Supramolecular Strategies for the Controlled Release of Protein Drugs

项目摘要 药物的疗效直接取决于其给药方法，这影响其治疗的各个方面。 药代动力学特性生物制药，包括蛋白质药物（例如，胰岛素，人体生长 因子）和抗体药物偶联物（ADC），为越来越广泛的药物治疗提供了巨大的希望。 它们是治疗组合的一部分，但它们在配制和递送期间非常容易失活。 其中最有前途的策略，为蛋白质药物的输送是亲和控制释放 (ACR)，其允许在中性水性环境中配制蛋白质药物， 保持蛋白质的结构和功能。ACR利用药物与其结合的选择性相互作用 配偶体固定在聚合物基质上以延长药物释放。释放的速度直接取决于 对复合物的结合亲和力的影响。然而，给定蛋白质的结合伴侣通常不是 可用，并且根据所需应用定制结合特性需要具有挑战性的开发 工作这项拟议中的研究旨在利用特殊的药物释放速率来完全控制药物的释放速率。 合成主体葫芦[7]脲（Q7）的性质。Q7在水溶液中结合有机客体， Kd值范围从毫摩尔到阿托摩尔。这种独特的编程结合亲和力的能力将 能够实现两个目的，特别是通过将药物缀合到药物载体上来控制药物从水凝胶中释放。 通过引入具有所需亲和力的客体，并用Q7改性水凝胶，并通过引入竞争性结合剂， 控制结合亲和力。如果成功，拟议的研究将产生新颖和通用的解决方案 涉及控制蛋白质药物从相容基质中持续释放的问题。它将 与本科生合著者一起发表5-6篇论文，并大大提高生物医学 Trinity大学的研究文化。

Project Summary The efficacy of a drug depends directly on its method of delivery, which influences all aspects of its pharmacokinetic properties. Biopharmaceuticals, including protein drugs (e.g., insulin, human growth factor) and antibody drug conjugates (ADCs), offer tremendous promise for an increasingly broad portfolio of treatments, but they are highly susceptible to deactivation during formulation and delivery. Among the most promising strategies for the delivery of protein drugs is affinity controlled release (ACR), which allows for the formulation of protein drugs in neutral aqueous environments and largely preserves protein structure and function. ACR uses the selective interaction of a drug with its binding partner immobilized on a polymer matrix to prolong drug release. The rate of release depends directly on the binding affinity of the complex. Binding partners for a given protein, however, are often not available, and tailoring the binding properties to a desired application requires challenging development work. The proposed research seeks to gain full control of the rate of drug release using the extraordinary properties of the synthetic host cucurbit[7]uril (Q7). Q7 binds organic guests in aqueous solution with Kd values ranging from millimolar to attomolar. This unique ability to program the binding affinity will enable two aims, specifically the control of drug release from a hydrogel by conjugating the drug to a guest of desired affinity and modifying the hydrogel with Q7, and by introducing competitive binders to control the binding affinity. If successful, the proposed research will yield novel and general solutions to the problem of controlling the sustained release of protein drugs from compatible matrices. It will generate 5-6 publications with undergraduate coauthors and considerably elevate the biomedical research culture at Trinity University.