離子對雙親分子(ion pair amphiphile, IPA)是由陰、陽離子型界面活性劑去除對離子後所形成具有兩條疏水性長碳鏈的雙親複合分子，可以自組裝成中空球型的液胞結構。成本低廉的陰陽離子液胞可取代傳統由磷脂質所形成的微脂粒，應用於藥物傳輸之載體。實驗研究指出，利用乙醇共溶劑所製備而成的陰陽離子液胞，在特定乙醇濃度範圍，有助於增加液胞穩定性。此外，於陰陽離子液胞中加入膽固醇，會影響液胞雙層膜之排列結構，提升機械強度，進而增加穩定性，並且擴展乙醇共溶劑使用的濃度範圍。然而，結合此兩種效應會形成複雜的相態，因此本研究利用分子動態模擬(molecular dynamics, MD)，從微觀的角度去分析於對稱碳鏈的長烷鏈三甲基—長烷鏈硫酸鹽(alkyltrimethylammonium-alkylsulfate，CnTMA+-CnS-) IPA雙層膜系統中添加乙醇及膽固醇對於結構、機械與相態性質之影響。從序列參數的分析中可知，增加酒精濃度可以引起疏水性區域排列之失序效應，並促使無序相(Lα)的生成，且短碳鏈IPA系統較易受滲入雙層膜中之酒精分子擾亂排列。此外，酒精共溶劑確實能降低雙層膜之機械強度。反之，膽固醇可以有效增強薄膜的機械強度，且對於不同鏈長IPA之排列序度產生不同的影響，於C12TMA-C12S系統中，膽固醇分子的長度小於IPA碳鏈長度，因此膽固醇添加於短碳鏈IPA系統會引起排列有序化。相反地，添加於長碳鏈之C16TMA-C16S系統中則是會引起失序效應。綜合乙醇及膽固醇對雙層膜之影響，發現高濃度膽固醇會抑制酒精滲入膜中；當XChol=0.5時，由於膽固醇會撐開IPA分子間距，酒精可靠近頭基，但仍無法滲入疏水性碳鏈區域。而滲入膜中酒精之含量和結構特性差異相關，其中膜中酒精數量與序度變化存在正相關性。由區域性IPA雙層膜厚度分析，發現到酒精會降低膜的局部厚度，且高濃度酒精造成雙重厚度分布。這些結果有助於判斷特定之乙醇與膽固醇組成下所形成的兩相共存現象。最後我們結合結構與機械特性之模擬數據，找出各相態之特徵值，進而定出C12TMA-C12S、C14TMA-C14S和C16TMA-C16S系統在乙醇共溶劑與膽固醇添加劑影響下之相圖。本研究所提出之IPA雙層膜分子觀點，有助於日後設計新型IPA液胞做為經皮藥物傳輸的載體之最適化配方組成。

Ion pair amphiphile (IPA) is a molecular complex composed of a pair of cationic and anionic amphiphiles. IPA can self-assemble into catanionic vesicles as potential drug carriers that are considered as low-cost liposome alternatives. Experimental results showed that the poor stability of catanionic vesicles can be improved by the way of ethanol co-solvent and cholesterol additive. Yet, the combination of ethanol and cholesterol can also induce complex phase behavior of IPA membranes. In this work, we utilized molecular dynamics (MD) simulation to examine the effect of ethanol co-solvent and cholesterol additive on the structural, mechanical, and phase properties of symmetrical alkyltrimethylammonium-alkylsulfate (CnTMA+-CnS-) IPA bilayer systems. Our result showed that increasing ethanol concentration can disrupt the packing order of the bilayers hydrophobic region and induces liquid-disordered phase formation. Also, the packing order of short-chained systems are easily disrupted by penetrated ethanol. Furthermore, the ethanol co-solvent can reduce mechanical strength of IPA membrane. In contrast, the cholesterol addition can enhance mechanical strength of the membrane but have complex alkyl chain ordering effects on IPA membranes in different chain lengths. The C12TMA-C12S IPA systems has shorter chains than cholesterol molecule, leading to an enhanced ordering effect even in gel phase membranes. In contrast, the C16TMA-C16S IPA systems is longer than cholesterol; and adding cholesterol can disrupt the alkyl chain packing order within the membrane. Combining both ethanol co-solvent and cholesterol additive, high XChol inhibits ethanol insertion within membrane. At XChol=0.5, cholesterol insertion induces the separation between IPA complexes, particularly within the hydrophilic region. Thus, ethanol can penetrate the head group region of the IPA membrane; yet ethanol still cannot permeate into the densely packed hydrophobic region. Furthermore, the number of permeate ethanol within the membrane hydrophobic region is highly correlated to the changes in the alkyl chain order parameters. Ethanol can also reduce the local bilayer thickness, leading to double membrane thickness distributions. These results helped confirm the coexistence of dual phases induced by cholesterol and ethanol. Based on the simulation results of structural and mechanical properties, we determined the characteristic values of different phases and proposed the phase diagrams for C12TMA-C12S, C14TMA-C14S and C16TMA-C16S systems under the effects of ethanol co-solvent and cholesterol additive. The molecular insights provided by our results can shed lights on future designs of novel ethosome-like IPA vesicles with most optimized formula as drug carriers for transdermal drug delivery applications.

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