溫度敏感性產氣式微脂粒載體於藥物傳輸上之應用

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研究生：	陳可潔
論文名稱：	溫度敏感性產氣式微脂粒載體於藥物傳輸上之應用 Development of a Thermo-responsive Bubble-generating Liposomal System and its Application for Drug Delivery
指導教授：	宋信文
口試委員:	王先知胡宇方甘霈林昆儒劉浩澧梁祥發宋信文
學位類別：	博士 Doctor
系所名稱：	工學院 - 化學工程學系 Department of Chemical Engineering
論文出版年：	2013
畢業學年度：	101
語文別：	中文
論文頁數：	67
中文關鍵詞：	微脂體、藥物傳輸、癌症、二氧化碳
相關次數：	點閱：3 下載：0
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本研究以癌症治療為目的，研發一具有藥物控制釋放能力之傳遞系統。實驗設計是將具有產氣能力之碳酸氫銨（NH4HCO3）材料包覆進載體水相核層內，做為一穴蝕（caviation）化核心，藉由碳酸氫銨與碳酸氫鈉分別在高溫（40  50 °C）與酸性環境下具有能及時分解產生二氧化碳之特性。此系統不需經由外加超聲波，即能藉由局部環境變化的觸發，產生瞬間穴蝕效應，達到破壞腫瘤細胞，或輔助調控釋放藥物傳遞之目的。系統中，載體內氣泡的生成，除了可加速藥物的釋放，亦具有增強聲場散射信號的作用，因此，本系統同時也可做為一可應用在至醫學影像上之超聲波對比劑，為一相當具潛力之治療及追蹤癌症疾病的平台技術。

The therapeutic effectiveness of chemotherapy is optimal only when tumor cells have maximum drug exposure. A thermoresponsive liposomal formulation (ThermoDox; Lysolipid liposomes) rapidly releases DOX in regions where local tissue temperatures are elevated to at least 40 °C. Although Lysolipid liposomes have considerable therapeutic potential, roughly 50% of encapsulated DOX is released within 1 h in physiological environments. Lysolipid dissociation from liposomes, which is mediated by plasma proteins, is a highly likely cause of their intravenous instability.
Thus, in study I, a thermoresponsive bubble-generating liposomal system that does not contain lysolipids was evaluated for its ability to trigger localized extracellular drug delivery. The key component in this liposomal formulation is encapsulated ammonium bicarbonate (ABC), which creates the transmembrane gradient needed for highly efficient DOX encapsulation. At an elevated temperature of 42 °C, ABC decomposition generates CO2 bubbles, creating permeable defects in the lipid bilayer that rapidly releases DOX and instantly increases the drug concentration locally. Because the generated CO2 bubbles are hyperechogenic, they also enhance ultrasound imaging results. Consequently, this novel liposomal system encapsulated with ABC may be able to monitor a temperature-controlled drug delivery process.
Study II examined the feasibility of using this thermoresponsive bubble-generating liposomal system (ABC liposomes) for tumor-specific chemotherapy under mild hyperthermia. Incubation of ABC liposomes with rat whole blood resulted in a significantly smaller decrease in the retention of encapsulated DOX than that by Lysolipid liposomes, indicating superior plasma stability. Biodistribution study results demonstrate that the ABC formulation circulated longer than its Lysolipid counterpart. After the ABC liposome suspension was injected into mice with tumors that were heated locally, decomposition of the ABC encapsulated in liposomes facilitated immediate thermal activation for CO2 bubble generation, leading to increased intratumoral DOX accumulation. Consequently, the antitumor efficacy of ABC liposomes was superior to that of their Lysolipid counterparts. These analytical results indicate that this thermoresponsive bubble-generating liposomal system is a promising local drug delivery system activated at hyperthermia temperatures for tumor-specific chemotherapy.
Since nonspecific distribution of therapeutic agents and nontargeted heating frequently cause undesirable side effects during cancer treatment, study III describes a novel liposomal system that can deliver both heat and a therapeutic agent, DOX, simultaneously into targeted tumor cells to exert its cytotoxicity intracellularly. A hybridized Mucin-1 aptamer was conjugated on the surface of test liposomes, which can function as a recognition probe to enhance their cell uptake, as well as a molecular beacon to signal when the internalized particles were maximized. Additionally, gold nanocages encapsulated in liposomes effectively converted near-infrared light irradiation into localized heat to directly damage cancerous cells and thermally trigger a high DOX release to reach the therapeutic threshold instantly. This combined treatment can signiﬁcantly increase the drug potency, making it a promising approach for cancer therapy.

ABSTRACT        I
TABLE OF CONTENT    III
LIST OF FIGURES    VI
LIST OF TABLES    X

Chapter 1    Introduction    1

Chapter 2    A Thermoresponsive Bubble-generating Liposomal System for Triggering Localized Extracellular Drug Delivery    4
2-1 Materials and Methods    6
2-1-1 Materials    6
2-1-2 Liposome preparation    7
2-1-3 Characterization of test liposomes    7
2-1-4 Release of DOX from test liposomes    7
2-1-5 Ultrasound imaging    8
2-1-6 SAXS measurements    8
2-1-7 Internalization of ABC liposomes    8
2-1-8 Intracellular accumulation of DOX    9
2-1-9 Cell viability assay    9
2-1-10 Statistical analysis    10
2-2 Results and Discussion    10
2-2-1 Characteristics of the test liposomes    10
2-2-2 In vitro release profiles    11
2-2-3 The role of ABC in triggering drug release    13
2-2-4 Extracellular release of DOX and its intracellular accumulation    17
2-3 Conclusions    20

Chapter 3    A Thermoresponsive Bubble-generating Liposomal System for Triggering Localized Extracellular Drug Delivery    21
3-1 Materials and Methods    23
3-1-1 Materials    23
3-1-2 Liposome preparation    24
3-1-3 Characterization of test liposomes    24
3-1-4 In vitro release of DOX from test liposomes    24
3-1-5 Animals and tumor cells    25
3-1-6 Ultrasound imaging and fluorescence imaging of tumor tissues    25
3-1-7 SPECT/CT imaging    26
3-1-8 Plasma stability assay    26
3-1-9 Antitumor efficacy study    27
3-1-10 Statistical analysis    27
3-2 Results and Discussion    27
3-2-1 Characteristics of test liposomes    27
3-2-2 In vitro drug release profiles    28
3-2-3 In vivo thermal activation of CO2 bubble generation and DOX release    30
3-2-4 Biodistribution of the test liposomes with and without lysolipids    32
3-2-5 Plasma stability    35
3-2-5 Antitumor efficacy    36
3-3 Conclusions    38

Chapter 4    Targeted Therapy of Locally Delivered Heat and Drug Using a Multifunctional Bubble-generating Liposomal System    39
4-1 Materials and Methods    41
4-1-1 Materials    41
4-1-2 Liposome preparation    41
4-1-3 In vitro drug release study    41
4-1-4 MD simulations    42
4-1-5 Internalization of test liposomes    42
4-1-6 Intracellular trafficking    42
4-1-7 Intracellular accumulation of DOX    43
4-1-8 Cell viability assay    43
4-1-9 Statistical analysis    43
4-2 Results and Discussion    43
4-2-1 Characteristics of the prepared Au NGs and test liposomes    43
4-2-2 In vitro drug release profiles    47
4-2-3 FRET measurements    47
4-2-4 Cellular uptake and intracellular trafficking    50
4-2-5 Intracellular release of DOX and its intracellular accumulation    52
4-3 Conclusions    54

References        55
著作目錄        64

                                

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