Establishing a Design Blueprint for Nanomedicines for Oral Drug Delivery

口服给药是迄今为止最优选的服药方式。其他给药途径与患者可接受性和依从性降低以及疼痛、高成本和风险（例如注射）相关。患者对口服给药的偏好反映在药物开发过程中，其中新的药物化合物几乎总是以口服递送为目标（在用于局部治疗的药物的情况下存在例外，例如用于皮肤状况的乳膏和用于哮喘的吸入器）。然而，目前不可能通过口服途径递送所有药物。这在很大程度上是因为一些药物1）易于在胃环境中降解，2）不能以足够的水平穿过肠壁以显示临床益处（药物需要在血液中才能发挥全身治疗作用）。一个很好的例子是胰岛素：需要胰岛素治疗的患者通常需要每天注射2-5次作为终身治疗。该项目的目标是建立一个工程药物载体的设计蓝图，使或改善口服药物输送。本项目中考虑的药物载体是基于极小的颗粒（直径相当于人头发厚度的千分之一）或具有穿过肠上皮的能力的纳米颗粒，其携带药物货物穿过肠壁。之前已经提出使用纳米颗粒来实现口服药物递送。然而，一个关键的问题是，纳米颗粒，类似于一些药物，如胰岛素和抗体为基础的药物，不容易穿过肠壁或上皮。这是因为肠上皮的解剖结构，其由一层紧密堆积和相互连接的细胞组成，形成栅栏，对物质从肠腔到血液的运动构成了强大的屏障。该项目的核心是合理设计和制造易于穿过肠上皮的纳米颗粒。为此，我们将首先创造一些化合物（肽），旨在通过通常转运生物分子的受体穿过肠组织屏障（上皮）。然后，我们将以不同的数量将这些“运输使能肽”附着在不同大小的纳米颗粒表面。将在基于在实验室中生长的人类肠上皮细胞的肠模型中评估所得系统，模拟肠组织。在以前的工作中，申请人已经确定了支持当前申请的一些关键技术进步。因此，拟议的项目是基于申请人的长期努力-包括与当前提案相关的先前工作-以改善口服药物递送。我们将创建一些不同的系统，使用基于以前的经验和初步数据的合理设计方法，并以稳健的方式对其进行测试。这将使我们能够识别出“装饰”有运输使能肽的纳米颗粒，这些肽很容易穿过肠组织屏障。这些系统的特征（例如，纳米颗粒尺寸和转运使能肽的特性）使得能够跨肠组织转运，这将产生具有跨肠壁携带药物货物的能力的纳米颗粒的设计蓝图，使得能够口服施用目前不能通过该途径服用的药物。

Oral administration is by far the most preferred way of taking medicines. Other drug administration routes are associated with decreased patient acceptability and compliance, as well as pain, high costs and risks (e.g. injections). Patient preference for oral administration is reflected in drug development processes, whereby a new drug compound is almost always aimed for oral delivery (exceptions exist in the case of drugs for local treatment such as creams for skin conditions and inhalers for asthma). However, currently it is not possible to deliver all drugs through the oral route. This is largely because some drugs are 1) prone to degradation in the stomach environment and 2) do not cross the intestinal wall in sufficient levels to show clinical benefit (drugs need to be in the blood to exert systemic therapeutic effect). A good example is insulin: patients requiring insulin therapy usually need between 2-5 injections per day as lifelong therapy. This project's ambition is to establish a design blueprint for engineering drug carriers that enable or improve oral drug delivery. Drug carriers considered in this project are based on extremely small particles (diameters equivalent to 1/1000th of the thickness of a human hair) or nanoparticles with the ability to cross the intestinal epithelium, carrying the drug cargo across the intestinal wall.The use of nanoparticles to enable oral drug delivery has been proposed before. However, a key problem is that nanoparticles, similarly to some drugs such as insulin and antibody-based medicines, do not readily cross the intestinal wall or epithelium. This is because of the anatomy of the intestinal epithelium, which consists of a layer of closely packed and interconnected cells forming a fence which presents a formidable barrier to the movement of material from the intestinal lumen to blood. Central to this project is rational design and fabrication of nanoparticles that readily cross the intestinal epithelium. To this end, we will first create a number of compounds (peptides) designed to cross the intestinal tissue barrier (epithelium) through receptors that normally transport biological molecules. We will then attach these 'transport enabling peptides' in varying amounts to the surface of nanoparticles of different size. The resulting systems will be evaluated in an intestinal model based on human intestinal epithelium cells grown in the lab, mimicking the intestinal tissue. In previous work the applicant has identified a number of key technological advances that underpin the current application. The proposed project is therefore based on the applicant's long-standing efforts - including prior work pertinent to the current proposal - to improve oral drug delivery. We will create a number of different systems, using a rational design approach based on previous experience and preliminary data, and test them in a robust way. This will enable us to identify nanoparticles 'decorated' with transport enabling peptides that readily cross the intestinal tissue barrier. The characteristics of these systems (e.g. nanoparticle size and identity of transport enabling peptide) that enable transport across the intestinal tissue will result in a design blueprint for nanoparticles with the ability to carry drug cargo across the intestinal wall, enabling oral administration of drugs that currently cannot be taken by this route.