||Gold Nanoparticles Conjugated with Antibody Fragments for Photothermal Therapy in Bladder Cancer
||Department of BioMedical Engineering
以熱能來殺死腫瘤細胞一直以來都是熱門的研究話題。包括使用雷射，聚焦超音波，微波等來瞄準目標減少周邊組織傷害。 然而，以一般簡單加熱的方式將會導致其路徑所經過的正常組織也一併死亡。而最新發展的奈米金粒子的光熱療法加上標靶療法的應用，就可以讓奈米金粒子辨識我們所要標定的腫瘤細胞，並加以摧毀。特別是當腫瘤還是肉眼不可見時，標靶療法即可有效的將金奈米粒子標定。而且因為其專一性，對週邊組織幾乎不會有任何傷害。本論文應用修飾過的抗體片段來製造免疫性金奈米粒子，並依據吸收波長搭配綠光雷射以達成光熱療法來治療泌尿上皮癌。以奈米殼層或奈米金屬粒子及近紅外光雷射治療腫瘤的報告近年曾被發表過。研究顯示腫瘤可確實被奈米金屬粒子及近紅外光雷射產生的光熱效應所殺死。 本論文是將泌尿上皮癌細胞，MBT2 (小鼠)， 9202(人類)， 8301(人類)和T24(人類)，先以表面抗原分析，確認EGFR， Mucin 7的表現，並利用其單株抗體結合上約47nm的奈米金粒子。 加以不同功率的532nm的綠光雷射照射後，觀察其細胞死亡的狀況，並觀察修飾過的抗體片段亦可達到相同的作用而且更穩定。再根據Xiao等學者所提出的泌尿上皮癌動物模式來將光熱治療推展至動物實驗。且發現可有效抑制膀胱腫瘤在老鼠膀胱的生長。正常的細胞在適當能量的綠光雷射照射情況下是不會死亡的。而癌症細胞則會因光熱療法被殺死。因為泌尿上皮癌是生長於膀胱內壁，預計將來以膀胱灌注與膀胱內照射的方式，可以用來治療表淺性泌尿上皮癌。因為不需要透過血液，將大大減低可能引起的副作用及毒性。
Various hyperthermia techniques have been widely developed for the treatment of cancers. The common approach is to utilize focused heat sources including laser, focused ultrasound, and microwaves to aiming at the target cells but avoiding the normal tissue. However, simple heating techniques often heat the tissues in the pathway and might damage the normal tissues. Recent development of photothermal therapy of gold nanoparticles combined with target therapy has been a viable approach for cancer treatment in which the nanogold can precisely target the tumor with monoclonal antibodies. The targeting nanogold may work even the tumor is too small to be detected by other imaging techniques. According to the specificity, the surrounding tissues will rarely be damaged. This aim of this project is to utilize photothermal therapy to treat urothelial cancer using antibody fragments conjugated gold nanoparticles and the exposure of green light laser. The tumor treated with gold nanoshells and nano particles and near infrared laser has been documented recently. Research has shown that the heat generated by metalic nanoparticles kills the malignant tumors. We cultured the urothelial cancer cell lines, MBT2 (mice), 9202(human), 8301(human) and T24 (human) and surveyed the surface antigen including the EGFR, and Mucin 7. The monoclonal antibodies can be conjugated to gold nanoparticles (48nm in diameter). Green light laser (532nm) at different power levels was chosen to heat the target gold particles bound to the urothelial cancer cells and then observe the effect of tumor suppression. The GNPs modified by antibody fragments had shown the same treatment effect and better stability. According to the animal model of urinary bladder TCC created in the previous study, we extended the study to in vivo experiment. The in vivo study showed the tumor was suppressed by photothermal therapy. After treated with antibody conjugated gold nanoparticles and laser exposures at a carefully selected level, the tumor cells will be ablated but the normal cell would survive. The developed technique is clinically useful because the urothelial cancer of urinary bladder is in the inner wall of urinary bladder. The intravesical instillation and laser emission will serve to ablate the superficial urothelial cancer but it does not pass through the blood stream alleviating the toxicity and side effects of gold nanoparticles. This method has the potential to enhance the efficiency of cancer treatments while reducing the risk of damage to normal cells.
TABLE OF CONTENTS
Table of Contents V
Table of Figures VII
Chapter 1 General Introduction 1
1.1 Urothelial Cancer of Urinary Bladder 1
1.2 Nanoparticles for Bladder Cancer 4
1.2.1 Metal/Gold Nanoparticles 4
1.2.2 Polymeric Nanoparticles 8
1.2.3 Liposome and Lipid Nanoparticles 9
1.2.4 Protein Nanoparticles 11
1.2.5 Overview and Discussion 12
1.3 Surface Plasma Resonance and Photothermal Therapy (PTT) 13
1.4 Photothermal Therapy with Gold Nanoparticles in Bladder Cancer 22
1.5 The Unmet Clinical Need and the Aim of this Study 23
Chapter 2 In vitro Photothermal Therapy with Immunized Gold Nanospheres 27
2.1 Brief Summary 27
2.2 Synthesis of Gold Nanoparticles 28
2.3 Antibody Labeled Gold Nanospheres 29
2.4 Cell Culture of the Malignant Tumors and Laser Therapy 29
2.5 Flow Cytometry System 31
2.6 Confocal Spectral Microscopy 31
2.7 Results 32
2.7.1 GNP Characterization 32
2.7.2 The Expression of Mucin 7 and EGFR in Four Cancer Cell Lines 33
2.7.3 Photothermal Therapy for Urothelial Cancer Cell Lines Using Anti-Mucin 7 Antibody Conjugated GNPs. 36
2.7.4 Anti-Mucin 7 Antibodies Conjugated vs. Anti-Mucin 7 Antibodies Blocked Gold Nanospheres 39
2.8 Discussion 41
2.9 Conclusions 44
Chapter 3 In vitro PTT with Antibody Fragments Labeled Gold Nanospheres 46
3.1 Brief Summary 46
3.2 Preparation of Antibody Fragments for Labeling of Gold Nanoparticles 46
3.3 Culturing of Bladder Cancer Cells 48
3.4 Field Emission Scanning Electron Microscopy (FE-SEM) 48
3.5 Sample Preparation for Transmission Electron Microscopy (TEM) 48
3.6 Flow Cytometry System 49
3.7 In vitro Laser Therapy 50
3.8 Results 51
3.8.1 Interaction between GNPs and Antibody Fragments 51
3.8.2 SEM and TEM Images 52
3.8.3 Photothermal Therapy with Anti-EGFR Antibody Fragments Conjugated Gold Nanospheres 54
3.8.4 Measurement of Variations in Temperature 55
3.9 Discussion 56
3.10 Conclusions 57
Chapter 4 In vivo PTT with antibody fragments labeled gold nanospheres 59
4.1 Brief Summary 59
4.2 Preparation of Antibody Fragments for Labeling of Gold Nanoparticles 60
4.3 Orthotopic Bladder Cancer Animal Model 61
4.4 In Vivo Laser Treatment 62
4.5 Results 63
4.6 Discussion 65
4.7 Conclusions 67
Chapter 5 Future Works and Conclusions 68
5.1 Future Works 68
5.2 Conclusions 69
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