Recently developed lipids with the trans-2-aminocyclohexanol (TACH) moiety represent unique pH-sensitive conformational switches (“flipids”) that can trigger the membrane of liposome-based drug delivery systems at lowered pH as seen in many pathological scenarios. A library of flipids with various TACH-based headgroups and hydrocarbon tails were designed, prepared, and characterized to systematically elucidate the relationship between their chemical structures and their ability to form and to trigger liposomes. Liposomes (fliposomes) consisting of a flipid, POPC and PEG-ceramide were stable at 4 °C, pH 7.4 for up to several months and yet released the encapsulated fluorophore in seconds upon acidification. The colloidal properties and encapsulation efficiencies of the fliposomes depended on the structure features of the flipids such as the polarity of the headgroups and the shape and fluidity of the lipid tails. The pH-triggered release also depended on the flipid structure, where shorter linear tails yielded more efficient release. The release of fliposomes was enhanced at different narrow pH ranges, depending on the basicity of the flipid headgroup, which can be estimated either by calculated pKa or by acid/base titration of the flipids while its conformation is monitored by ¹H NMR. The structure-activity relationship of the flipids supports “lipid tail conformational shortening” as the mechanism to disrupt lipid membranes and would provide great flexibility in the design of pH-sensitive drug delivery systems.

最近开发的脂质与反式-2-氨基环己醇（TACH）部分代表独特的pH敏感的构象转换（“脂质”），可以在降低的pH值下触发基于脂质体的药物递送系统的膜，如在许多病理情况下所见。设计，制备和表征具有各种基于TACH的头基和烃类尾基的类脂库，以系统地阐明其化学结构与其形成和触发脂质体能力之间的关系。由脂质，POPC和PEG-神经酰胺组成的脂质体（脂质体）在4°C，pH 7.4下稳定达数月之久，并且在酸化后几秒钟内释放出封装的荧光团。脂质体的胶体性质和包封效率取决于脂质体的结构特征，例如头基的极性以及脂质尾巴的形状和流动性。pH触发的释放还取决于流体结构，其中较短的线性尾部产生更有效的释放。在不同的较窄pH范围内，脂蛋白小体的释放有所增强，具体取决于脂蛋白首基的碱性，这可以通过计算的pKa或通过对脂蛋白进行酸/碱滴定来估算，而其构象可通过监测¹ H NMR。脂质的结构-活性关系支持“脂质尾部构象缩短”作为破坏脂质膜的机制，并在pH敏感药物递送系统的设计中提供极大的灵活性。