Biomimetic Hetero-Multivalent Binding Nanoparticles for Cell Recognition

纳米材料最吸引人的特性之一是它们作为药物载体的能力。它们可以将药物运送到这些药物无法到达的作用部位，这是基于它们的物理化学性质。然而，这种策略的一个基本问题是识别靶细胞的特异性。尽管文献中已经描述了纳米材料与细胞相互作用的一些原理，但它们几乎不允许纳米材料区分它在穿过生物体的过程中可能接触的靶细胞和非靶细胞。相比之下，病毒本质上也是纳米颗粒，它们已经发展出高度复杂的技术来处理目标细胞识别问题。他们使用几种不同类型的配体，这些配体一个接一个地与细胞表面的受体结合，以确认其身份。本项目的目标是在合成纳米材料中实现这种仿生杂多价结合。我们将研究两种设计策略。第一种方法将利用不同长度的聚乙二醇系链来安排两种受体配体在纳米颗粒表面的延迟可见性。第二种依赖于配体对细胞的初始识别，并通过其酶促激活纳米颗粒表面上的预配体的能力来确认细胞的身份。最终的目标是获得完全被靶细胞内化的粒子。系膜细胞可作为治疗靶点。它们在糖尿病肾病期间负责纤维化过程，糖尿病肾病是终末期肾脏疾病的主要原因。该项目旨在探索仿生颗粒作为药物载体的潜力，用于治疗难以获得治疗选择的疾病。

One of the fundamentally attractive properties of nanomaterials is their ability to serve as drug carriers. They can deliver drugs to sites of action that these would not be able to reach based on their physicochemical properties. However, a fundamental problem involved with this strategy is the specificity of recognizing the target cells. Even though a number of principles of nanomaterial interactions with cells have been described in the literature, they hardly allow a nanomaterial to distinguish between the target- and off-target cells that it may have contact to on its way through the organism. Viruses in contrast, which are essentially nanoparticles too, have developed highly sophisticated techniques to cope with the problem of target cell identification. They use several different types of ligands that bind one after another to receptors on the cell surface to confirm its identity. Goal of this project will be to implement this type of biomimetic hetero-multivalent binding in synthetic nanomaterials. We will work on two design strategies. The first will make use of polyethylene glycol tethers of different length to arrange for a delayed visibility of two receptor ligands on the nanoparticle surface. The second rests on the initial recognition of a cell by a ligand and the confirmation of the cell's identity by its ability to activate a proligand on the nanoparticle surface enzymatically. The ultimate goal will be to obtain particles that are internalized exclusively by their target cells. Mesangial cells will serve as therapeutic target. They are responsible for fibrotic processes during diabetic nephropathy the leading cause of end-stage kidney disease. The project is intended to explore the potential of biomimetic particles as a drug carrier for treating a disease for which therapeutic options are hardly available.