SBIR Phase I: A Novel Method for Identifying Synthetic Binding Agents for Targeting Drugs to Specific Tissues

这个小企业创新研究（SBIR）项目的更广泛的影响/商业潜力是开发一种筛选方法，以可靠地识别可用于靶向药物到特定组织或细胞类型的结合剂。靶向药物可以增加其有效性并减少其副作用，因此开发能够筛选可用于增强具有全身活性的药物的结合剂的方法非常重要。现有的方法并不试图复制使用结合剂的环境，因此在实验室中看起来很有希望的药物往往在临床中失败。该筛选方法将纳米级药物载体（即纳米载体）纳入筛选过程中，使其所附着的在筛选过程中表现良好的结合剂在实践中也有望表现良好。提出的这种可靠的药物靶向系统具有巨大的商业价值。一些分析人士认为，到2021年，纳米载体将占到1360亿美元纳米技术药物输送市场的40%。由于靶向药物递送相对于等效的非靶向系统的好处预计是巨大的，因此靶向纳米载体预计将占据这一巨大市场的大部分。该SBIR项目旨在生产一种靶向药物输送系统，这是同类中首个原位靶配体筛选程序。靶向给药是一种最有希望以最小副作用优化药物疗效的策略，但目前用于识别高特异性靶向配体的筛选技术存在两个缺点：(1)它们只能检测单个的高亲和力结合配体（而多种使用的组织良好、可控的多种低亲和力/高亲和力结合配体被认为能提供最佳的特异性和抑制）；(2)它们在筛选过程中呈现配体的方式与靶向药物配方中呈现配体的方式完全不同，这导致了高失败率。本项目开发的方法解决了这些问题，通过(a)产生一个使用精确控制的纳米载体的筛选库，每种类型都装饰有一组独特的相同靶向配体，以及(b)作为靶向递送载体或抑制剂，在筛选过程中确定对给定目标具有最佳优先结合亲和力的纳米载体。这是第一种利用这种原位配体筛选方法开发靶向纳米载体的方法。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project is the development of a screening method to reliably identify binding agents that can be used to target drugs to specific tissues or cell types. Targeting drugs can increase their effectiveness and reduce their side effects, thus it is important to develop methods that can screen for binding agents that can be used to enhance drugs that would otherwise have systemic activity. Existing methods do not attempt to replicate the environment in which binding agents are used, therefore agents that appear promising in the lab often fail in the clinic. The screening method incorporates a nano-scale drug carrier (i.e., nanocarrier) into the screening process, so that binding agents attached to it that perform well during screening can be expected to perform well in practice. A reliable drug targeting system of the type proposed could have enormous commercial value. Some analysts believe nanocarriers will account for 40% of a $136 billion nanotechnology-enabled drug delivery market by 2021. Because the benefits of targeted drug delivery over equivalent non-targeted systems are expected to be substantial, targeted nanocarriers are expected to account for most of this vast market.This SBIR project aims to produce a targeted drug delivery system that is a first-of-its-kind in situ target ligand screening procedure. Targeted drug delivery is one of the most promising strategies for optimizing drug efficacy with minimal side effects, but current screening techniques for identifying highly specific targeting ligands suffer two drawbacks: (1) they only detect individual, high-affinity binding ligands (whereas well-organized, controllable, multiple, low-affinity/high-affinity binding ligands used in plurality are thought to provide the optimal specificity and inhibition); and (2) the manner in which they present ligands during screening in no way approximates the way ligands are presented in a targeted drug formulation, which leads to a high failure rate. The method developed in this project remedies these issues by (a) producing a screening library that employs precisely controlled nanocarriers, each type decorated with a unique collection of identical targeting ligands, and (b) employing as a targeted delivery vehicle or inhibitor, the nanocarrier with the optimal preferential binding affinity for a given target as identified during screening. This is the first method for developing a targeted nanocarrier that employs this type of in situ ligand screening.