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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林文澧(Win-Li Lin) | |
| dc.contributor.author | Chi-Feng Chiang | en |
| dc.contributor.author | 江季峰 | zh_TW |
| dc.date.accessioned | 2021-05-11T05:00:21Z | - |
| dc.date.available | 2019-12-03 | |
| dc.date.available | 2021-05-11T05:00:21Z | - |
| dc.date.copyright | 2019-12-03 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-11-11 | |
| dc.identifier.citation | [1] D. Hanahan, R.A. Weinberg, The hallmarks of cancer, Cell 100 (2000) 57–70.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/handle/123456789/739 | - |
| dc.description.abstract | 熱治療結合化療藥物為一有效之腫瘤治療策略，能強化奈米藥物穿透進入腫瘤組織並強化其療效。本研究分為兩部分，第一部分探討脈衝式超音波熱治療是否可增強 PEGylated liposomal doxorubicin (PLD) 對於轉移乳癌模式之療效。本實驗使用小鼠乳癌細胞4T1 種植於 BALB/c 小鼠腦部，以活體影像系統追蹤腫瘤成長。腫瘤植入後六天，投予 PLD 並於腫瘤區域施打脈衝式超音波熱治療。實驗結果顯示脈衝式超音波熱治療可增加 PLD 於腫瘤區域之累積。此外，化療藥物 PLD 加上脈衝式超音波熱治療能有效抑制腫瘤之生長，而免疫染色及細胞凋亡測試亦佐證其效用。此研究證實應用脈衝式超音波熱治療能促進化療藥物有效進入腦腫瘤組織並達到治療之效果。
第二部分則結合脈衝式超音波熱治療與自噬抑制劑 chloroquine (CQ) 以進一步強化奈米藥物之療效並抑制腫瘤之復發。自噬作用在腫瘤細胞經常扮演重要的存活機制，因此抑制自噬作用是一可能之腫瘤輔助治療策略。本實驗使用小鼠乳癌細胞 4T1 種植於 BALB/c 小鼠皮下，於腫瘤植入後第五天投予 PLD 與 CQ，並於腫瘤局部施打脈衝式超音波熱治療，之後觀察腫瘤的生長變化並追蹤其復發。實驗結果證實 CQ 能更加強化脈衝式超音波與奈米藥物對腫瘤的抑制效果，並且能延緩腫瘤復發的時間。免疫染色與西方點墨法也證實了 CQ 對腫瘤細胞能有效抑制自噬作用。此研究證實結合脈衝式超音波熱治療與 CQ 能更加強化奈米藥物之抗腫瘤效果，並能長期抑制腫瘤復發。 | zh_TW |
| dc.description.abstract | Chemotherapeutic agents and hyperthermia are known to have synergistic effect in cancer treatment. Focused ultrasound sonication enhances the delivery of nanodrug into tumor and strengthens the efficacy of thermo-chemotherapy.
In the first part of our study, we investigated the enhancing effect of pulsed-wave ultrasound hyperthermia (pUH) on the delivery and therapeutic efficacy of PEGylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer cells 4T1 were implanted into mouse striatum as a metastatic brain tumor model, and the tumor growth was monitored with in vivo imaging system (IVIS). The mice were intravenously injected with PLD followed by transcranial pUH or continuous ultrasound hyperthermia (cUH) treatment on day-6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain and tumor tissues were measured with fluorometry. The tumor growth responses for the control, pUH, PLD, PLD+cUH, and PLD+pUH groups were evaluated with IVIS. The PLD distribution and cell apoptosis were assessed with immunofluorescence staining. The results showed that pUH significantly enhanced the PLD delivery into brain tumors and the tumor growth was further inhibited by PLD+pUH without damaging the sonicated normal brain tissues. This indicates that low-dose transcranial pUH is a promising method to selectively enhance nanodrug delivery and improve the brain tumor treatment. In the second part of our study, we combined pUH and an autophagy inhibitor chloroquine (CQ) to further strengthen the antitumor efficacy of PLD and postponed the recurrence of tumor. Autophagy often serves as an important surviving mechanism for cancer cells, therefore inhibiting autophagy has been considered as an adjuvant anti-cancer strategy. In this study, BALB/c mice implanted with subcutaneous 4T1 tumor were used as an animal tumor model. On Day 5 after tumor implantation, tumor-bearing mice received intravenous injection of PLD (10 mg/kg) plus 15-minute on-tumor pUH and were then fed with CQ (50 mg/kg daily) thereafter. It was shown that prolonged suppression of tumor growth was attained with PLD+pUH+CQ treatment, whereas in PLD+pUH group tumors quickly recurred after an initial inhibition. Immunohistochemical staining and Western blotting showed that autophagy of cancer cells was blocked for the mice receiving CQ. This study proves that PLD+pUH+CQ is a promising strategy to treat cancer for a sustained inhibition. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-11T05:00:21Z (GMT). No. of bitstreams: 1 ntu-108-F99548050-1.pdf: 2913086 bytes, checksum: 65cd460f06465f1392c430df3846362a (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 口試委員審定書 i
致謝 ii 中文摘要 iii Abstract iv Contents vi List of Figures x List of Tables xv Chapter 1. Background & Objectives 1 1.1 Difficulties in cancer treatment 1 1.2 Cancer nanomedicine 2 1.2.1 Preferential accumulation due to EPR effect 2 1.2.2 Prolonged circulation time of PEGylated liposomes 3 1.2.3 Synergy between hyperthermia and of nanomedicine 4 1.3 Ultrasound Hyperthermia 4 1.3.1 Thermal effect of ultrasound 5 1.3.2 Ultrasound hyperthermia-enhanced drug delivery 6 1.3.3 Non-thermal effects of ultrasound 6 1.4 Autophagy inhibition in cancer treatment 7 1.5 Objectives 8 1.6 Thesis outline 8 Chapter 2. Pulsed-wave Ultrasound Hyperthermia Selectively Facilitates the Delivery of PEGylated Liposomal Doxorubicin and Improves the Antitumor Efficacy against Brain Metastasis of Breast Cancer 10 2.1 Introduction 10 2.2 Materials and Methods 12 2.2.1 PEGylated liposomal doxorubicin (PLD) 12 2.2.2 In vitro investigation of PLD accumulation in cancer cells enhanced by ultrasound 13 2.2.3 Preparation of tumor cells and the brain tumor model 14 2.2.4 Focused ultrasound (FUS) system and pulsed-waved FUS hyperthermia 14 2.2.5 Experimental grouping 15 2.2.6 Quantification of PLD entering the normal brain and tumor tissues 15 2.2.7 Measurement of tumor growth by in vivo imaging system (IVIS) and mouse survival 16 2.2.8 Immunofluorescence and PLD distribution 16 2.2.9 TUNEL assay 17 2.2.10 Statistical analysis 17 2.3 Results 18 2.3.1 Pulsed-wave ultrasound better enhances PLD delivery into tumor cells 18 2.3.2 Low-dose pulsed-wave ultrasound hyperthermia enhances the antitumor action in brain tumors 18 2.3.3 PLD delivery to normal brain and tumor tissues by low-dose pulsed-wave/continuous-wave ultrasound hyperthermia 19 2.3.4 Immunofluorescence detection of PLD deposition 20 2.3.5 TUNEL staining for apoptotic cancer cells in the tumors 20 2.4 Discussion 21 2.5 Conclusions 24 Chapter 3. Pulsed-wave Ultrasound Hyperthermia Enhanced Nanodrug Delivery Combined with Chloroquine Exerts Effective Antitumor Response and Postpones Recurrence 35 3.1 Introduction 35 3.2 Materials and Methods 37 3.2.1 Chemical Reagents 37 3.2.2 Tumor cells 37 3.2.3 In vitro fluorescence assay of PLD internalization by 4T1 cells with or without CQ 37 3.2.4 MTT Cytotoxicity Assay 38 3.2.5 In vivo tumor model 39 3.2.6 Animal treatment experiment 39 3.2.7 Histopathological Examination and Immunohistochemical Study 40 3.2.8 TUNEL Assay 41 3.2.9 Western Blotting 42 3.2.10 Statistical analysis 42 3.3 Results 43 3.3.1 In vitro fluorescence assay of PLD internalization by 4T1 cells with or without CQ 43 3.3.2 MTT Cytotoxicity Assay 43 3.3.3 Combination treatment of PLD+pUH and CQ inhibited cancer tumor growth and delayed its recurrence 43 3.3.4 Immunohistochemical study proved autophagy of tumor cells blockaded by CQ administration 44 3.3.5 TUNEL assay showed apoptosis increased by PLD+pUH, not by CQ 45 3.3.6 Western Blotting 45 3.4 Discussion 46 3.5 Conclusions 50 Chapter 4. Summary and Future Work 63 References 65 | |
| dc.language.iso | en | |
| dc.subject | 腫瘤 | zh_TW |
| dc.subject | 脈衝式超音波熱治療 | zh_TW |
| dc.subject | 奈米藥物 | zh_TW |
| dc.subject | doxorubicin | zh_TW |
| dc.subject | 氯? | zh_TW |
| dc.subject | 自噬抑制 | zh_TW |
| dc.subject | 癌症 | zh_TW |
| dc.subject | pulsed-wave ultrasound hyperthermia | en |
| dc.subject | tumor | en |
| dc.subject | cancer | en |
| dc.subject | autophagy inhibition | en |
| dc.subject | chloroquine | en |
| dc.subject | doxorubicin | en |
| dc.subject | nanodrug | en |
| dc.title | 應用脈衝式超音波熱治療與氯喹強化癌症奈米藥物治療 | zh_TW |
| dc.title | Enhancing Cancer Tumor Treatment of Nanomedicine with Pulsed-wave Ultrasound Hyperthermia and Chloroquine | en |
| dc.date.schoolyear | 108-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 季匡華(Kwan-Hwa Chi),繆希椿(Shi-Chuen Miaw),張富雄(Fu-Hsiung Chang),駱俊良(Chun-Liang Lo),陳景欣(Gin-Shin Chen) | |
| dc.subject.keyword | 脈衝式超音波熱治療,奈米藥物,doxorubicin,氯?,自噬抑制,癌症,腫瘤, | zh_TW |
| dc.subject.keyword | pulsed-wave ultrasound hyperthermia,nanodrug,doxorubicin,chloroquine,autophagy inhibition,cancer,tumor, | en |
| dc.relation.page | 77 | |
| dc.identifier.doi | 10.6342/NTU201904281 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2019-11-12 | |
| dc.contributor.author-college | 工學院 | zh_TW |
| dc.contributor.author-dept | 醫學工程學研究所 | zh_TW |
| 顯示於系所單位： | 醫學工程學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-108-1.pdf | 2.84 MB | Adobe PDF | 檢視/開啟 |
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