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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/97429完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李心予 | zh_TW |
| dc.contributor.advisor | Hsinyu Lee | en |
| dc.contributor.author | 廖晏慈 | zh_TW |
| dc.contributor.author | Yen-Tzu Liao | en |
| dc.date.accessioned | 2025-06-05T16:14:04Z | - |
| dc.date.available | 2025-06-06 | - |
| dc.date.copyright | 2025-06-05 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-05-15 | - |
| dc.identifier.citation | References
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/97429 | - |
| dc.description.abstract | 神經母細胞瘤是一種生長快速並好發於兒童的惡性腫瘤，通常是由於交感神經系統的神經脊細胞在發育過程中產生突變而生成。在MYCN基因異常放大的高危險群中，預後極差，且需要依賴高劑量的化療來控制病情，但治療過程往往伴隨嚴重的副作用。此外，傳統的藥物篩選平台雖然促進了新療法的發展，但因為需要大量的腫瘤細胞進行篩選，且臨床轉化率偏低，使這些傳統篩選平台難以應用在個人化醫療的發展。為了解決這些問題，我們開發了一種仿生奈米液滴處理（BioNDP）平台，該平台能夠同時進行高通量以及多種藥物組合的篩選，可以大幅降低細胞數目需求至100個，同時又可以減少實驗溶液的體積至200 nL。在本研究中，我們利用 BioNDP 平台對cyclophosphamide、doxorubicin和vincristine這三種臨床常用的化療藥物進行組合篩選，並在 SK-N-DZ 神經母細胞瘤細胞株以及來自 TH-MYCN 轉基因小鼠的原代腫瘤細胞中評估其細胞毒性。研究結果顯示，我們篩選出了一種特定的藥物組合，在SK-N-DZ及原代神經母細胞瘤細胞中展現出顯著的協同細胞毒性，能夠有效誘導腫瘤細胞死亡。此外，該藥物組合在 TH-MYCN 轉基因小鼠模型中完全消除了腫瘤並顯著延長了小鼠的存活時間，與單獨使用這些藥物相比，療效顯著增強。再者，該藥物組合的安全性結果顯示，其治療並未引起明顯的血液學毒性，也未對關鍵器官如肝臟、腎臟和脾臟造成損傷。此外，當我們將該組合的劑量轉換為人類等效劑量時，發現其僅需臨床標準劑量的 11%，顯示出較低的毒性風險，進一步支持其潛在的臨床可行性。本研究突顯了 BioNDP 平台在神經母細胞瘤藥物篩選中的潛力。該平台不僅能夠在有限的原代細胞數量條件下，篩選出具協同效應的藥物組合，還能有效銜接體外與體內的研究結果，在 TH-MYCN 轉基因小鼠中展現出強效的抗腫瘤作用，且無明顯副作用，顯示出極高的臨床應用價值。因此，本研究提供了一種創新的策略，有望在未來的個人化神經母細胞瘤治療中發揮關鍵作用，提升治療效果的同時降低毒性風險，為高風險神經母細胞瘤患者帶來新的治療選擇。 | zh_TW |
| dc.description.abstract | Neuroblastoma is a highly aggressive pediatric cancer with poor prognosis, especially in MYCN-amplified high-risk cases. The severe side effects of high-dose chemotherapy further complicate the treatments. Despite advances in drug screening, traditional platforms still require large cell quantities and have low translational success from bench to bed, limiting their use in personalized medicine. To overcome these challenges, we have developed the Bioinspired Nanodroplet Processing (BioNDP) platform, which has been reported to enable screening of multiple drug combinations for prostate cancer with significant reduced cell input of 100 and low assay volumes of 200 nL per well. In this study, we screened combinations of cyclophosphamide, doxorubicin, and vincristine for the cytotoxicity of SK-N-DZ neuroblastoma cells and primary cells from TH-MYCN transgenic mice using BioNDP. Our results identified specific drug combinations that exhibited strong synergistic cytotoxicity in SK-N-DZ and primary neuroblastoma cells. The combination completely eradicated tumors and significantly improved survival in TH-MYCN mice. Furthermore, neither notable hematological nor histological toxicities were observed in mice with combination treatment. Notably, the refined combination required only 11% of the standard clinical dosage when it converted to human equivalent dosage. This study highlights the BioNDP platform’s potential to identify synergistic drug combination by using limited primary cell, bridge in vitro and in vivo findings, and identify an improved combination treatment for TH-MYCN transgenic mice with minimal adverse effects. Our approach offers a promising strategy for personalized neuroblastoma treatment in future, enhancing efficacy while reducing toxicity. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-06-05T16:14:04Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-06-05T16:14:04Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | Table of Contents
口試委員會審定書 i 致謝 ii 中文摘要 iii Abstract iv Table of Contents v List of Figures vii Chapter 1. Introduction 1 1.1. Introduction of Neuroblastoma 1 1.1.1 Development and Characteristics of Neuroblastoma 1 1.1.2 Neuroblastoma Classification 2 1.1.3 Current Treatment of Neuroblastoma 3 1.2 Preclinical In Vivo Models for Anti-Cancer Drug Evaluation 5 1.2.1 Xenograft Models 5 1.2.2 Transgenic Model 8 1.3 TH-MYCN transgenic mice model 9 1.3.1 Development and Characteristics of TH-MYCN mice model 9 1.3.2 Therapeutic Evaluation Using the TH-MYCN Mice Model 10 1.4 Current Drug Screening Strategies for Neuroblastoma 11 1.4.1 Challenges in Conventional Drug Screening Platform 12 1.4.2 Cellular Microarray-Based Drug Screening 15 1.5 Bio-inspired Nanodroplet Cell-Processing Platform 16 Specific Aims 19 Chapter 2. Material & Method 20 2.1 Fabrication of BioNDP chip 20 2.2 Cell Culture 20 2.3 384-well Plate Cell Viability Assay 21 2.4 Drug Combination Screening on the BioNDP Platform 21 2.5 Primary Tumor Cell Isolation 22 2.6 Flow Cytometry 22 2.7 Animal Experiment 23 2.8 Biochemical and Hematological analyses 24 2.9 Histological analysis 24 2.10 In Vivo Dosage Calculation for animal experiments 25 2.11 Statistical Analysis 26 Chapter 3. Results 27 3.1 Optimization of the BioNDP Platform for Neuroblastoma Drug Screening 27 3.2 Single-Drug Dose-Response Evaluation and Platform Validation in SK-N-DZ Neuroblastoma Cells 29 3.3 Identification of Synergistic Drug Combinations in SK-N-DZ Neuroblastoma Cells 30 3.4 Isolation and Characterization of Primary Neuroblastoma Cells From TH-MYCN Mice 31 3.5 Screening and Validation of Drug Combinations in Primary Neuroblastoma Cell 32 3.6 Evaluating the In Vivo Efficacy of a Refined Drug Combination Using TH-MYCN Mice 33 3.7 Assessment of Side Effects in TH-MYCN Mice Treated with the Refined Drug Combination 36 Conclusion 39 Chapter 4. Discussion 40 Figures 46 References 73 Appendix 95 | - |
| dc.language.iso | en | - |
| dc.subject | 化療 | zh_TW |
| dc.subject | 奈米液滴 | zh_TW |
| dc.subject | 協同效應 | zh_TW |
| dc.subject | 基因轉殖小鼠 | zh_TW |
| dc.subject | 藥物篩選 | zh_TW |
| dc.subject | 神經母細胞瘤 | zh_TW |
| dc.subject | Drug screening | en |
| dc.subject | Chemotherapy | en |
| dc.subject | BioNDP | en |
| dc.subject | Neuroblastoma | en |
| dc.subject | Synergy | en |
| dc.subject | TH-MYCN mice | en |
| dc.title | 利用新型奈米液滴平台篩選對於神經母細胞瘤基因轉殖小鼠最佳協同化療藥物組合之研究 | zh_TW |
| dc.title | Synergistic Drug Combination Screening Using a Nanodroplet Processing Platform to Enhance Neuroblastoma Treatment in TH-MYCN Transgenic Mice | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 許文明;郭清德;廖永豐;吳沛翊 | zh_TW |
| dc.contributor.oralexamcommittee | Wen-Ming Hsu;Ching-Te Kuo;Yung-Feng Liao;Pei-Yi Wu | en |
| dc.subject.keyword | 神經母細胞瘤,化療,藥物篩選,基因轉殖小鼠,協同效應,奈米液滴, | zh_TW |
| dc.subject.keyword | Neuroblastoma,BioNDP,Chemotherapy,Drug screening,TH-MYCN mice,Synergy, | en |
| dc.relation.page | 108 | - |
| dc.identifier.doi | 10.6342/NTU202500891 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2025-05-15 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生命科學系 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 生命科學系 | |
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