建立雙離子高分子修飾蛋白質技術與分析;Development and Characterization of Zwitterionization for Proteins

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Title:	建立雙離子高分子修飾蛋白質技術與分析;Development and Characterization of Zwitterionization for Proteins
Authors:	黃新棠;Huang, Hsin-Tang
Contributors:	生醫科學與工程學系
Keywords:	聚乙二醇化蛋白質;雙離子高分子聚合物;原子轉移自由基聚合;半衰期
Date:	2023-07-25
Issue Date:	2024-09-19 15:19:58 (UTC+8)
Publisher:	國立中央大學
Abstract:	根據報導與研究，我們可以發現許多聚乙二醇化的藥物廣泛地應用在臨床治療，是因為經修飾後的藥物可以增加在體內的半衰期並降低細胞毒性。然而，在最近的研究中發現，有些人體內已經產生抗聚乙二醇的抗體，抗體的存在降低了聚乙二醇化藥物的治療效果，並且在臨床報告中增加了過敏反應的風險。而在有些研究中發現，增加與聚乙二醇相關產品接觸的機會，會促進健康的人體產生抗聚乙二醇的抗體。在本研究第一部份中，選用 2-甲基丙烯醯氧基氧基乙基磷酸膽鹼 (MPC) 與 [2-(甲基丙烯酰氧基 )乙基 ]二甲基 -(3-磺丙基 )氨基甲酸銨 (SBMA)兩種單體透過原子轉移自由基聚合的方法，合成具有 N-羥基琥珀酰亞胺 (NHS) 末端的兩性離子聚合物此聚合物需有可以控制的分子量與窄的分子量分佈，並利用此雙離子高分子聚合物接合牛血清蛋白 (Bovine serum albumin, BSA)。研究第二部份中，使用小鼠作為動物實驗對象，注射藥品後，測量其體內血清中抗 BSA抗體濃度變化，以推估蛋白質經雙離子高分子聚合物 (pMPC, pSBMA) 這類材料接合後能否比只有 BSA注射時，有更好的體內半衰期，延長蛋白質在體內存留時間。經由實驗結果證明了相較常見的原子轉移自由基聚合電子轉移再生活化之原子轉移自由基聚合可以在除氧條件不佳的情況下，依然可以控制分子量與擁有窄的分子量分布，並經由小鼠實驗證明接枝雙離子高分子聚合物的蛋白質相較於未接枝雙離子高分子聚合物的蛋白質有較長的體內存留時間。雙離子高分子聚合物與蛋白質接枝後的能力提供新的藥物設計途徑並具有修飾市售蛋白質藥物功能與醫學應用上進一步發展的潛力。;PEGylated agents are broadly used in clinical therapy due to the increase in the half-life efficacy and decrease in the cytotoxicity. However, in the recent research, the existence of anti-PEG antibodies has been found, which deteriorates the efficacy of the therapeutic PEGylated drugs and enhances the risk of allergic reaction in some clinical reports. It has been found that the increasing exposure to PEG-related products will promote anti-PEG antibodies in the healthy human. In this research, we synthesized N-hydroxysuccinimide-terminated 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers and N-hydroxysuccinimide-terminated 2-(Methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide(SBMA) through atom transfer radical polymerization (ATRP). After synthesis, using Nuclear Magnetic Resonance spectrum to characterize the structure of polymer and calculate its molecular weights. Also, using Gel Permeation Chromatography to check molecular weights and polydispersity index. Then, Bovine serum albumin was used to conjugate with zwitterionic polymer. Finally, polymer-protein conjugates were introduced into mice to know their pharmacokinetics to investigate their circulation time. The experimental results showed that Activators regenerated by electron transfer atom transfer radical polymerization (ARGET-ATRP) compares to normal atom transfer radical polymerization (ATRP) has less critical deoxygenation for the polymerization to control the molecular weight of polymer and less polydispersity index, and experiment in mice proved that the protein-zwitterionic polymer conjugation had longer circulation time in body than the non-conjugation protein. The potential of zwitterionized therapeutic proteins was evaluated to justify their role in medical applications. More aggressively, the safety issue and biocompatibility of polymer-protein conjugates will be comprehensively identified and contemplated. A new avenue to molecular design for polymer-protein conjugates will be explored.
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