Supramolecular Strategies for the Controlled Release of Protein Drugs

项目摘要 一种药物的疗效直接取决于它的给药方式，这影响到它的各个方面 药代动力学特性。生物制药，包括蛋白质类药物(例如，胰岛素、人体生长 因子)和抗体药物结合物(ADC)，为日益广泛的 治疗组合，但它们在配制和交付过程中极易失活。 亲和力控制释放是最有前景的蛋白质药物传递策略之一 (ACR)，它允许在中性水环境中和在很大程度上 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 固定在聚合物基质上的伙伴可延长药物释放。释药速度直接取决于 关于络合物的结合亲和力。然而，特定蛋白质的结合伙伴通常不是 可用，并且根据所需的应用程序定制绑定属性需要具有挑战性的开发 工作。这项拟议的研究试图利用超常的药物释放来完全控制药物的释放速度。 合成的宿主瓜环(Q7)的性质。Q7将水溶液中的有机客体与 Kd值从毫摩尔到全摩尔不等。这种对绑定亲和力进行编程的独特能力将 实现两个目的，具体地说，通过将药物连接到水凝胶中来控制药物释放 所需亲和力的客体和用Q7修饰水凝胶，并通过引入竞争性粘结剂 控制绑定亲和力。如果成功，这项拟议的研究将产生新颖而普遍的解决方案 涉及控制蛋白质药物从相容骨架中的持续释放的问题。会的 与本科生合作出版5-6篇论文，显著提升生物医学 三一大学的研究文化。

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.