雙離子遮蔽效應對於基因轉殖效率和人體血液相容性質的影響

邱琬芯

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雙離子遮蔽效應對於基因轉殖效率和人體血液相容性質的影響

Zwitterionic shielding effects on the gene transfer efficiency and blood compatibility

邱琬芯 , Masters　　Advisor：張雍　　

繁體中文

血液相容性質；基因釋放；雙離子共聚物； Blood compatibility ； Zwitterionic-based copolymer ； Gene delivery

Abstract │ Reference (46) │ Altmetrics

Abstract 〈TOP〉

一般常見的基因載體是以帶正電荷之物質包覆帶負電荷之核酸(Plasmid DNA)來形成基因載體，但當基因載體接觸生物環境時，會與蛋白質產生吸附，進而引發凝血或血栓反應等現象，會導致基因載體降低或喪失其原有的功能性質，甚至會影響到未來使用於人體的安全性。因此，本研究以仿生基因載體的設計概念出發，使用雙離子性共聚高分子為研究系統，並探討其帶有不同鏈長的帶正電分子鏈對於血液相容性質與基因轉殖效果的影響。
本論文的第一部分為探討雙離子性共聚高分子之血液相容性質，以材料界面系統為研究模型。透過原子轉移自由基聚合法(ATRP)，以雙離子基團之單體 (sulfobetaine methacrylate, SBMA)與帶硫酸根離子之單體([2-(Methacryloyloxy)ethyl] trimethylammonium, SA)，製備出帶負電鏈段之雙離子共聚高分子(PSA20-b-PSBMA40)，以靜電作用力方式固定於帶有正電荷之基材表面進行雙離子對正電離子基團之遮蔽效應控制研究，並探討其血液相容性質。實驗過程中與人體血液接觸，並使用影像來觀察血球貼附與凝集的情形。實驗結果顯示，經共聚高分子PSA20-b-PSBMA40 覆蓋的帶正電材料界面，由於雙離子鏈段展現出水合遮蔽效應，能有效降低人體血小板活化及紅血球貼附，證實雙離子基團可用於遮蔽正電荷基團來提升其血液相容性質。
本論文的第二部分為探討雙離子性共聚高分子之基因轉殖控制，以溶液系統為研究模型。透過ATRP的方式，以雙離子單體SBMA與帶三級胺單體之聚甲基丙烯酸二甲胺乙酯(Dimethylaminoethyl Methacrylate, DMAEMA)，經由不同單體組成比例合成出三組帶正電鏈段之雙離子性共聚高分子(PSBMA20-b- PDMAEMA10; PSBMA20-b-PDMAEMA20; PSBMA20-b-PDMAEMA40)，做為基因載體。實驗過程中，以正電鏈段之雙離子性共聚高分子PSBMAm-b-PDMAEMAn包覆帶負電荷之Plasmid DNA來形成基因載體，並探討雙離子遮蔽效應對於基因載體於溶液中之血液相容性質與基因轉殖入細胞中之效果。由溶血以及凝血實驗結果顯示，基因載體的雙離子鏈段PSBMA有效展現雙離子遮蔽效應，既不會破壞紅血球，也不會加速凝血，表示此基因載體具有良好的血液相容性質。在細胞轉染實驗結果中顯示，共聚高分子PSBMA20-b-PDMAEMA10與Plasmid DNA製備而成的基因載體，在N/P比例為5時，表現出最佳的細胞轉染效果，且保有與控制組相當的細胞存活率。

Parallel Abstract 〈TOP〉

In general, gene-delivery carriers are widely studied from the nano-complex conjugate of cationic materials combined with negatively charged plasmid DNA. However, the conjugate have a nature tendency of non-specific protein adsorption as contacting with biological systems, leading thrombogenic reaction in human blood. A key limitation in the future development of such gene-delivery carriers is the lack of safe control for gene delivery in human body. Therefore, from the molecular design of biomimetic structure, zwittterinic copolymers were prepared to investigate the effect of different composition ratios between zwitterionic and cationic blocks on their blood compatibility and gene transfection. 
In the first part of this dissertation, blood compatibility of zwitterionic copolymers was investigated using the research model of material interfacial system. Zwitterionic monomer of sulfobetaine methacrylate (SBMA) and anionic monomer of 11-mercaptoundecyl sulfonic acid (SA) were used to prepare zwitterionic copolymers with anionic block using atom transfer radical polymerization (ATRP). A surface with cationic polymer brushes was used to immobilize the prepared copolymers and study their zwitterionic shielding effects on the blood compatibility as contacting with human blood. Results showed that a positively charged surface covered with zwitterionic copolymer of PSA20-b-PSBMA40 performs a good resistance of platelet activation and blood cell attachment. This is due to the formation of hydration layer around the zwitteironic polymer chains. It indicates that zwitterionic groups may have a shielding effect on positively charged groups to improve their blood compatibility.
In the second part of this dissertation, gene delivery control of zwitterionic copolymers was investigated using the research model of solution system. Zwitterionic monomer of SBMA and cationic monomer of dimethylaminoethyl methacrylate (DMAEMA) were used to prepare zwitterionic copolymers with cationic block using ATRP. Three copolymer samples with different ratios of monomer composition (PSBMA20-b-PDMAEMA10; PSBMA20-b-PDMAEMA20; PSBMA20-b-PDMAEMA40) were used as gene carriers. Zwitterionic copolymers of PSBMA-b-PDMAEMA with cationic block was used to form a nano-complex conjugate with negatively charged plasmid DNA and study the zwitterionic shielding effects on their blood compatibility and transfect efficiency as gene carrier contacting with human blood. Results of hemolysis and blood cloting showed that gene carriers with zwitterionic PSBMA blocks perform good zwitterionic shielding and result in excellent blood compatibility. Results of gene trasfection into cells showed that gene-delivery carriers prepared from PSBMA20-b-PDMAEMA10 with plasmid DNA at N/P=5 perform excellent transfect efficiency and high cell activity.

Reference ( 46 ) 〈TOP〉

1. Chang, Y.; Cheng, T. Y.; Shih, Y. J.; Lee, K. R.; Lai, J. Y., Biofouling-resistance expanded poly(tetrafluoroethylene) membrane with a hydrogel-like layer of surface-immobilized poly(ethylene glycol) methacrylate for human plasma protein repulsions. Journal of Membrane Science 2008, 323, 77-84.
連結：
2. Chang, Y.; Chen, S.; Yu, Q.; Zhang, Z.; Bernards, M.; Jiang, S. Y., Development of Biocompatible Interpenetrating Polymer Networks Containing a Sulfobetaine-Based Polymer and a Segmented Polyurethane for Protein Resistance. Biomacromolecules 2007, 8, 122-127.
連結：
3. Chang, Y.; Chen, W. Y.; Yandi, W.; Shih, Y. J.; Chu, W. L.; Liu, Y. L.; Ruaan, R. C.; Higuchi, A., Dual-thermoresponsive phase behavior of blood compatible zwitterionic copolymers containing nonionic poly(N-isopropyl acrylamide). Biomacromolecules 2009, 10, 2092-2100.
連結：
4. Chang, Y.; Shih, Y. J.; C.Y. Ko; Jhong, J. F.; Liu, Y. L.; Wei, T. C., Hemocompatibility of poly(vinylidene fluoride) membrane grafted with network-like and brush-like antifouling layer controlled via plasma-induced surface PEGylation. Langmuir 2011, 26, 5445-5455.
連結：
5. Chang, Y.; Shu, S. H.; Chu, C. W.; Shih, Y. J.; Ruaan, R. C.; Chen, W. Y., Hemocompatible mixed-charge copolymer brushes of pseudo-zwitterionic surfaces resistant to nonspecific plasma protein fouling. Langmuir 2010, 26, 3522-3530.
連結：

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