poly(2-ethyl-2-oxazoline)（PEOz）為一水溶性高分子，除了高親水性外，亦具備了酸鹼應答性及生物相容性，近幾年亦被FDA認可通過做為生物黏著劑。此外，由於PEOz易於製備團聯共聚物(copolymer)之特性，更使PEOz的應用與設計無限寬廣。本研究之主要構想是以親水性高分子PEOz為主體，製備功能性之奈米基因載體，以期應用於基因治療。本研究將分三部份分別陳述。

第一部份、酸鹼應答型高分子微胞做為細胞內基因傳輸載體及在基因傳輸上的應用。本部分研究目的在設計一具酸鹼應答性及生物相容性之陽離子型高分子團聯共聚物poly(oxazoline/ethylenimine)-b -poly(2-ethyl-2-oxazoline)-NH2, P(EOz/EI)-b-PEOz-NH2），此團聯共聚物之P(EOz/EI) 鏈段為陽離子高分子，可與DNA經靜電作用結合成聚複合體(polyplex)，而控制P(EOz/EI)水解程度及調整適當的電荷強度，則可降低細胞毒性及提高基因傳輸效率。此外殼PEOz具有安定聚複合體結構、提高親水性、低毒性及避免受免疫系統辨識之優點，而PEOz所特有的酸鹼應答性更可在基因聚複合體進入細胞後，達到結構破壞進而幫助基因脫附的效果。此外本研究利用巨起始劑之方法所形成之團連共聚物末端具有胺基(amino group)，可進一步與各種功能型官能基產生鍵結，提升其應用價值。實驗結果顯示，雙團聯共聚物P(EOz/EI)-b-PEOz相較於Branched-Poly(ethylenimine) (B-PEI)具有低細胞毒性，本身具有酸鹼應答性，轉染效率也與市售載體相當，藉由設計始末端帶有NH2官能基更讓此載體之發展性大幅提昇。因此本研究所合成之雙團聯共聚物為優良的陽離子高分子基因載體，故具有應用在基因治療的潛力。
第二部份、三聚離子型基因載體之研發及其在基因傳遞上之應用。本部分研究目的在設計一具備複合型結構之高分子基因載體，利用具生物相容性之PEOz與於中性環境下帶負電性之PMAA (polymethacrylic acid)合成雙團聯共聚物 (poly(2-ethyl-2-oxazoline)- b-poly(methacrylic acid), PEOz-b-PMAA )，再進一步藉由電性吸引方式與表面帶正電性之B-PEI/DNA聚複合體前驅物結合，形成具有複合結構的非病毒型基因載體。親水性高分子PEOz裸露於載體外殼，以提高載體於血液循環中之安定性，避免被巨噬細胞所吞噬，降低載體本身之細胞毒性，並利用內層B-PEI之高轉染效率來達到改善基因傳輸之效率。整體而言，利用PEOz-PMAA與B-PEI/DNA所結合之複合結構微胞可大幅提升B-PEI/DNA聚複合體之生物相容性，且表現出相當程度的轉染與細胞吞噬效率。

第三部份、基因傳輸之影像分析及癌症治療之療效研究，本部分研究首先選取前兩部分結果較佳之高分子與微胞組成，分別針對微胞粒徑大小、界面電位、高分子材料毒性、微胞毒性及轉染效果等做比較，探討兩者之間差異，進而選擇較適當的基因載體，進行基因傳輸影像分析及癌症治療之療效研究。分析結果顯示，第一部份之高分子基因載體P(EOz/EI)-b-PEOz具有較佳之表現。以P(EOz/EI)-b-PEOz進行後續的研究，包覆抗血管增生因子human Endo::Angio（hEA），藉由觀察腫瘤大小及活體影像來探討基因治療之效果。實驗結果顯示本研究所設計之P(EOz/EI)-b-PEOz高分子基因載體，包覆hEA後能有效的抑制腫瘤成長，在注射後短時間內（3小時）能有效的聚集在癌細胞處，並於24小時後藉由代謝系統漸漸累積在膀胱處，顯示此基因載體在基因治療上應當是相當有發展性。

The research synthesized the non-viral gene vectors based on poly(2-ethyl-2-oxazo-line) and it’s copolymer.

Part 1: This study synthesized the non-viral and pH-sensitive gene carrier, poly((2-ethyl-2-oxazoline)-co-ethylenimine)-block-poly(2- ethyl-2-oxazoline) (P(EOz/EI)-b-PEOz). The gene carrier contains both cationic poly((2-ethyl-2-oxazoline)-co-ethylenimine) (P(EOz/EI)) segments and charge-neutral poly(2-ethyl-2-oxazoline) (PEOz) segments. In this study, PEOz was used as biocompatibility shell and as the core source. A technique using methanesulfonyl poly((2-ethyl-2-oxazoline)-co-ethylenimine, (P(EOz/EI)-OMs) as a macroinitiator to modify the outer shell PEOz segment provided an amino group at the chain terminus. P(EOz/EI)-b-PEOz were coordinated with plasmid DNA, and the resulting complexes were characterized by gel permeation chromatography and 1H NMR spectra. The P(EOz/EI)-b-PEOz polyplexes showed suitable mean particle size, low cytotoxicity, and acceptable transfection because of shielding of PEI by PEOz outer shell. TEM morphology showed that the stable core-shell structure of ternary polyplexes at pH 7.4 collapsed and released plasmid at pH 5. Observations of cell uptake of the B-PEI/DNA polyplex and P(EOz/EI)-b-PEOz/DNA polyplexes by CLSM revealed that P(EOz/EI)-b-PEOz polyplexes started to accumulate after 6 h incubation and accumulated significantly after 12 h. The results indicated that the hydrophilic, charge-neutral PEOz shell stabilized polyplex formation, and enhanced polyplex cell viability. Polyplex transfection efficiencies were as high as those of commercially available transfection reagents. Our results suggest that this novel gene carrier, based on the diblock copolymer P(EOz/EI)-b-PEOz, has potential for in non-viral gene therapy applications.

Part 2: This investigation demonstrates new ternary gene delivery systems, based on the pH-responsive diblock copolymer poly(2-ethyl-oxazoline)-block-poly(methacrylic acid) (PEOz-b-PMAA), and the branched-poly (ethylenimine) (B-PEI). The plasmid DNA is complexed with B-PEI and further with PEOz-b-PMAA to obtain ternary polyplexes (DNA/B-PEI/PEOz-b-PMAA). PMAA was partially dissociated at neutral pH with a negative charge, to attach to the positively charged surface of the B-PEI/DNA polyplex. The ternary polyplexes also desorb and return to the original pre-poly complex to help gene release after cell uptake due to PMMA becomes neutral charge under an acid environment in endosome. The ternary polyplexes show suitable mean particle size, low cytotoxicity, and acceptable transfection at pH 7.4 because of shielding of B-PEI by PEOz-b-PMAA. A transmission electron microscopy morphological examination shows that the stable core-shell structure of ternary polyplexes at pH 7.4 collapsed and released plasmid at pH 5. Observations of the cell uptake of the B-PEI/DNA polyplex and ternary polyplexes by confocal laser-scanning microscope revealed that ternary polyplexes started to accumulate after 3 h of incubation and accumulated significantly after 6 h. In conclusion, the ternary polyplex improves the cytotoxicity of the single B-PEI/DNA polyplex, and presents a pH-responsive behavior to enhance gene escape from the polyplex. The ternary polyplex constitutes a useful approach for gene carrier design.

Part 3: The primary objective of this study is to explore the feasibility of inhibiting tumor growth via the delivery of endostatin-angiostatin (hEA) fusion gene by above non-viral gene carrer. We first compared above two gene carriers in particles size, zeta potential, cell toxicity and gene transfection efficiency. The results indicated that the gene carrier P(EOz/EI)-b-PEOz from first part had better quality for gene delievery, so we chose P(EOz/EI)-b-PEOz for further research. The results indicated that gene carrier P(EOz/EI)-b-PEOz with hEA led to a higher degree of tumor growth inhibition, and can be easily accumulated in tumor and metabolized. In conclusion, the P(EOz/EI)-b-PEOz constitutes a useful approach for gene carrier design.

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