Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC , USA and.
J Drug Target. 2013 Dec;21(10):940-55. doi: 10.3109/1061186X.2013.847098.
It is well known that hydrophobic small molecules penetrate cell membranes better than hydrophilic molecules. Amphiphilic molecules that dissolve both in lipid and aqueous phases are best suited for membrane transport. Transport of biomacromolecules across physiological barriers, e.g. the blood-brain barrier, is greatly complicated by the unique structure and function of such barriers. Two decades ago we adopted a simple philosophy that to increase protein delivery to the brain one needs to modify this protein with hydrophobic moieties. With this general idea we began modifying proteins (antibodies, enzymes, hormones, etc.) with either hydrophobic fatty acid residues or amphiphilic block copolymer moieties, such as poy(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (pluronics or poloxamers) and more recently, poly(2-oxasolines). This simple approach has resulted in impressive successes in CNS drug delivery. We present a retrospective overview of these works initiated in the Soviet Union in 1980s, and then continued in the United States and other countries. Notably some of the early findings were later corroborated by brain pharmacokinetic data. Industrial development of several drug candidates employing these strategies has followed. Overall modification by hydrophobic fatty acids residues or amphiphilic block copolymers represents a promising and relatively safe strategy to deliver proteins to the brain.
众所周知，疏水性小分子比亲水性小分子更容易穿透细胞膜。既能溶解在脂质相又能溶解在水相的两亲性分子最适合用于膜转运。生物大分子跨生理屏障（如血脑屏障）的转运由于这些屏障的独特结构和功能而变得非常复杂。二十年前，我们采取了一种简单的理念，即要增加蛋白质向大脑的输送，就需要用疏水性基团对这种蛋白质进行修饰。基于这个总体思路，我们开始用疏水性脂肪酸残基或两亲性嵌段共聚物修饰蛋白质（抗体、酶、激素等），如聚（环氧乙烷）-聚（环氧丙烷）-聚（环氧乙烷）（泊洛沙姆或普朗尼克），最近又用聚（2-恶唑啉）。这种简单的方法在 CNS 药物输送方面取得了令人瞩目的成功。我们回顾了这些始于 20 世纪 80 年代苏联的工作，然后在美国和其他国家继续进行。值得注意的是，一些早期的发现后来得到了脑药代动力学数据的证实。随后，采用这些策略的几个候选药物已进入工业开发阶段。总的来说，用疏水性脂肪酸残基或两亲性嵌段共聚物进行修饰代表了一种有前途且相对安全的向大脑输送蛋白质的策略。
