CO2響應性藥物傳遞系統，核鹼基功能化超分子載體和羅丹明6G衍生物在強效癌症化療應用中的開發

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研究生：	Enyew Alemayehu Bayle Enyew Alemayehu Bayle
論文名稱：	CO2響應性藥物傳遞系統，核鹼基功能化超分子載體和羅丹明6G衍生物在強效癌症化療應用中的開發 Development of CO2-responsive Drug Delivery Systems with Nucleobase-Functionalized Supramolecular Carriers and Rhodamine 6G Derivatives for Potent Cancer Chemotherapy Applications
指導教授：	鄭智嘉 Chih-Chia Cheng
口試委員:	謝永堂 Yeong-Tarng Shieh 張永 Yung Chang 楊昌謀 Chang-Mou Yang 陳仁坤 Jem-Kun Chen 廖愛和 Ai-Ho Liao 鄭志佳 Chih-Chia Cheng
學位類別：	博士 Doctor
系所名稱：	應用科技學院 - 應用科技研究所 Graduate Institute of Applied Science and Technology
論文出版年：	2024
畢業學年度：	112
語文別：	英文
論文頁數：	180
中文關鍵詞：	抗癌治療、化療、CO2敏感、藥物傳遞系統、疏水性-親水性轉換、高碳酸氣體腫瘤微環境、超分子微胞、選擇性細胞內吸收、罗丹明6G 、選擇性細胞毒性
外文關鍵詞：	Anticancer treatment, Chemotherapy, CO2-responsive, drug delivery system, Hydrophobic-hydrophilic transition, Hypercapnic tumor microenvironment, Supramolecular micelle, Selective cellular internalization, Rhodamine 6G, Selective cytotoxicity
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上一筆

過去幾十年來，科學家們為了對抗對健康構成嚴重威脅的腫瘤，尤其是在開發化療方面，投入了大量努力。儘管如此，傳統化療仍然存在許多問題，如療效有限、藥物釋放不受控以及非特異性和無差別藥物傳遞帶來的多種副作用。為了克服這些障礙，我們可以利用癌症特徵來開發智能生物響應藥物傳遞系統。因此，在第一項研究中，我們設計了一種策略，開發二氧化碳敏感的超分子藥物傳遞系統，以提高癌症治療的效率。
我們設計了一種抗癌劑，由二氧化碳敏感的Imidazole-containing rhodamine 6G (I-R6G) 和功能化帶有尿嘧啶的水溶性聚乙二醇奈米粒子 (U-PEG) 組成。由於U-PEG和I-R6G之間的強親和相互作用，U-PEG被I-R6G有效包裹，並在水中自發組裝成球形奈米顆粒。這些奈米顆粒具有可調節的I-R6G負載量和粒徑、強烈的螢光特性、良好的結構穩定性、在水溶液生理環境中的抗溶血特性、選擇性和快速的二氧化碳響應，以及可控的二氧化碳敏感I-R6G釋放。在靶向癌細胞時，I-R6G包裹的U-PEG奈米製劑展現出顯著的選擇性毒性，而對正常細胞無害。更重要的是，細胞實驗證實，當培養基中含有二氧化碳時，癌細胞對I-R6G包裹奈米顆粒的選擇性內化顯著增加。隨著奈米顆粒崩解，I-R6G與二氧化碳的相互作用加速，最終促進了癌細胞的凋亡。因此，將二氧化碳敏感的抗癌劑I-R6G納入這種自組裝奈米載體系統，成為提高化療效率並減少副作用的重要策略，為改進化療提供了有前途的途徑。
因此，在第二項研究中，我們開發了二氧化碳響應螢光材料，這些材料有望成為有效的抗癌劑和生物成像熒光探針。我們成功合成了一種由帶有pH敏感螺環單元的R6G和自互補多重氫鍵腺嘌呤基團 (AR) 組成的二氧化碳敏感螢光材料。AR在微酸性水溶液中具有顯著的低水溶性，但在典型的有機溶劑中容易溶解。腺嘌呤基團的獨特極性雜環結構賦予其化學反應性，使其能夠對二氧化碳產生反應。因此，疏水性的AR在引入二氧化碳後能迅速完全溶解於水中，形成自組裝的球形奈米粒子。這些納米粒子在水中展示出獨特的自發螢光特性。此外，它們的光物理特性、表面電荷、酸鹼行為和自組裝結構可以通過二氧化碳和氮氣交替鼓泡進行精確和穩定的調控。這種能力使得AR的物理性質可以精確操控。令人感興趣的是，體外細胞實驗顯示，二氧化碳誘導的腺嘌呤基團質子化顯著增強了AR的抗溶血特性，導致在低劑量下對癌細胞具有高度選擇性和強效的細胞毒性，而對正常細胞無影響。相反，原本的AR在正常或癌細胞中並不顯示出選擇性毒性。因此，這種新型二氧化碳敏感系統在提高抗腫瘤藥物的安全性和有效性方面具有重要潛力。
在第三項研究中，我們進一步拓展了新型二氧化碳敏感羅丹明基材料和含有胞嘧啶基團的奈米載體，以通過抗癌劑和奈米載體之間的自互補氫鍵相互作用來提高藥物負載含量，從而提高癌症化療的安全性和效率。我們成功開發了一種二氧化碳敏感的強效抗癌劑（Cy-R6G）和超分子奈米載體（Cy-PEG。Cy-PEG具有有效包裹Cy-R6G的能力，並且由於Cy-R6G和Cy-PEG的胞嘧啶組分之間的自互補氫鍵相互作用，在水性環境中自發形成球形奈米粒子。
Cy-R6G負載的Cy-PEG奈米製劑展示了許多獨特的物理特性，包括可調節的粒子大小、獨特的光吸收和螢光特性、在含血清的生理環境中出色的Cy-R6G負載穩定性、對SRBCs的強抗溶血特性、高靈敏度和選擇性的二氧化碳響應，以及通過二氧化碳/pH敏感實現優秀的釋放Cy-R6G的能力。
細胞毒性評估顯示，Cy-R6G負載的Cy-PEG奈米製劑對HeLa癌細胞表現出選擇性的細胞毒性，而對健康細胞沒有顯著的細胞毒性影響。此外，相較於原Cy-R6G和普通培養基中的Cy-R6G負載Cy-PEG，這些奈米製劑在二氧化碳豐富的培養基中顯示出更高水平的細胞毒性。更有趣的是，細胞內吸收（共聚焦顯微鏡）和細胞毒性機制（流式細胞儀）檢測結果清楚地表明，在培養基中引入二氧化碳顯著提高了Cy-R6G負載的Cy-PEG奈米製劑選擇性吸收進入癌性HeLa細胞的速率，通過微胞吞作用，促進了包裹的Cy-R6G在細胞內的釋放，並導致癌細胞的強效凋亡誘導，與普通培養基中的Cy-R6G負載Cy-PEG奈米製劑相比，效果更加顯著。
因此，這種創新系統不僅對於二氧化碳敏感抗癌載體系統的發展具有重要貢獻，而且在提高癌症治療的有效性和安全性方面具有巨大潛力。

A great deal of effort has been made over the last few decades to combat tumors that pose severe health risks. A persistent effort has been made to develop effective treatments for cancer, particularly chemotherapy. Despite this, traditional chemotherapy is still hindered by weak points, such as limited therapeutic efficacy and uncontrolled release of drugs, as well as numerous side effects brought by the non-specific and indistinguishable delivery of drugs. To overcome these barriers, smart bio-responsive drug delivery systems can be developed by using cancer features. Thus, in the first study, we have developed a strategy to design CO2-sensitive supramolecular drug distribution systems for efficient cancer treatment.
An anticancer agent comprising a CO2-sensitive imidazole-containing rhodamine 6G (I-R6G) and water-soluble poly(ethylene glycol) nanoparticles functionalized with uracil (U-PEG) was designed. As a result of the strong affinity interaction between U-PEG and I-R6G, I-R6G was effectively encapsulated by U-PEG and co-assembled spontaneously into spherical nanoobjects in water. These nanoparticles have tailorable I-R6G-loading and size of particles, as well as intense fluorescence characteristics, good structural durability, antihemolytic activity in aqueous physiological settings, selective and rapid CO2 response, and well-monitored CO2-sensitive I-R6G release. I-R6G-encapsulated U-PEG nanoformulations demonstrated remarkably selective cytotoxicity in targeting cancer cells while leaving normal cells unharmed. Importantly, cellular assays verified that including CO2 in the culture media significantly enhanced cancer cells' selective internalization of I-R6G-encapsulated nanoparticles. Consequently, there was an intensified intracellular I-R6G release as the nanoparticles disassembled, facilitating its interaction with CO2. This process ultimately expedited the induction of apoptotic cell death in cancer cells. Hence, the incorporation of a CO2-sensitive anticancer agent I-R6G into this self-organized nanocarrier system emerges as a crucial element, offering a promising avenue to improve the efficiency of chemotherapy while mitigating its adverse effects. This inspired us to further develop a CO2-sensitive rhodamine-based potent anticancer agent using a CO2-responsive component.
Therefore, in the second study, we have created CO2-responsive fluorescent materials that hold promise as effective anticancer agents and as bioimaging fluorescent probes. A CO2-sensitive fluorescent material comprised of rhodamine 6G with a pH-sensitive spiro cyclic unit and a self-complementary multiple hydrogen-bonded adenine group (AR) was synthesized successfully in just two simple steps. AR exhibited remarkably low water solubility, even in a mildly acidic aqueous environment, yet it readily dissolved in typical organic solvents. The distinctive polar heteroaromatic structure of the adenine group grants chemical reactivity, enabling it to respond to CO2. Consequently, the hydrophobic AR can swiftly and fully soluble in water upon simple CO2 introduction, forming self-organized spherical-like nanoobjects. The resulting nanoobjects exhibited distinctive spontaneous fluorescent properties in water. Furthermore, their photophysical attributes, surface charge, acid-base behavior, and self-assembled structure can be readily and consistently modulated (on and off) through alternative cycles of CO2 and N2 bubbling. This capability enables precise manipulation of AR’s physical property. Interestingly, in vitro cell assays revealed that the adenine group’s protonation by CO2 significantly augments the anti-hemolytic properties of AR. This enhancement leads to highly selective and potent cytotoxic effects against cancer cells at low doses while leaving normal cells unaffected. In contrast, pristine AR didn’t display a selective cytotoxic effect on normal or cancer cells. Hence, this newly innovated CO2-sensitive system holds significant promise in improving the safety and efficacy of antitumor drugs.
In our third study, we have extended the advancement of novel CO2-sensitive rhodamine-based material and a nanocarrier with cytosine moieties in order to have substantial drug-loading content enhanced by the self-complementary interactions of hydrogen bonding between the anticancer agent and the nanocarrier to improve the safety and efficiency of cancer chemotherapy. Thus, a CO2-responsive potent anticancer agent (Cy-R6G) and supramolecular nanocarrier (Cy-PEG) were successfully developed. Cy-PEG exhibited the capacity to efficiently encapsulate Cy-R6G with tunable and substantial loading contents leading to the spontaneous formation of spherical nanoparticles in aqueous environments due to the self-complementary hydrogen bonding interactions between the cytosine components of Cy-R6G and Cy-PEG. The Cy-R6G-loaded Cy-PEG nanoformulations exhibited numerous unique physical properties, including a tunable size of particles, distinctive optical absorption, fluorescence features, and excellent Cy-R6G-loading stability in biological media with serum under physiological settings, robust anti-hemolytic activity against SRBCs, higher sensitivity and selectivity of CO2-response in water, and excellent on-demand release of Cy-R6G facilitated by the CO2/pH-sensitive disruption. Cytotoxicity evaluations indicated that Cy-R6G-loaded Cy-PEG nanoformulations exhibited selective cytotoxicity of cancerous HeLa cells without significant cytotoxic impacts on healthy cells. Additionally, it exhibited higher levels of cytotoxicity at lower doses in CO2-rich culture media relative to pristine Cy-R6G and Cy-R6G-loaded Cy-PEG in regular culture media. More interestingly, examinations of intracellular uptake (confocal microscopy) and mechanisms of cytotoxicity (flow cytometry) provided clear evidence that the inclusion of CO2 in the culture medium notably enhanced the selective absorption rate of Cy-R6G-loaded Cy-PEG nanoformulations into cancerous HeLa cells through micropinocytosis. This in turn facilitated the encapsulated Cy-R6G intracellular release and resulted in robust induction of death of cancer cells apoptotically relative to cells planted with Cy-R6G-loaded Cy-PEG nanoformulations in normal media. Consequently, this innovative system not only offers valuable contributions to the advancement of CO2-sensitive anticancer vehicle systems but also holds considerable potential for enhancing the effectiveness and safety of cancer treatment.

Declaration	i
Acknowledgments	ii
Dedication	iii
摘要	iv
Abstract	vi
List of Figures	xv
List of Tables	xix
List of Schemes	xix
List of Appendix Figures	xx
List of Abbreviations	xx
CHAPTER ONE	1
Introduction	1
1. Background	1
2. Motivation	5
3. Objectives of the Study	7
3.1. General Objectives	7
3.2. Specific Objectives	7
4. Dissertation Organization	7
CHAPTER TWO	9
Review of Literature	9
1. Cancer	9
2. Nanomedicine	12
3. Polymeric Micelles	13
3.1. Formation of PMs	13
3.2. Structure of PMs	14
3.3. Properties and Characterizations of PMs	15
3.3.1. Critical Micelle Concentration	15
3.3.2. Determination of Shape, Size, and PDI (Polydispersity Index)	16
3.4. Stability of PMs	17
3.5. Applications of PMs in Drug Delivery	18
3.6. Passive Targeting of PMs	18
3.7. Active Targeting of PMs	20
3.8. Stimuli-responsive PMs	20
3.8.1. pH-responsive PMs	21
4. CO2-responsive Materials	21
4.1. CO2-responsive Functional Moieties	22
5. Supramolecular Nucleobase Functionalized Nanomaterials	24
6. Rhodamine 6G and Its Derivatives	26
6.1. Anticancer Activity of Rhodamine Dyes	27
6.2 Isomeric Forms of R6G Derivatives	28
CHAPTER THREE	29
Materials and Methods	29
1. Chemicals and Materials	29
2. Synthesis of I-R6G	29
3 Synthesis of U-PEG	30
4. Synthesis of Primary Monoamine Adenine Derivate (Adenine-amine)	30
5. Synthesis of Adenine-functionalized R6G (AR)	30
6. Synthesis of Cytosine-methyl Acrylate (Cy-MA)	30
7. Synthesis of Cytosine-propyl Amine (Cy-amine)	31
8. Synthesis of Cytosine-R6G (Cy-R6G)	31
9. Synthesis of Cy-PEG	31
10. Determination of Critical Micelle Concentration (CMC)	32
11. Preparation of I-R6G-, Cy-R6G- and R6G-loaded Polymeric Nanoparticles	32
12. Preparation of Aqueous Solutions of Samples Treated with CO2/N2	33
13. Preparation of CO2-Treated DMEM	33
14. Characterizations	33
14.1. Fourier Transform Infrared (FTIR) and Nuclear Magnetic Resonance (1H-/13C-NMR) Spectra	33
14.2. Mass Spectrometry	33
14.4. Size Exclusion Chromatography (SEC)	34
14.5. Thermogravimetric Analysis (TGA)	34
14.6. Photoluminescence (PL) and Ultraviolet-Visible (UV-Vis) Spectroscopies	34
14.7. Dynamic Light Scattering (DLS) and Zeta Potentials	34
14.8. Kinetic Stability of Polymeric Micelles	35
14.9. Atomic Force (AFM) and Scanning Electron (SEM) Microscopies	35
15. In Vitro Drug Release Evaluations	35
16. Cell Lines and Culture Conditions	36
17. Hemolysis Assays	36
18. Cytotoxicity Assays	36
19. Cellular Internalization Studies	37
20. Assessment of Cellular Uptake of Polymeric Nanoparticles by Flow Cytometry	37
21. Assessment of Apoptotic and Necrotic Cell Death	38
22. Statistical Analysis	38
CHAPTER FOUR	39
Development of CO2-responsive Supramolecular Drug Carrier System for Potential Application in Anticancer Treatment	39
1 Introduction	39
2. Results and Discussion	43
2.1. Synthesis of the Supramolecular Nanocarrier	43
2.2. Synthesis of I-R6G	45
2.3. Size and Morphologies of I-R6G-encapsulated and Pristine U-PEG Micelles	46
2.4. CO2-response of I-R6G-encapsulated U-PEG Nanogels	50
2.5. Kinetic Stability and In Vitro I-R6G Release Property of the Micelle	53
2.6. In Vitro Cytotoxicity and Cellular Uptake Studies	56
2.7. Cell Death Mechanism Study	62
3. Summary	65
CHAPTER FIVE	66
CO2-Responsive Adenine Nucleobase: New Insight into Manipulating the Photophysical Properties and Biological Activities of Functional Fluorescent Molecules	66
1. Introduction	66
2. Results and Discussion	68
2.1. Synthesis and Characterizations of Adenine-amine	69
2.2. Synthesis and Characterizations of AR	70
2.3. Solubility and pH-responsive Behavior of AR	72
2.4. CO2-Responsiveness of AR	75
2.5. Effect of CO2 Bubbling on Morphological Changes of AR	78
2.6. Reversible Optophysical Properties of AR upon Alternative CO2/N2-treatment	79
2.7. Effect of Temperature on Optophysical Properties of CO2-treated AR	81
2.8. Hemolysis Study	82
2.9. In Vitro Cytotoxicity Study	83
3. Summary	85
CHAPTER SIX	86
A CO2-Responsive Nano-Carrier System Developed Via Self-Complementary Interactions Between Cytosine-Functionalized Chemotherapeutic Agent and Carrier for Selective Cancer Treatment	86
1. Introduction	86
2. Result and Discussion	90
2.1. Synthesis and Characterization of Cy-MA	91
2.2. Synthesis and Characterization of Cy-amine	92
2.3. Synthesis and Characterization of Cytosine-R6G (Cy-R6G)	94
2.4. Solubility of Cy-R6G in Organic Solvents	96
2.5. pH-responsiveness of Cy-R6G	97
2.6. CO2-responsive Properties of Cy-R6G and Morphological Changes	99
2.7. Reversible Optophysical Properties of Cy-R6G on Alternative CO2-/N2-treatment	103
2.8. Temperature Effect on the Optophysical Properties of CO2-treated Cy-R6G	105
2.9. Synthesis and Characterizations of Cy-PEG	107
2.10. Cy-R6G Encapsulation and Morphology of Cy-R6G-loaded Cy-PEG	111
2.11. CO2-response of Cy-R6G-loaded Cy-PEG Nanoparticles	113
2.12. Kinetic Stability, Cy-R6G Release, and Disassembly of Cy-R6G-loaded Cy-PEG	114
2.13. Hemolysis Assays	117
2.14. Cytotoxicity and Cell Viability Study	118
2.15. Cellular Uptake Evaluations	119
2.16. Cell Death Mechanism	122
3. Summary	125
CHAPTER SEVEN	127
Conclusions and Future Outlooks	127
1. Conclusions	127
2. Future Outlooks	130
References	131
Appendix  A	152
Appendix  B	155
Appendix  C	156
                                

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全文公開日期 2029/08/05 (校內網路)
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