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研究生： Tilahun Ayane Debele
Tilahun - Ayane Debele
論文名稱： POLYSACCHARIDE BASED NANOCARRIERS FOR ANTICANCER DRUG AND PHOTOSENSITIZER DELIVERY TO ENHANCE CHEMOTHERAPEUTIC EFFICIENCY AND PHOTODYNAMIC THERAPY OF CANCERS
POLYSACCHARIDE BASED NANOCARRIERS FOR ANTICANCER DRUG AND PHOTOSENSITIZER DELIVERY TO ENHANCE CHEMOTHERAPEUTIC EFFICIENCY AND PHOTODYNAMIC THERAPY OF CANCERS
指導教授： 蔡協致
Hsieh-Chih Tsai
口試委員: 王丞浩
Chen-Hao Wang
何郡軒
Jinn-Hsuan Ho
駱俊良
Chun-Liang Lo
朱一民
I-Ming Chu
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： 2017
畢業學年度： 105
語文別： 英文
論文頁數： 204
中文關鍵詞： 光動力治療 、β-谷固醇 、聚乙烯亞胺 、肝素 、微胞 、奈米凝膠 、酞 、菁鋅 、小紅莓 、腦磷脂質
外文關鍵詞： Nanogels, β-Sitosterol, Cephalin, Zinc phthalocyanine
相關次數： 點閱：860  下載：0 
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    • 癌症是DNA序列改變導致細胞異常增生，影響正常生理機能，而主要治療方式有手術、化療和放射線治療。現今非侵入式光動力治療(PDT)被受矚目，將光敏感物質標於癌細胞位置再以特定波長的光照射，產生光化反應形成自由基(ROS)毒殺細胞。然而傳統化療和光敏感物質的溶解性不佳、缺乏選擇性和多重抗藥性至今仍然是所面臨的問題。本論文合成高分子多醣基(polysaccharide)衍生物作為載體包覆抗癌藥物(Dox)用於增強藥物傳遞效率，且同時為光敏感物質包覆酞菁鋅(ZnPc)用於光動力治療。多醣基納米顆粒具生物相容性和生物可降解性，應用於多方面藥物傳遞系統中。
    第一部分為HPC奈米凝膠由肝素(heparin)、聚乙烯亞胺(PEI)和半胱氨酸(L-cys)合成，再由傅立葉紅外線光譜儀(FT-IR)、氫譜核磁共振(1H-NMR)鑑定，藉由穿透式電子顯微鏡(TEM)和動態光散射儀(DLS)得知粒徑大小為<200nm。再以透析法將抗癌藥物酞菁鋅(ZnPc)包覆於HPC膠中，藉由氧化還原應答將藥物釋放，且從單態氧檢測中得知酞菁鋅能夠均勻包覆於奈米凝膠，以增強光動力治療效果。結果證實雙硫鍵膠聯奈米凝膠HPC載體能夠藉由光動力治療傳遞藥物治療。
    上述研究HPC奈米凝膠中，聚乙烯亞胺(PEI)毒性仍然太高，因此第二部分藉由磷脂(phospholipids)和肝素(heparin)修飾PEI，以增加藥物包覆並且將毒性降到最小。由肝素(heparin)、L-磷脂酰乙醇胺和組胺酸(L-his)藉由EDC/NHS合成具有酸鹼應答的微胞HDH。以傅立葉紅外線光譜儀(FT-IR)、氫譜核磁共振(1H-NMR)鑑定，藉由動態光散射儀(DLS)得知粒徑大小為111.57 ± 12.36 nm和電位-59.8 ± 5.2 mV。而微胞藥物含量高達14.52 ± 1.2%、藥物包覆率為65.47 ± 1.87%。第96小時在不同pH 條件下的體外釋放效率，顯示微胞在酸性環境(pH 5) 釋放酞菁鋅高達91%相較於中性環境(pH 7.4)63%佳。觀察微胞和子宮頸癌細胞(Hela cell)的生物特性，由螢光顯微鏡得知細胞吞噬影像，此外ZnPc-HDH細胞毒性高於ZnPc。
    雖然上述方法(手術、化療和放射線治療)能夠制治療癌症，但仍然有其它方式可抑制癌細胞擴散。第三部分、設計Heparin-β-Sitosterol氧化還原應答微胞做為載體，並且包覆抗癌藥物小紅莓(Dox)研究體外癌細胞轉移性。光譜儀(FT-IR)、氫譜核磁共振(1H-NMR)和掃描式電子顯微鏡(FE-SEM)鑑定bHSC共聚物，藉由動態光散射儀(DLS)得知粒徑大小為145.07 ± 2.97 nm和電位-56.1 ± 2.16 mV mV，此外細胞毒性由MTT和流式細胞儀分析。由透析法包覆抗癌藥物，藥物含量為16.49 ± 1.2%和藥物包覆率58.47 ± 1.87%。體外48小時藥物釋放為比較氧化還原應答能力，含有 GSH (5 mM)藥物釋放量89%高於沒有GSH藥物釋放52%。螢光顯微鏡下觀察HeLa細胞內吞作用，明顯有紅色螢光訊號分佈於細胞核中，證實包覆藥物的載體成功被細胞吞噬，並且小紅莓從載體中釋放。此外，刮痕試驗(scratch assay)和溶血(hemolysis assays)測定細胞轉移性和血溶性測試，螢光顯微鏡中F-肌動蛋白(F-actin)訊號結果證實肝素(heparin)和bhsc能夠成功抑制癌細胞轉移。上述現象可知bHSC微包具有毒性低、血容性高和抗轉移性特性，適合做為藥物釋放標的載體和同時可抑制癌細胞轉移。

    Cancer is a multi-gene, multi-step devastating disease with an altered DNA sequence (mutation) which grow uncontrollable by disregarding the normal rule of cell division. The current available treatment methods of cancers are primarily centered on Surgery, Irradiation and the Systemic administration of Chemotherapeutics agents. Recently, photodynamic therapy (PDT) is also an alternative, non-invasive combinatorial therapeutic modality using light, photosensitizer (PS), and oxygen for the treatment of cancer and other diseases. However, those conventional chemotherapy and photosensitizers (PSs) used nowadays have certain limitations (a) Low (non) water solubility, (b) Lack of selectivity and (c) Multidrug resistance (MDR). Hence, a technology platform that can effectively increase PSs and chemotherapeutic agent’s solubility and confer targeting potential is highly sought after. Nano-formulating of chemotherapeutic agents and PSs with polymeric nanoparticles poses as potential strategy to satisfy the requirements of an ideal chemotherapy and PDT system. In this dissertation, polysaccharide based nanocarrier were synthesized and characterized to deliver anticancer drugs (Doxorubicin) and PSs (Zinc phthalocyanine) that have been used to enhance the chemotherapeutic efficacy and photodynamic therapy against cancers. Polysaccharide-based nanocarriers have a great interest as a vesicle of several anti-cancer drugs and PSs due to their unique multi-functional groups in addition to their physicochemical properties, including biodegradability, water solubility and biocompatibility. The presence of multi-functional groups on the polysaccharide backbone allows facile biochemical or chemical modification to synthesize polysaccharide based nanocarriers with miscellaneous structures. Hence, in this abstract several heparin derivitized based nanoparticle (i.e. nanogels and micelles) as the carrier of PS and anticancer drug were summarized session by session to clearly investigate its role in enhancing PDT activity and chemotherapeutic efficiency.
    In the first work, bioreducible heparin polyethyleneimine (HPC) nanogel composed of heparin, branched polyethyleneimine (PEI) and L-cysteine was synthesized and characterized. 1H-NMR and FTIR analysis confirmed the formation of HPC nanogels while TEM and dynamic light scattering revealed uniform spherical nanoparticles with average diameter of <200 nm. Zinc phthalocyanine (ZnPc) was encapsulated via the dialysis method and the drug is released in vitro from disulfide-containing HPC nanogels in a redox-sensitive manner. Additionally, HPC nanogels possess bright blue fluorescence which eliminates the use of additional probing agent in image-guided drug delivery. Moreover, singlet oxygen detection revealed that nanogels prevented ZnPc aggregation thus enhancing 1O2 generation and photodynamic therapy (PDT) efficacy. These results showed that disulfide crosslinked HPC nanogels are promising vehicles for stimulated photosensitizer delivery in advanced PDT.
    Even though, the cytotoxicity of PEI are highly improved, the synthesized HPC nanogels has minimum amount of drug loading capacity (~ 42%). Therefore, to enhance drug loading capacity and to minimize cytotoxicity we were designed our second works based on biocompatible heparin and phospholipids. In the second work, we describe the synthesis of a stable, pH-sensitive micelle from heparin, 1, 2-distearoyl-sn-glycerol-3-phosphoethanolamine, and L-histidine (HDH) through EDC/NHS chemistry. 1H-NMR and FTIR analysis confirmed the formation of HDH copolymers and DLS measurements indicated a particle size of 111.57 ± 12.36 nm and zeta potential of -59.8 ± 5.2 mV for the nanoparticles. The drug-loading and encapsulation efficiency of the micelles were 14.52 ± 1.2% and 65.47 ± 1.87%, respectively. Drug release studies showed approximately 91% zinc phthalocyanine (ZnPc) release from micelles in acidic conditions (pH 5.0) in comparison with 63% release physiological conditions (pH 7.4) after 96 h of incubation. Singlet oxygen detection revealed that the micelles prevented ZnPc aggregation and enhanced 1O2 generation. Cellular uptake of ZnPc-loaded micelles (ZnPc-HDH) was observed using confocal microscopy. Phototoxicity experiments in HeLa cells showed that ZnPc-loaded micelles had higher toxicity than the same concentration of free ZnPc had. Hence, pH-sensitive HDH micelles are a promising carrier for hydrophobic ZnPc and improvement of PDT efficacy.
    Although there are several clinical attempts to treat tumors (including surgery, radiotherapy, chemotherapy and combined therapy) at the primary site there are still a little available therapy to inhibit the spread of metastatic cancer. In the third work, a redox sensitive Heparin-β-Sitosterol micelle was synthesized as the carrier of pharmaceutical agents (Dox) and also antimetastasis activities of the micelles was investigated in vitro using scratch assay. 1H-NMR and FTIR analysis confirmed the formation of bHSC copolymers while DLS used to measure particle size (145.07 ± 2.97 nm) and zeta potentials (-56.1 ± 2.16 mV) of micelle. Spherical like surface morphology of bHSC micelle also investigated using FE-SEM. Both MTT and Flow cytometry analysis were confirmed less toxicity of synthesized micelle. Dox was encapsulated via the dialysis method and the Dox loading and encapsulation efficiency was 16.49 ± 1.2% and 58.47 ± 1.87%, respectively. In vitro Dox release study was evaluated by mimicking the intracellular levels of GSH (5 mM) and approximately 89% and 52% of the Dox was released in the 48 h of incubation in the presence and absence of GSH respectively, which clearly shows synthesized micelle was a redox sensitive. The cellular internalization of Dox-loaded bHSC nanoparticles was studied using confocal laser scanning microscope and the strong fluorescence intensity signals (red fluorescence) was observed mainly in the cell’s nucleus. This confirms the Dox loaded bHSC was up taken by HeLa cells and the Dox were released from bioreducible bHSC micelle. In addition to this, antimetastasis and hemocompatibility of bHSC was evaluated via scratch and hemolysis assays respectively. F-actin fluorescence microscopy result shows, heparin and bHSC treated HeLa cells had poorly oriented stress fibers. In summary, due to its less toxicity, an excellent hemocompatibility and antimetastasis effects, the synthesized bHSC micelle is the best candidate carriers in the drug delivery system and can be used to inhibit metastatic cancers as well.

    Contents 摘要 iii Abstract v Acknowledgements ix Table of Contents xi List of Figures xv List of Table xix List of Schemes xx List of abbreviations xxi CHAPTER 1 1 1.1. Introduction 1 1.2. Objective 4 1.2.1. General objective 4 1.2.2. Specific objective 5 CHAPTER 2 6 2.1. Historical Background of Photodynamic Therapy 6 2.2. Principle and mechanism of photodynamic therapy 6 2.2.1 Photosensitizer 8 2.2.2. Light source in PDT 11 2.3. Anti-tumor activity of PDT 12 2.3.1. Direct Tumor Cell Kill 12 2.3.2. Vascular Damage 14 2.3.3. Inflammatory and Immune Response 14 2.4. Chemotherapy 16 2.5. Drug delivery systems 17 2.5.1. Polysaccharide 20 2.5.1.1. Heparin 20 2.5.1.2. Chitosan 21 2.5.1.3. Hyaluronic acid 22 2.5.1.4. Alginate 23 2.5.1.5. Pullulans 24 2.5.1.6. Pectin 25 2.5.1.7. Chondroitin sulfate 26 2.5.1.8. Cellulose 26 2.5.2. Polysaccharide based nanoparticle synthesis 30 2.5.2.1. Polyelectrolyte complexation (PEC) 30 2.5.2.2. Self-assembly 30 2.5.2.3. Covalent cross linking 31 2.5.2.4. Ionic crosslinking 32 2.5.3. Polysaccharide-Based Nanogels Drug Delivery Systems 34 2.5.4. Polysaccharide-Based micelle Drug Delivery Systems 36 CHAPTER 3 37 3.1. Synthesis and characterization of bioreducible heparin-polyethyleneimine nanogels: application as imaging-guided photosensitizer delivery vehicle in photodynamic therapy (PDT) 37 3.2. Experimental Section 39 3.2.1. Materials 39 3.2.2. Preparation of HPC nanogels 40 3.2.3. Characterization of HPC nanogels 40 3.2.3.1. Particle size and zeta-potential 40 3.2.3.2. Fourier transformed infrared spectroscopy (FTIR) analysis 40 3.2.3.3. Nuclear magnetic resonance (1H-NMR) analysis 41 3.2.3.4. Transmission electron microscopy (TEM) 41 3.2.3.5. Scanning electron microscopy (SEM) 41 3.2.3.6. Fluorescence spectrophotometer 41 3.2.4. In vitro cytotoxity 42 3.2.5. Drug loading 42 3.2.6. Detection of singlet oxygen generation 43 3.2.7. Drug release study 44 3.2.8. Cellular uptake study of ZnPc-loaded HPC nanogels by confocal microscopy 44 3.2.9. Photodynamic cytotoxicity of ZnPc-HPC nanogels and ZnPc 45 3.3. Results and discussion 46 3.3.1. Preparation and characterization of HPC nanogels 46 3.3.2. Fluorescence properties of HPC nanogels 53 3.3.3. ZnPc loading in HPC nanogels 55 3.3.4. In vitro drug release 57 3.3.5. Detection of singlet oxygen generation 59 3.3.6. Cellular uptake of ZnPc-loaded HPC nanogels 61 3.3.7. Photodynamic cytotoxicity effect of ZnPc-HPC nanogels and ZnPc 62 3.4. Conclusion 64 CHAPTER 4 65 4.1. A pH sensitive micelle from heparin, phospholipid and histidine as the carrier of photosensitizer: application to enhance photodynamic therapy of cancer 65 4.2. Experimental Section 67 4.2.1. Materials 67 4.2.2. Synthesis 67 4.2.2.1. Synthesis of pH sensitive Heparin-1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine (HDH) conjugate 67 4.2.3. Characterization of HDH conjugates 68 4.2.3.1. FTIR analysis 68 4.2.3.2. NMR analysis 68 4.2.4. Synthesis of HDH micelle 69 4.2.5. In vitro stability of nanoparticles 69 4.2.6. Determination of critical micellization concentration (CMC) 70 4.2.7. In vitro cytotoxicity 70 4.2.8. Drug loading 71 4.2.9. Detection of singlet oxygen generation 72 4.2.10. Drug release study 73 4.2.11. Cellular uptake study 73 4.2.12. Phototoxicity of ZnPc loaded HDH and free ZnPc 74 4.3. Result and Discussion 75 4.3.1. Preparation and characterization of HDH micelle 75 4.3.2. Size and zeta potential 80 4.3.3. Micelle formation and Determination of critical micelle concentration (CMC) 83 4.3.4. In vitro cytotoxicity of HDH 86 4.3.5. ZnPc loading in HDH 86 4.3.6. ZnPc release from HDH micelle 88 4.3.7. Detection of singlet oxygen generation 90 4.3.8. Photodynamic cytotoxicity effect of ZnPc-HDH micelle and ZnPc 93 4.3.9. In vitro uptake study 95 4.4. Conclusion 95 CHAPTER 5 97 5.1. Synthesis and characterization of redox sensitive Heparin-β-Sitosterol micelle: Application as the carrier of pharmaceutical agents (Dox) and investigation Antimetastasis Activities of the micelles in vitro 97 5.2. Experimental section 101 5.2.1. Materials 101 5.2.2. Synthesis 101 5.2.2.1. Synthesis of thiolated heparin 101 5.2.2.2. Synthesis of bioreducible heparin- β-Sitosterol (bHSC) conjugate 102 5.2.3. Characterization of bHSC conjugates 102 5.2.3.1. FTIR analysis 102 5.2.3.2. 1H-NMR analysis 102 5.2.4. Synthesis of bHSC micelle 103 5.2.5. Determination of critical micellization concentration (CMC) 103 5.2.6. In vitro cytotoxicity 104 5.2.7. Drug loading 105 5.2.8. In vitro stability of Dox-bHSC nanoparticles 105 5.2.9. Drug release study 106 5.2.10. Cellular uptake study 106 5.2.11. Hemolysis Assay 107 5.2.12. Scratch Assay 107 5.2.13. Fluorescence microscopy of Actin Cytoskeleton 107 5.2.14. Cell Apoptosis/Necrosis by Flow cytometry 108 5.3. Result and Discussion 108 5.3.1. Characterization of thiolated heparin and bHSC conjugates 108 5.3.2. Critical Micelle concentration (CMC) 113 5.3.3. Dox loading and release study 116 5.3.4. In vitro stability of Dox-bHSC nanoparticles 119 5.3.5. In Vitro Cytotoxicity of Heparin, bHSC, free Dox and Dox-bHSC 121 5.3.6. Hemocompatibility test 125 5.3.7. Cellular uptake of Dox-bHSC 127 5.3.8. In vitro Scratch Assay 127 5.3.9. Fluorescence Microscopy of Actin Cytoskeleton 128 5.4. Conclusion 130 CHAPTER 6 132 6.1. General Summary 132 6.2. Recommendation 133 7. Bibliography 135 8. Appendix 180 8.1. List of publication 180

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