PAMAM Dendritic Mediated Nanocarriers as Effective Vehicles for siRNA, Chemotherapeutic and Immunotherapeutic Drugs in Cancer Therapy

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研究生：	Endiries Yibru Hanurry Endiries Yibru Hanurry
論文名稱：	PAMAM Dendritic Mediated Nanocarriers as Effective Vehicles for siRNA, Chemotherapeutic and Immunotherapeutic Drugs in Cancer Therapy PAMAM Dendritic Mediated Nanocarriers as Effective Vehicles for siRNA, Chemotherapeutic and Immunotherapeutic Drugs in Cancer Therapy
指導教授：	蔡協致 Hsieh-Chih Tsai 鄭智嘉 Chih-Chia Cheng
口試委員:	高震宇 Chen-Yu Kao 鄭智嘉 Chih-Chia Cheng Yi-Chun Chen Yi-Chun Chen Jui-Yang Lai Jui-Yang Lai Shuian-Yin Lin Shuian-Yin Lin Yu-Shuan Chen Yu-Shuan Chen 蔡協致 Hsieh-Chih Tsai
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：	2020
畢業學年度：	109
語文別：	英文
論文頁數：	173
中文關鍵詞：	Adipic acid dihydrazide 、Apoptosis 、Biotin 、Cytokines 、Doxorubicin 、Hydrazone Bond 、Hydrogel 、Indoximod 、Immunochemotherapy 、Immunogenic Cell Death 、PAMAM dendrimer 、Oligoalkylamine 、Small interference RNA
外文關鍵詞：	Adipic acid dihydrazide, Apoptosis, Biotin, Cytokines, Doxorubicin, Hydrazone Bond, Hydrogel, Indoximod, Immunochemotherapy, Immunogenic Cell Death, PAMAM dendrimer, Oligoalkylamine, Small interference RNA
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癌症是由原致癌基因，腫瘤抑制基因或DNA修復基因的丟失，突變或失調引起的疾病的集合，這些疾病導致細胞亞族群的失控生長。儘管發現了用於癌症治療的先進治療方法，但治療效率常常受到多重抗藥性，免疫抑制和嚴重副作用的影響，目前癌症仍然是奈米醫學的主要關注領域。此外，腫瘤選擇性靶向的持續釋放是抗癌治療劑的主要缺點。
奈米醫學特別是以可控的PAMAM樹枝狀聚合物等智慧奈米載體的靶向給藥系統的開發已成為解決上述問題和提高抗腫瘤藥效的重要策略。PAMAM樹狀大分子表現出高載藥量、非免疫原性、高單分散性、多功能表面基團、多孔腔、理想的滯留性和生物可利用的特性，這些特性目前尚未在所有其他現有的奈米載體中同時觀察到。奈米尺度體系的形成具有明確的尺寸和形狀，在藥物遞送和基因轉染等生物醫學應用中相當普遍。PAMAM樹枝狀聚合物因此吸引我們將其用於基因、化療和免疫療法來治療癌症。本文對PAMAM樹枝狀載體進行了全面的研究，以提高siRNA和抗腫瘤藥物的效率。
首先，以低烷基胺修飾的PAMAM樹枝狀奈米粒子作為非病毒載體來傳遞siRNA。PAMAM樹狀分子與二乙烯三胺和四乙烯五胺共軛，然後結合siRNA通過靜電相互作用形成不同N/P比的多聚體。多聚體(N/P=8)具有球形奈米粒子，表現出完整的siRNA結合效率，保護了siRNA不被酶破壞。單枝狀聚合物具有無毒、有效改善細胞內化的特點。多聚體在細胞溶膠中發生非定域性並廣泛傳播，表明siRNA在HeLa細胞中具有良好的胞內分佈與傳播。因此，低烷基胺修飾的PAMAM樹枝狀聚合物可以成為體外適當的siRNA奈米載體。
利用生物素功能化PAMAM樹枝狀奈米粒子，通過運輸介導的內分泌增強吉西他濱的腫瘤特異性傳遞和細胞內化。PG4.5先用DETA修飾，再加入生物素與吉西他濱封裝。PG4.5-DETA-BT/Gem奈米粒子的粒徑為81.6±6.08 奈米，電位為0.47±1.25 mV。PG4.5-DETA-BT/GEM奈米粒子還幫助藥物在酸性環境下持續釋放。PG4.5-DETA-BT/GEM奈米粒子具選擇性靶向癌細胞能力，提高了細胞內化效率。PG4.5-DETA-BT/GEM奈米粒子也顯著增強抗癌細胞增殖活性並誘導凋亡。因此，生物素官能化PAMAM樹枝狀奈米載體可以提供將吉西他濱輸送到癌細胞中的靶向遞送系統。
此外也製備了具pH響應型PAMAM樹枝狀奈米粒子結合熱敏感水凝膠，用於免疫化療藥物的輸送，以提高免疫原性細胞死亡和抗腫瘤免疫力。用己二酸二酰肼對聚氨酰胺樹狀大分子進行修飾，再用生物素和阿霉素結合，通過酸易損的腙鍵制備PAB-DOX。IND成功地負載在樹枝狀奈米粒子中，然後加入到PCLA-PEG-PCLA熱響應水凝膠中。PAB-DOX/IND奈米粒子具有球形形貌和表面電荷微小的奈米載體，粒徑為121.53 nm。該奈米粒子改善了藥物的持續釋放和細胞吸收效率。PAB-DOX/IND奈米粒子也顯著降低了細胞存活率和誘導凋亡。此外，在生理溫度下含有熱響應性水凝膠的樹枝狀奈米粒子表現出凝膠狀態，並進一步延長了藥物的緩釋時間。此系統能有效抑制腫瘤生長，增強免疫刺激性細胞因子的表達，引發凋亡，減輕腫瘤細胞增殖和誘導的CD8+T細胞活化，共同促進HeLa細胞移植裸鼠的ICD和免疫應答。
最後，本研究設計與合成了經修飾PAMAM樹狀大分子納米載體和水凝膠，對其理化和生物學效能進行了表徵和檢測。結果證實，這些藥物被有效地遞送，並提高了其效率。因此，PAMAM樹枝狀聚合物載體可作為有效遞送siRNA、化療和免疫治療藥物的良好選擇。在論文的結尾預測了臨床應用之前，加強這一發現的其他展望。

Cancer is a collection of diseases arises from loss, mutation or dysregulation of proto-oncogenes, tumor suppressor genes or DNA repair genes that led to uncontrolled growth of cell. Despite the discovery of advanced therapeutic approaches for cancer treatment, the efficiency of therapeutics were frequently affected by multidrug resistance, immune suppression and severe side effects; and cancer remains a major focusing area of nanomedicine. The ability to deliver into selective and targeted site of tumor with sustain release is also another challenge of therapeutic agents.
The progress of controlled delivery system such as tunable PAMAM dendrimer has become a magnificent strategy to address aforementioned issues. PAMAM dendrimer exhibit a unique characteristics of high drug loading capacity, multifunctional surface groups and free cavities that have not been fully observed in any other currently available nanocarriers. In spite of their significant advantage to entrap multiple and high quantity of therapeutic agents, rapid release before its final destination and optimal release at targeted site; and toxicity are still the main challenges. Stimuli responsive linkers and targeting ligands are required to monitor sustained release and enhance the accumulation of therapeutic agent at site of action. Herein, we carried out a comprehensive investigations on the fabrication of stable and biocompatible surface modified PAMAM dendritic based carriers to enhance the efficiency of therapeutic agents by improving their sustained release and accumulation at the targeted site.
In the first series of investigation, oligoalkylamine modified PAMAM dendritic nanoparticles were developed as non-viral vector to deliver siRNA as precursor to design a personal medicine. It was fabricated by the conjugation of PAMAM dendrimer generation 4.5 (PG4.5) with diethylenetriamine and tetraethylenepentamine followed by siRNA binding to form polyplexes at different N/P ratio through electrostatic interaction. The polyplexes (N/P = 8) exhibited spherical nanoparticles, showed perfect binding efficiency and protected the siRNA against enzyme digestion. Oligoalkylamines modified PG4.5 alone were exhibited nontoxic property and effectively improved cellular internalization. The polyplexes were delocalized and widely spread throughout the cytosol to indicate a decent intracellular biodistribution and endosomal escape of siRNA in HeLa cells.
In the second series of investigation, biotin functionalized PAMAM dendritic nanoparticle was fabricated to improve targeted delivery of gemcitabine via transporter-mediated endocytosis. PAMAM dendrimer was initially coupled with DETA followed by biotin conjugation and gemcitabine encapsulation. PG4.5-DETA-BT/Gem nanoparticles revealed a spherical shape with 81.6 ± 6.08 nm particle size and 0.47 ± 1.25 mV zeta potential. PG4.5-DETA-BT/GEM nanoparticle also assisted the sustain release at low pH. PG4.5-DETA-BT/GEM nanoparticle was specifically targeted cancer cells, significantly enhanced anti-proliferative activity and induced apoptosis. Biotin-functionalized PAMAM dendritic nanocarrier could, therefore, provide a targeted delivery system to convey gemcitabine into cancer cells.
In the last series of investigation, pH responsive PAMAM dendritic nanoparticle incorporated thermo-sensitive hydrogel was constructed for the local co-delivery of immunochemotherapeutic drugs to improve immunogenic cell death and antitumor immunity. PAMAM dendrimer was effectively coupled with adipic acid dihydrazide followed by biotin and DOX conjugation to fabricate PAB-DOX via acid vulnerable hydrazone bond. IND was successfully loaded into dendritic nanoparticle and then incorporated into PCLA-PEG-PCLA thermo-responsive hydrogel. The PAB-DOX/IND nanoparticle were exhibited spherical morphology and slightly neutral surface charged nanocarrier with 121.53 nm particle size. The nanoparticle improved the sustained release of drugs and cellular uptake efficiency. PAB-DOX/IND nanoparticle was also significantly reduced proliferation activity and encouraged the induction of program cell death. In addition, dendritic nanoparticle incorporated thermo-responsive hydrogel were further extended the sustained release and accumulation of drugs at the site of action. This formulation was effectively inhibited tumor growth, enhanced immune stimulatory cytokines expression, triggered apoptosis, mitigated tumor cell proliferation and induced CD8+ T cells activation that collectively promote ICD and immune response in HeLa cells grafted nude mice.
To sum up, PAMAM dendrimer based vehicles could be good candidates to convey siRNA, chemo and immunotherapeutic drugs into tumor tissue. Additional outlooks to strengthen this finding before clinical applications are predicted at the end of the thesis.

ABSTRACT (CHINESE)    I
ABSTRACT    III
ACKNOWLEDGMENTS    VI
TABLE OF CONTENS    VIII
LIST OF FIGURES    XIII
LIST OF TABLES    XVII
LIST OF SCHEMES    XVIII
ABBREVIATIONS    XVIII
CHAPTER – 1    1
   Introduction    1
1    Background    1
2    Objectives of the Thesis    4
3    Chemicals, Reagents and Instruments    5
3.1    Chemicals and Reagents    5
3.2    Instruments    6
4    Statistical Analysis    6
CHAPTER – 2    7
   Literature Review    7
1    Overview of Cancer    7
2    Therapeutic of Cancer    9
3    Nanotechnology in Cancer Therapy    13
4    Targeting Strategies of Nanocarriers in Cancer Therapy    16
5    Stimuli Responsive Nanocarrier System    17
6    Dendrimer    21
7 Poly (amido)amine Dendrimer    22
6.1    Properties of PAMAM Dendrimer    23
6.2    Synthesis of PAMAM Dendrimer    25
6.3    Surface Modification of PAMAM Dendrimer    26
6.4    Surface Modification with Adipic Acid Dihydrazide    28
6.5    Surface Modification with Oligoamines    28
6.6    Biotinylation    29
8    Application of PAMAM Dendrimer    30
8.1 PAMAM Dendrimer in Gene Delivery    31
8.2 PAMAM Dendrimer in Drug Delivery System    34
CHAPTER – 3    37
   Oligoalkylamine Modified PAMAM Generation 4.5 Dendritic Nanocarrier for the Transfection of Small Interfering RNA    37
1    Introduction    37
2    Experiments    39
2.1    Synthesis and Characterization of PG4.5-DETA and PG4.5-TEPA    39
2.2    Fabrication of PG4.5-DETA and PG4.5-TEPA Polyplexes    39
2.3    Binding Ability of PG4.5-DETA and PG4.5-TEPA to siRNA    41
2.4    Hydrodynamic Diameter and Surface Charge of Polyplexes    41
2.5    Morphology of Polyplexes    41
2.6    Heparin-induced siRNA Release Assay of Polyplexes    42
2.7    Serum Protection Assay of Polyplexes    42
2.8    Cytotoxicity of PG4.5-DETA and PG4.5-TEPA    42
2.9    Cellular Uptake of Polyplexes    43
2.10    Intracellular Distribution of Polyplexes    44
3    Results and Discussion    44
3.1    Synthesis and Characterization of PG4.5-DETA and PG4.5-TEPA    44
3.2    Binding Ability of PG4.5-DETA and PG4.5-TEPA to siRNA    48
3.3    Hydrodynamic Diameter and Surface Charge of Polyplexes    49
3.4    Morphology of PG4.5-DETA and PG4.5-TEPA Polyplexes    50
3.5    Heparin-induced siRNA Release    51
3.6    Serum Stability of Polyplexes    52
3.7    Cytotoxicity of PG4.5-DETA and PG4.5-TEPA    53
3.8    Cellular Uptake of PG4.5-DETA and PG4.5-TEPA Polyplexes    55
3.9    Intracellular Biodistribution of PG4.5 DETA and PG4.5-TEPA Polyplexes    56
4    Conclusions    58
CHAPTER – 4    59
   Biotin Functionalized Dendritic Nanoparticle to Enhance Antiproliferative and Apoptotic Activity of Gemcitabine in cancer Treatment    59
1    Introduction    59
2    Experiments    61
2.1    Synthesis of PG4.5-DETA and PG4.5-DETA-BT    61
2.2    Preparation and Characterization of Gemcitabine-Loaded Nanoparticles    62
2.3    In vitro Release of Gemcitabine from PG4.5-DETA-BT/GEM Nanoparticle    64
2.4    Cellular Uptake of PG4.5-DETA-BT/GEM Nanoparticle    64
2.5    Cytotoxicity of PG4.5-DETA-BT/GEM Nanoparticle    65
2.6 In vitro Apoptosis Assay of PG4.5-DETA-BT/GEM Nanoparticle    65
3    Results and Discussion    66
3.1    Synthesis and Characterization of PG4.5-DETA and PG4.5-DETA-BT    66
3.2    Characterization of PG4.5-DETA-BT/GEM Nanoparticle    68
3.3    In vitro Release of Gemcitabine    71
3.4    Cellular Uptake of PG4.5-DETA-BT/GEM Nanoparticle    72
3.5    Cytotoxicity of PG4.5-DETA-BT/GEM Nanoparticle    74
3.6    Apoptosis Assay of PG4.5-DETA-BT/GEM Nanoparticle    75
4    Conclusions    76
CHAPTER – 5    78
   Bioresponsive PAMAM Dendritic Nanoparticle Incorporated Hydrogel to Enhance Immunogenic Cell Death and Immune Response in Cancer Immunochemotherapy    78
1    Introduction    78
2    Methods    81
2.1    Synthesis of PADH    81
2.2    Synthesis of PAB    81
2.3    Synthesis of PADH-DOX and PAB-DOX    83
2.4    Synthesis of PCLA-PEG-PCLA triblock Copolymer    84
2.5    Preparation of Indoximod Loaded PAB-DOX Nanoparticles    85
2.6    Preparation of Gel/PAB-DOX/IND and Its Sol-Gel Phase Transition Diagram    85
2.7    Biodegradation of Hydrogel    85
2.8    Release Profile of DOX and IND from Nanoparticle and Hydrogel    86
2.9    Cellular Uptake of PAB-DOX/IND Nanoparticle    86
2.10    In vitro Cell Viability of PAB-DOX/IND Nanoparticle    87
2.11    In vitro Apoptosis Study of PAB-DOX/IND Nanoparticle    88
2.12    In Vivo Studies of Gel/PAB-DOX/IND    88
3    Results and Discussion    90
3.1    Synthesis and Characterizations of PADH, PAB and PAB-DOX    90
3.2    Physicochemical Characterization of PAB-DOX/IND Nanoparticles    94
3.3    Sol-Gel Phase Transition and Biodegradation of Gel/PAB-DOX/IND    95
3.4    In Vitro Releasing of DOX and IND from Nanoparticle and Hydrogel    96
3.5    In Vitro Cellular Uptake of PAB-DOX/IND Nanoparticle    97
3.6    In vitro Cell Viability of PAB-DOX/IND Nanoparticle    99
3.7    In vitro Apoptotic Effect of PAB-DOX/IND Nanoparticle    101
3.8    In Vivo Tumor Growth Inhibition Activity of Gel/PAB-DOX/IND    102
3.9    Histopathology and Immunohistochemistry (IHC) Analysis    105
3.10    Evaluation of Cytokines Expression    106
3.11    In vivo Systemic Toxicity Effect of Gel/PAB-DOX/IND    108
CHAPTER – 6    111
   General Summary and Future Perspectives    111
1    General Summary    111
2    Future Perspectives    112
REFERENCES    114
APPENDIX    143


                                

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