臺灣博碩士論文加值系統

背景：卵巢癌仍是婦女健康上的一大威脅並在治療上仍屬困難。治療卵巢癌在臨床上仍有極大挑戰因為多晚期診斷，台灣目前每年平均有每十萬人口中，6.39人罹患卵巢癌，民國92年女性卵巢癌症有833人，而在國民健康署102年的資料來看，一年新增卵巢癌是1321新病例。目前已知已有治療的對策中針對癌細胞代謝是有未來的潛力。多年來耐克螺 (niclosamide)在作用腸道寄生蟲的粒線體抑制上已廣泛研究許多，儘管近來研究顯示耐克螺作用在治療癌症上有多層面的探討，包括抑制腫瘤生長及阻止腫瘤轉移，但是其藥物拒水性難溶於水的特性仍尚待克服。
目的：本研究目的是就新發展的劑型，奈米化耐克螺 (Nano-niclosamide)在治療卵巢癌的臨床前的應用。目前卵巢癌依照特性分成第一型及第二型卵巢癌，第一型包括內膜細胞型及亮細胞癌為主，而第二型卵巢癌則是高度惡性的漿液細胞癌，目前針對癌症幹細胞的癌症治療已經漸被接受，我前團隊實驗室的研究利用癌幹細胞的抑制找尋可能有潛力的抑癌藥物耐克螺，然而耐克螺的難溶於水特性，我們合作的實驗室團隊以雷射電噴霧使耐克螺奈米化方法增加其水溶性，之前已知耐克螺用在治療癌細胞上多方的訊息傳遞路徑。是老藥新用的一個前瞻範例。我們針對奈米化耐克螺的功效，包括抑制癌症細胞生長，癌症細胞的醣解及氧化磷酸化代謝變化，幹細胞特性中球體形成能力，在大鼠中藥物動力學做初步分析研究。
結果：奈米化耐克螺在治療卵巢癌的藥效上確實比較原始劑型表現較佳，在細胞實驗及動物實驗中得以驗證，對卵巢癌細胞株產生代謝抑制及代償性的代謝轉移現象，口服試驗中對免疫缺陷小鼠肝腎大腦及腸道等重要器官毒性不明顯，血液毒性不明顯。奈米化耐克螺在口服大鼠的藥物動力學中，有快速吸收且快速排出體外及較好口服生物可利用率的初步實驗結果。
結論：奈米化耐克螺對於卵巢癌治療有效且具有未來臨床發展潛力，若可以則可進行第一期人體試驗。

Background: Ovarian cancer still remains the most incurable disease of women health issue. Treatment of ovarian malignancy is still hard due to late diagnosis. There are 1,321 new diagnosed cases in Taiwan. The most common histopathology cell type is serous cystadenocarcinoma about 28% of all the cases. Ovarian cancer treatment remains a clinical obstacle. Recently, targeting cancer cell metabolism represents a new promising strategy. Niclosamide is an old anti-helminthic drug that uncouples the mitochondria of intestinal parasites. Although recent studies demonstrate that niclosamide is a potential anticancer agent that targets multiple pathways for cancer cell growth and metastasis, its poor water solubility needs to be overcome before further preclinical and clinical investigations.
Objectives: The aims of this study were first to investigate there is a pressing need to develop a novel agent for ovarian cancer treatment.
Targeting cancer stem cells has recently become an emerging concept in cancer therapy. Niclosamide was found to show inhibitory activity on human ovarian cancer. However, niclosamide is a hydrophobic drug and is difficulty in dissolving in water and reduces its effects in cancer treatments. Therefore, nanoparticle of niclosamide (nano-niclosamide) was developed to increase the solubility in water. In this study, we constructed a preclinical trial of nano-niclosamide on ovarian cancer.　Furthermore, recent studies indicate that Niclosamide exhibits anticancer effects in various human cancers by acting on multiple signaling pathways. Therefore, NI is considered to be an old drug with the potential for new use for cancer.　The novel nano-formulation of NI (nano-NI) provides an opportunity for ovarian cancer treatment. Before clinical applications, preclinical efficacy, toxicity, and pharmacokinetic/ pharmacodynamic studies are achieved.　In this study, we aimed to evaluate the in vitro and in vivo activity and toxicity of the nano-NI in cell and animal models. We investigated how the novel formulation would affect water solubility and ovarian cell metabolism. Then, we determined the oral bioavailability and pharmacological response of the new formulation. The information gleaned from the present study should pave the way for future clinical investigations.
Results: Nano-niclosamide effectively inhibits the growth of ovarian cancer cells and causes a metabolic shift to glycolysis in vitro, and suppresses tumor growth without obvious toxicity in vivo. Pharmacokinetic study after oral medication, nano-niclosamide reveals fast absorption and a better bioavailability.
Conclusion: Nano-niclosamide has great potential to become a new treatment modality for ovarian cancer. Phase I clinical study may be take into consideration.

CONTENTS
誌 謝 III
LIST OF TABLES VII
LIST OF FIGURES VIII
中文摘要 XI
ABSTRACT XIII
CHAPTER 1 BACKGROUND 1
1.1 Ovarian cancer 1
1.2 Current therapies for ovarian cancer 3
1.3 Cancer stem cells (cancer initiating cells) 4
1.4 Old drug for new use 6
1.5 Nanomedicine in cancer 7
1.6 Niclosamide 8
CHAPTER 2 SPECIFIC AIMS 11
2.1 Nano-niclosamide inhibit ovarian cancer growth in vitro 11
2.2 Does Nano-niclosamide interrupt ovarian cancer growth in vivo 11
2.3 Toxicity evaluation and bioavilability and pharmacological response of the new formulation nano-Niclosamide. 11
CHAPTER 3 CONCEPTUAL FRAMEWORK 12
CHAPTER 4 MATERIALS AND METHODS 13
4.1 Preparation of the NI nanosuspension by using a single-capillary electrospray 13
4.2 Nano-niclosamide inhibitory ovarian cancer growth in vitro 14
4.3 Nano-niclosamide interrupt ovarian cancer growth in vivo 18
4.4 Phamacokinetic studies of nano-niclosamide in vivo 20
4.5 Pharmacokinetic animal study 23
4.6 Statistical analyses 25
CHAPTER 5 RESULTS 26
5.1 Nano-NI suppresses ovarian cancer cell proliferation in vitro 26
5.2 Nano-NI disrupts ovarian cancer cell metabolism 27
5.3 Oral nano-NI inhibits ovarian cancer growth in vivo 28
5.4 Toxicity evaluation of nano-NI in vivo 29
5.5 Bioavailability of nano-NI after oral administration in SD rats 30
CHAPTER 6 DISCUSSION 32
CHAPTER 7 CONCLUSION 39
CHAPTER 8 REFERENCES 40

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