程度的放射抵抗性，即便在高科技發展下的現今，可以精密準確的給予放射能量，腫瘤復發的情況依舊存在。放射增敏機制有其臨床應用價值，並可為新藥研制開發提供理論基礎。放射增敏劑與放射治療結合，通過信號傳導、細胞週期調控、細胞凋亡、及血管生成因子等多種途徑影響放射增敏效應，提高放射治療的療效。奈米科技因有以下優點：透過高渗透長滯留效應以增加藥物溶解度、控制釋放、主動標靶癌細胞，將其應用在放射增敏劑是值得研究的主題。

在第一部分，我嘗試建立放射增敏劑研究之平台。Polo-like kinase (PLK) 在G2/M phase表現量最多，參與細胞分裂並維持細胞核完整性。抑制PLK是目前新穎熱門的抗癌治療，作為放射增敏劑之理論基礎為：處於G2/M phase的細胞對於放射線最敏感，而PLK 抑制劑也是主要作用於細胞M期，兩者同時給予應可達到很好的癌症治療效果。因此，我以高效PLK抑制劑 (Volasertib)為放射增敏劑，以台灣常見之食道鱗狀細胞癌為癌細胞株，以細胞實驗及動物模式探討兩者之協同效應。在第一部分的實驗結果證明抑制PLK確實可以提升放射治療之癌細胞毒殺能力，其機轉為破壞細胞週期，並在小鼠動物模式中得到應證，也確認了放射增敏劑研究平台之可行性。

在第二部分，我應用奈米科技製作出新一代的放射增敏劑，期望其可毒殺類癌幹细胞，達到更好的癌症治療效果。類癌幹细胞對放射治療存在抵抗性並使癌症復發。Prominin-1 (CD133)為類癌幹細胞之獨特表面分子標誌。因此，此新一代之放射增敏劑以Irinotecan為傳統之放射治療增敏劑，以去鐵蛋白為載體，並在其外表連接Prominin-1專一附著之胜肽鏈，使其具有靶向作用可主動標靶癌細胞，並能降低藥物對正常組織的副作用。在第二部分的實驗結果證明此新一代的放射增敏劑確實可以主動靶向至癌幹細胞，其放射治療增敏效果非常好，並也在小鼠動物模式中得到應證，展示了奈米科技可應用在放射增敏劑的證據。

在“展望”中我提到如何繼續這個研究主題，以及怎樣應用到臨床上。我希望這個研究的結果可以協助達成“放射增敏劑增進放射治療效果且不增加毒性”的目標。

關鍵字

放射增敏劑 ； 放射治療 ； 奈米藥物 ； PLK 抑制劑 ； 類癌幹?胞

並列摘要

Radiation therapy (XRT) is very important in the field of cancer treatment, and about 70% of cancer patients require XRT. Cancer cells often present with radioresistance; tumor recurrence occurs despite using advanced techniques and accurate targeting of radiation doses. Radiosensitizers have their unique clinical values, and provide a theoretical basis for the research and development of new drugs as well. Radiosensitizers improve the efficacy of XRT by modulating signal transduction, cell cycle progression, apoptosis, or expression of angiogenic factors. Nanotechnology offers the following advantages: increased solubility through enhanced permeability and retention effect, controlled release, and targeted delivery. Thus, studies on the application of radiosensitizers are needed for the development of improved treatment methods.

First, I have attempted to build a platform to study the radiosensitizers. Polo-like kinase (PLK) is mainly expressed in the G2/M phase, participating in mitosis and maintaining nuclear integrity. PLK inhibition is considered a novel anticancer treatment. The theory of using a PLK inhibitor as a radiosensitizer is as follows: cells in the G2/M phase are the most sensitive to radiation, and PLK inhibitors mainly act during the M phase; combining both factors may lead to increased tumoricidal effects. I used a highly potent PLK1 inhibitor (volasertib) as a radiosensitizer in an esophageal squamous cell carcinoma cell line. The synergistic combined effect of XRT and PLK inhibition was studied in vitro and in vivo. I first demonstrated that inhibition of PLK can indeed enhance the effects of XRT by a mechanism involving significant cell cycle interruption. In vivo studies also showed that PLK1 inhibition with volasertib during irradiation significantly improved local tumor control. The first part of the study also confirmed the feasibility of using the radiosensitizer research platform.

In the second part, I applied nanotechnology to produce a new generation of radiosensitizers targeting cancer stem-like cells to improve the tumoricidal effects of the combination therapy. The resistance of cancer stem cells to XRT remains a major obstacle to successful cancer management. Prominin-1 is a marker of cancer stem-like cells. This new-generation radiosensitizer, developed using the traditional radiosensitizer, irinotecan, was biocompatible with apoferritin as the nanocarrier and actively targeted cancer stem-like cells through surface-modified CD133-specific ligands. The second part of the study showed that this new-generation radiosensitizer actively targeted cancer stem-like cells. Excellent synergistic radiosensitizing effects were observed in vitro and in vivo. Thus, nanotechnology can be applied to radiosensitizers.

In the Prospect, I mainly described how to continue the current projects and apply the data in clinical use. The results of this study would help in meeting the requirement of enhancing the efficacy of XRT, with low toxicity, in cancer treatment.

並列關鍵字

Radiosensitizer ； Radiation therapy ； Nanoparticle ； Polo-like kinase inhibitor ； Cancer stem-like cell

參考文獻

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