Exploiting Membrane Lipidation for Advanced Drug Delivery

药物化学中的一个基本概念是药物跨越血脑屏障的能力。血脑屏障是一层限制分子从血流进入神经系统的能力的细胞层。一些分子，如营养素，能够通过使用特定的转运蛋白选择性地越过血脑屏障。其他分子，如药物，由于其分子特性，必须非选择性地穿过血脑屏障。通常情况下，疏水性较强(脂溶性)的分子更容易通过屏障。然而，如果分子疏水性太强，它们就不能溶于水。这种跨越血脑屏障的能力和溶解性之间的紧张关系导致了药物疏水性和活性之间的抛物线关系。简单地说，随着疏水性的增加，直到最佳值，由于更容易通过血脑屏障进行分配，活性也会增加。当疏水性超过最佳值时，水的溶解性成为限制因素，活性降低。本项目的主要目标是提供一种新的药物释放方法，利用分子与细胞膜中脂质的内在反应性。高可溶性(低疏水性)化合物只有在到达其目标细胞膜时才会转化为疏水衍生物，例如血脑屏障中的细胞膜。一旦穿过屏障，疏水衍生物就会在细胞内转化回可溶性化合物。这种方法将特别使高极性化合物能够穿越血脑屏障，扰乱疏水性和药物活性之间的抛物线关系。我们的方法有可能在以前被认为难以或不可能到达的地点开发具有高靶点选择性的药物。

A fundamental concept in medicinal chemistry is the ability of a drug to cross the blood brain barrier. The blood brain barrier is a layer of cells that restricts the ability of molecules to pass from the blood stream into the nervous system. Some molecules, such as nutrients, are able to cross the blood brain barrier selectively through the use of specific transporters. Other molecules, such as drugs, must cross the blood brain barrier non-selectively by virtue of their molecular properties. Conventionally, molecules that are more hydrophobic (fat soluble) cross the barrier more easily. However, if molecules are too hydrophobic they are insoluble in water. This tension between ability to cross the blood brain barrier and solubility leads to a parabolic relationship between drug hydrophobicity and activity. In simple terms, as hydrophobicity increases, up to an optimal value, the activity increases due to more facile partitioning across the blood brain barrier. As hydrophobicity increases above the optimal value, aqueous solubility becomes a limiting factor and the activity decreases.The primary goal of this project is to furnish a new method for drug delivery that exploits the inherent reactivity of molecules with lipids in cell membranes. Highly soluble (low hydrophobicity) compounds will be transformed into hydrophobic derivatives only upon reaching their target cell membranes, such as the membranes of cells in the blood brain barrier. Once across the barrier, the hydrophobic derivatives will be converted back to soluble compounds inside the cell. This approach will specifically enable highly polar compounds to traverse the blood brain barrier and disrupt the parabolic relationship between hydrophobicity and drug activity. Our approach has the potential to enable the development of drugs with high target selectivity at sites that would previously have been considered difficult or impossible to reach.