Exploiting Membrane Lipidation for Advanced Drug Delivery

药物化学的一个基本概念是药物通过血脑屏障的能力。血脑屏障是一层细胞，它限制了分子从血流进入神经系统的能力。一些分子，如营养物质，能够通过使用特定的转运体选择性地穿过血脑屏障。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，疏水性（脂溶性）更强的分子更容易穿过屏障。然而，如果分子过于疏水，它们就不溶于水。通过血脑屏障的能力和溶解度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，当疏水性增加到最佳值时，由于更容易通过血脑屏障进行分配，活动增加。当疏水性超过最佳值时，水溶性成为限制因素，活性降低。该项目的主要目标是提供一种新的药物递送方法，利用分子与细胞膜中的脂质固有的反应性。高可溶性（低疏水性）化合物只有在到达靶细胞膜（如血脑屏障中的细胞膜）后才会转化为疏水衍生物。一旦穿过屏障，疏水衍生物将在细胞内转化为可溶化合物。这种方法将特别使高极性化合物能够穿过血脑屏障，并破坏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位点开发具有高靶向选择性的药物。

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.