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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 楊台鴻 | |
dc.contributor.author | Jin-He Ke | en |
dc.contributor.author | 柯錦和 | zh_TW |
dc.date.accessioned | 2021-06-15T07:10:02Z | - |
dc.date.available | 2012-10-22 | |
dc.date.copyright | 2010-10-22 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-10-19 | |
dc.identifier.citation | chapter1
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48716 | - |
dc.description.abstract | 傳遞治療型的核酸來治療基因所引起的疾病被認為是一種有效的治療方法。因此發展安全且有效果的基因傳遞載體在臨床的基因治療研究中是必要的。正電型高分子為非病毒型基因載體中廣泛被探討的主要類型之一。本篇論文的主軸欲發展一種有效且低毒性的正電型基因載體於基因傳遞的應用。
論文的第一部份針對基因傳遞過程中,會遇到一些障礙與常見的正電型高分子提出簡單的說明。 在論文的第二部份中,以自由基聚合反應合成一系列的poly (N-substituent acrylamide)s (PAms),他們在結構上具有不同長度的alkylamine側鏈。這些PAm被設計來試驗alkylamine側鏈methylene數目(2∼12個)對細胞毒性、DNA鍵結親和力、細胞攝取效率和基因表現上的影響。於HEK293細胞中,側鏈長度的增加會造成細胞毒性降低的趨勢。根據IC50數值,所有的PAms比PEI毒性要低。這些以一級胺為主的PAm能夠有效率的將DNA凝集並形成大小分佈在100∼350奈米的顆粒。在具有同樣主鏈構造的PAms中,PAms的基因轉殖能力由其側鏈長度決定,具有octylamine側鏈的P8Am能得到較高的基因表現。雖然PAm的基因轉殖能力不如PEI好,但我們發現P8Am的吞噬能力並不會受到侷限。這可以從chloroquine對轉殖效率的影響來獲得證實。特別的是,由P8Am所形成的複合體比起PEI具有更高被細胞吞噬的能力。由Heparin replacement assay實驗中可得知,這種現象歸因於適當的高分子結構使得P8Am能夠將DNA包覆形成穩定的奈米粒子。在高分子結構對於轉殖能力的影響上提供我們有用的資訊,並且有助於發展出更有效的高分子基因載體。 在本論文的第三部份中,我們採取化學修飾的方法來給予P8Am多種能力以克服基因傳遞過程中所遭遇的障礙。因此,我們將imidazole與PEG鍵結在P8Am上,期望能獲得高基因表現、低毒性、抗凝血和抗血清抑制的正電高分子基因載體。細胞毒性測試結果顯示,不同取代比例的P8Am衍生物比沒有修飾的P8Am及PEI有更好的生物相容性。從粒徑分析與表面電位量測結果發現,他們能夠將DNA包覆成微米以下(135 ∼ 625奈米)且表面帶正電的粒子(+ 10 ∼ + 43 mV)。而取代比例較高的衍生物會影響其包覆DNA的能力,形成表面電位較低且顆粒較大的粒子。流式細胞儀分析結果發現,官能基取代的比例會影響細胞吞噬效率,其中較低取代比例的衍生物有著較高的細胞吞噬效率。由luciferase assay來評估其基因轉殖能力。結果顯示取代比例低的P8Am-IM11(含11 mole % imidazole)和P8Am-PG7(含7 mole % PEG)比起未經修飾的P8Am有較高的基因轉殖能力。因此同時具有兩種功能性分子(imidazole和PEG)的P8Am-IM11-PG7根據最佳化的取代比例進行合成。在含血清環境中,比起未經修飾的P8Am,P8Am-IM11-PG7明顯的提升基因轉殖效率且毒性低。此外,紅血球凝集測試結果發現P8Am-IM11-PG7與未經修飾的P8Am和PEI相比具有較好的血液相容性。結果表示經由化學修飾的努力,P8Am-IM11-PG7擁有能克服在基因轉殖過程中遭遇到的困難的能力。然而,我們也發現藉由此化學程序,似乎會阻礙P8Am原有的細胞攝取親和特性。 在論文的第四部份中,以正電高分子(PEI或P8Am)包覆DNA形成核心複合體,再以PAA包覆於其外,反轉其表面電位,接著再加入正電高分子(PEI或P8Am)形成四元結構的複合體。藉由具細胞攝取親和性的P8Am包覆後,核心PEI複合體能夠改善其細胞毒性與細胞吞噬效率。由於P8Am無法藉由質子海綿作用讓複合體從endosome內釋放,因此核心中包含PEI對P8Am包覆的四元複合體來說是必要的。我們可藉由陰離子型高分子與正電型高分子以layer-by-layer方式輪流包覆得到一個有效率且安全性高的非病毒型基因載體。藉此方式能夠獲得克服基因轉殖過程中遭遇障礙所需的能力。具有極低毒性且最大轉殖能力的四元複合體出現在pDNA/PEI/PAA/P8Am重量組成為1/1.5/3/5 的條件下。相反地,以PAm為核心,其最外層以PEI包覆,雖具有同樣組成,但此組成順序則顯示高毒性與低的轉殖效率。這表示四元複合體的組成順序(pDNA/PEI/PAA/P8Am)與其中高分子功能性的選擇對設計安全且可信賴的基因傳遞載體來說是很重要的。在此,我們證明了以細胞攝取親和性正電型高分子作為最外層來增加細胞吞噬程度,同時在其核心內則包含具有緩衝能力的正電型高分子增加endosomal釋放能力,以改善基因傳遞效率。 論文的最後一部份則總結各章節的成果,並對於目前的發現提出一些建議及未來的展望。 | zh_TW |
dc.description.abstract | Therapeutic nucleic acid delivery has been considered as a powerful strategy for treating gene-related diseases. Development of safe and efficient gene delivery vector is essential for clinical use in gene therapy. Polycations are the major type of the nonviral gene vectors widely investigated for gene delivery. The purpose of this dissertation attempts to develop an efficient with minimal toxicity polycationic gene vector for gene delivery.
The first part of this dissertation gives a broad discussion of the current comprehension of the biological barriers and common discussed polycations in gene delivery. In the second part of this dissertation, a series of poly (N-substituent acrylamide)s (PAms) that differ in alkylamine side chain was synthesized via free radical polymerization. The PAms were designed to examine the effects of the methylene numbers (from two to twelve) in the alkylamine side chain on cytotoxicity, plasmid DNA (pDNA) binding affinity, cellular uptake efficiency and gene expression. The cytotoxicity of PAms evaluated in HEK293 cells using the MTT assay showed a trend of decreasing toxicity with the side chain length and the IC50 values of all PAms were lower than that of polyethylenimine (PEI) control. The primary amine-based polymers were able to efficiently condense pDNA to form complexes with size ranging from 100 to 350 nm. The gene transfection ability of PAms is dominantly determined by the specific side chain length that P8Am (with octylamine side chain) reveals higher gene expression than other PAms containing the same backbone structure. Although the gene transfection efficiency of PEI was better than all of PAms, PAms were found not to be uptake-limited. This was supported by the effect of chloroquine on transfection activity, based on the protease inhibition activity of chloroquine. Especially, complexes formed from P8Am displayed high uptake level relative to PEI, which was attributed to the proper structure of P8Am to compact pDNA to form stable nanoparticles under the heparin replacement assay. This offers the understanding to polymer structure that influences the transfection ability and gives useful information to develop efficient polymeric gene vector. In the third part of this dissertation, chemical modification was performed to give P8Am multi-functionalities to overcome the gene delivery barriers encountered during transfection. Hence, a novel cationic polymer was developed by conjugating imidazole and polyethylene glycol (PEG) on poly(N-(8-aminooctyl)acrylamide) (P8Am) to exhibit high gene expression with low cytotoxicity and the resistance against erythrocyte agglutination and serum inhibition. Cytotoxicity results indicated that these P8Am derivatives in varied substitutions were more of biocompatibility than unmodified P8Am and PEI control. Moreover, the particle size and zeta potential experiment demonstrated that they were capable of complexing pDNA into sub-micro (135 ~ 625 nm) and positive charge (+10 ~ +43 mV) particles, while high degree of substitution might impede their pDNA complexation ability that formed less positive and larger polyplexes. Flow cytometry analysis demonstrated the cellular uptake efficiency was depended on the degree of substitution; low degree of substitution would mediate high uptake efficiency. The gene transfection ability was evaluated by luciferase assay that revealed low substitution P8Am-IM11 (substituted with 11 mole % of imidazole moiety) and P8Am-PG7 (substituted with 7 mole % of PEG moiety) transfected cells more efficient than unmodified P8Am, respectively. Therefore, the multi-functional P8Am derivative, P8Am-IM11-PG7 – containing both imidazole and PEG, was developed according to the optimized contents. In the presence of serum, P8Am-IM11-PG7 polyplexes significantly enhanced the gene transfection efficiency relative to unmodified P8Am polyplexes. Moreover, it exhibited minimal cytotoxicity and the erythrocyte aggregation assay showed that P8Am-IM11-PG7 polyplexes revealed good blood compatibility as compared to P8Am polyplexes and PEI polyplexes. This indicated that by the efforts of chemical modification, P8Am-IM11-PG7 could possess required abilities to overcome the difficulties encountering in gene transfection. However, the chemical strategy seems to impede the cell-uptake favorable property of P8Am. In the fourth part of this dissertation, quaternary polyplexes were prepared by sequential addition of polycations (polyethylenimine (PEI) or poly (N-(8-aminooctyl)-acrylamide) (P8Am)) for loading pDNA into the core polyplexes and poly (acrylic acid) (PAA) for reversing charges to deposit additional polycation (PEI or P8Am) layer. It was found the cytotoxicity and cellular uptake expression of PEI core polyplexes could be improved by coating a cell uptake-favorable P8Am layer. Conversely, P8Am could not facilitate endosomal release through the proposed proton sponge effect so the PEI core was required for the P8Am-coated quaternary polyplexes to ensure efficient transfection. Consequently, an efficient and safe non-viral gene vehicle was constructed by layer-by-layer deposition, using alternate polyanion and polycation with required functionalities to overcome the obstacles met in the process of transfection. Maximum transfection activity with minimal toxicity was observed when the quaternary polyplex of pDNA/PEI/PAA/P8Am was prepared at a weight ratio of 1/1.5/3/5. Conversely, the same composition in different position such as the cell-favorable P8Am core was externally deposited with the endosome lytic moiety, PEI showed high toxicity and low efficiency. This indicates the pDNA/PEI/PAA/P8Am sequence for a quaternary polyplex is as important as the functional polymer selection for designing safe and reliable gene delivery vehicles. We demonstrate here that gene delivery efficiency may be improved by increasing the uptake level and the endosomal buffering release through an additional layer of cell uptake-favorable polycations associated with the core polycations possessing endosomal release ability. In the last part of the dissertation, achievements of each chapter in this dissertation were concluded, and some suggestions and prospection were provided according to the present findings. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T07:10:02Z (GMT). No. of bitstreams: 1 ntu-99-D94549011-1.pdf: 7060740 bytes, checksum: 6e6009fa5a64a49d170a2097bd3981cd (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 摘要…………………………………………………………………Ⅰ
Abstract……………………………………………………………Ⅳ Contents……………………………………………………………VIII List of Tables…………………………………………………VIII List of Schemes………………………………………………VIII List of Figures………………………………………………VIII 1 Polymeric Gene Delivery Systems…………………………1 1.1 Introduction………………………………………………1 1.2 Delivery Barriers for Polycationic Gene Therapy…3 1.3 Polycation Gene Vectors…………………………………7 1.4 Research Objectives……………………………………10 1.5 References………………………………………………11 2 Design, Synthesis and Evaluation of Cationic Poly (N-substituent acrylamide)s for In Vitro Gene Delivery……………………………………17 2.1 Introduction……………………………………………17 2.2 Materials and Methods………………………………19 2.2.1 Materials……………………………………………19 2.2.2 Monomers and polymers synthesis…………………… 2.2.2.1 General procedure of the synthesis of mono(Boc)-protected-alkyl-diamine, 2……………………19 2.2.2.2 General procedure of the synthesis of acrylation of mono(Boc)-protected-alkyl-diamine, 3……………………21 2.2.2.3 General procedure of free radical polymerization to synthesize PAm-BOC…………………………………………………24 2.2.2.4 General procedure of deprotection to produce poly(N-alkylamine)acrylamide, PAm………………………25 2.2.3 Characterization…………………………………………27 2.2.4 Preparation of polymer/pDNA complexes (polyplexes)……………27 2.2.5 Cytotoxicity Measurement of PAms and PAm polyplexes……27 2.2.6 Agarose gel electrophoresis assay…………………………………29 2.2.7 Particle size and zeta potential analyses……………29 2.2.8 In vitro gene transfection…………………………29 2.2.9 Heparin replacement assay…………………………………30 2.2.10 Cellular uptake………………………………………31 2.3 Results…………………………………………………………32 2.3.1 Monomers and polymers characterization………………32 2.3.2 Cytotoxicity of PAm polymers……………………………33 2.3.3 Gel retardation assay…………………………………34 2.3.4 Physico-chemical properties of polyplexes………34 2.3.5 In vitro transfection and cytotoxicity of polyplexes………………35 2.3.6 Heparin displacement of polyplexes at optimized weight ratios……35 2.3.7 Cellular uptake…………………………………36 2.3.8 Chloroquine effect………………………………36 2.4 Discussion……………………………………………………38 2.5 Conclusion…………………………………………………41 2.6 References…………………………………………………42 3. Imidazole/Poly(ethylene glycol) Substituted Poly(N-(8-aminooctyl)acrylamide) as Biocompatible and Efficient Gene Vector………………………………………………………………55 3.1 Introduction………………………………………………55 3.2 Materials and methods…………………………………57 3.2.1 Materials……………………………………………57 3.2.2 Characterization……………………………………57 3.2.3 Polymer synthesis…………………………………57 3.2.3.1 General procedure of conjugated imidazole moieties into P8Am, P8Am-IM…………………………………………58 3.2.3.2 General procedure of conjugated PEG moieties into P8Am, P8Am-PG…………………………………………………58 3.2.3.3 Synthesis of multi-conjugated P8Am, P8Am-IM11-PG7…59 3.2.4 Preparation of polymer/pDNA complexes (polyplexes)……………59 3.2.5 Cytotoxicity Measurement of P8Am derivatives and their polyplexes………………………………………………59 3.2.6 Particle size and zeta potential analyses……60 3.2.7 In vitro gene transfection………………………61 3.2.8 Cellular uptake……………………………………62 3.2.9 Erythrocyte aggregation assay…………………62 3.2.10 Statistical analysis……………………………63 3.3 Results………………………………………64 3.3.1 Synthesis of P8Am derivatives…………………………64 3.3.2 Cytotoxicity of P8Am derivatives……………………65 3.3.3 Determination of complexation ability of P8Am derivatives with pDNA………………………………………………66 3.3.4 Effect of imidazole/PEG substitution of P8Am on gene transfection efficiency……………………………………67 3.3.5 Cellular uptake of optimized P8Am-IM polyplexes and P8Am-PG polyplexes………………………………………67 3.3.6 Evaluation of P8Am-IM11-PG7 polyplexes on gene transfection efficiency, cellular uptake, cytotoxicity, and erythrocyte aggregation…………………68 3.4 Discussion………………………………………………70 3.5 Conclusion……………………………………………74 3.6 References………………………………………………75 4. Multilayered Polyplexes with the Endosomal Buffering Polycation in the Core and the Cell Uptake-Favorable Polycation in the Outer Layer for Enhanced Gene delivery………………………………………………92 4.1 Introduction……………………………………92 4.2 Materials and methods………………………………94 4.2.1 Preparation of binary, ternary and quaternary pDNA polyplexes…94 4.2.2 Particle sizes and surface charges………………………94 4.2.3 Agarose gel electrophoresis assay………………………95 4.2.4 Cellular toxicity…………………………………………95 4.2.5 Cellular uptake…………………………………………96 4.2.6 Intracellular localization of TPⅠ/P8Am polyplexes…96 4.2.7 In vitro gene transfection…………………………97 4.3 Results……………………………………………………98 4.3.1 Physicochemical properties of PEM polyplexes…98 4.3.2 Cytotoxicity of PEM polyplexes……………………99 4.3.3 Cellular uptake of PEM polyplexes…………………100 4.3.4 In vitro transfection of PEM polyplexes…………101 4.4 Discussion………………………………………………103 4.5 Conclusion………………………………………………108 4.6 References………………………………………………109 5. Conclusion and Future works………………………120 5.1 Conclusion…………………………………………120 5.2 Future works………………………………………121 5.3 References………………………………………122 Publication Lists…………………………………………124 Appendix…………………………………………………125 A. PAms for biomedical applications: as delivery vehicles for therapeutic/diagnostic agents, such as antitumor drug and contrasting agent-Fe3O4 and as neuron culture biomaterial…………………………125 A.1 Introduction……………………………………………125 A.2 Cell uptake-favorable P8Am as an antitumor drug carrier……………127 A.2.1 Formation of DOX-loaded vehicle - (PAA/DOX)/P8Am ternary complex…………………………………………127 A.2.2 Cytotoxic effect of DOX-loaded vehicle……………127 A.3 PAms as contrasting agent vehicles…………………129 A.3.1 Formation of IOC/PAm ternary complexes……………129 A.3.2 Prussian Blue and Cytotoxicity of IOC/PAms………129 A.4 PAms as new neuron culture biomaterials……………130 A.4.1 Immunocytochemical characterization………………130 A.5 Summary………………………………………………………132 A.6 References…………………………………………………133 B. Synthesis of PO4Am and NMR spectrum……………143 | |
dc.language.iso | zh-TW | |
dc.title | 設計、合成與評估具細胞攝取親合性的正電型高分子於基因傳遞及在其他生物醫學方面的應用 | zh_TW |
dc.title | Design, synthesis and evaluation of cell uptake-favorable polycation for gene delivery and other biomedical applications | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 徐善慧,謝銘鈞,宋信文,陳志平,陳三元,陳月枝,楊銘乾 | |
dc.subject.keyword | 基因治療,正電高分子,細胞攝取,高分子合成, | zh_TW |
dc.subject.keyword | gene therapy,polycation,cell uptake,polymer synthesis, | en |
dc.relation.page | 169 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2010-10-20 | |
dc.contributor.author-college | 工學院 | zh_TW |
dc.contributor.author-dept | 高分子科學與工程學研究所 | zh_TW |
顯示於系所單位: | 高分子科學與工程學研究所 |
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