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Continuously Variable Protein Delivery Using a Photoactivated Depot

使用光激活库进行连续可变的蛋白质递送

基本信息

批准号：
10606514
负责人：
SIMON H FRIEDMAN
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-03-31
项目状态：
未结题

项目摘要

Project Summary The administration of drugs like insulin requires continuously variable delivery. This is because blood glucose is itself continuously varying, and the insulin requirement parallels the amount of glucose in the blood. The only clinically used method to permit continuously variable deliver of therapeutic proteins like insulin is a pump. Pumps can vary therapeutic delivery but they do so at a high cost: a physical connection of the outside of the patient, where the drug reservoir resides, and the inside of the patient, where drug absorption will ultimately take place. This connection in the case of insulin pumps is a cannula or needle, which can be dislodged, crimped, snagged, infected and most importantly, rapidly gets biofouled after implantation. This leads to variable and unpredictable delivery. Instead, we are developing the Photoactivated Depot or PAD approach and applying it to insulin use. With the PAD approach, an insulin containing material is injected into the skin, just like regular insulin, but remains there inactive until a light source that is outside the body stimulates the injected material through the skin with light to release insulin. Our first generation PAD designs linked insulin to a polymer via a light-cleaved linker. When a pulse of light from an LED illuminates this material, insulin is released, and the amount released is proportional to the amount of light. We have demonstrated that these materials work in diabetic animals to release insulin and reduce blood glucose. Despite this success, these first generation materials have performance that makes them untenable for human use. Specifically, the linked polymer that is used to insure that insulin stays at the site of injection makes up >90% of the material, meaning that the total insulin present is less than what is needed for human efficacy. In addition, the low density of insulin means that the rate of photo-cleavage is also insufficient. Because of this, we are proposing multiple approaches to address these issues. In Specific Aim 1 we are creating multiple new PAD materials that eliminate the polymer required in our first generation materials, and in so doing create much higher density materials that are 90% insulin. In Specific Aim 2 we are incorporating new light-cleaved linkers that will release insulin using higher wavelengths of light. This will increase the amount of light that reaches the depot, and hence the ease of insulin release, because longer wavelengths of light penetrate tissues more easily. Finally, in Specific Aim 3 we are closely examining these new materials for their ability to control blood glucose in diabetic animals. By executing these three aims, we anticipate creating a new and revolutionary approach to continuously variable protein delivery, one that minimizes invasiveness, and maximizes the close matching of therapeutic with patient requirements. Relevance The successful completion of the proposed work will create a new method to administer insulin that effectively eliminates most of the injections normally required or the need of a pump and reduces variations in blood sugar. This has the potential to improve both the quality of life and the quality of health of diabetics who depend on insulin to live.

项目概要胰岛素等药物的给药需要连续可变的输送。这是因为血糖本身是不断变化的，胰岛素的需求量与胰岛素的量平行血液中的葡萄糖。临床上唯一使用的允许连续可变输送的方法胰岛素等治疗性蛋白质是一个泵。泵可以改变治疗输送，但它们的速度是不同的高成本：药物储存器所在的患者外部的物理连接，以及患者体内，药物最终发生吸收的地方。此连接在胰岛素泵的外壳是插管或针头，它们可能会移位、卷曲、卡住、感染和最重要的是，植入后会迅速生物污染。这会导致变化和不可预测的情况送货。相反，我们正在开发光激活仓库或 PAD 方法并将其应用于胰岛素的使用。通过 PAD 方法，将含有胰岛素的材料注射到皮肤中，就像常规胰岛素，但保持不活动状态，直到体外光源刺激通过光将注射材料通过皮肤释放胰岛素。我们的第一代 PAD 设计通过光裂解连接体将胰岛素连接到聚合物上。当 LED 发出的光脉冲亮起时这种物质，胰岛素被释放，释放量与光量成正比。我们已经证明这些材料可以在糖尿病动物中发挥作用，释放胰岛素并减少血液葡萄糖。尽管取得了这一成功，这些第一代材料的性能使其不适合人类使用。具体来说，用于确保胰岛素保持在注射部位占材料的 90% 以上，这意味着存在的总胰岛素少于人类功效需要什么。此外，胰岛素的低密度意味着胰岛素的速率光裂解也不充分。因此，我们提出多种方法来解决这些问题。在具体目标 1 中，我们正在创造多种新型 PAD 材料，以消除聚合物我们第一代材料所需的材料，这样做创造出密度更高的材料 90%是胰岛素。在 Specific Aim 2 中，我们正在整合新的光切割连接器，该连接器将释放使用更高波长的光来注射胰岛素。这将增加到达的光量储存，因此易于释放胰岛素，因为较长的光波长可以穿透组织更容易。最后，在具体目标 3 中，我们正在仔细研究这些新材料的能力控制糖尿病动物的血糖。通过实现这三个目标，我们预计创建一个连续可变蛋白质递送的新的革命性方法，一种最大限度地减少侵入性，并最大化治疗与患者需求的密切匹配。关联成功完成拟议的工作将创造一种新的胰岛素管理方法，有效地消除了通常所需的大部分注射或泵的需要，并减少了血糖的变化。这有可能提高生活质量和生活质量依赖胰岛素生存的糖尿病患者的健康。