Continuously Variable Protein Delivery Using a Photoactivated Depot

项目摘要 像胰岛素这样的药物的给药需要不断变化的递送。这是因为 血糖本身是不断变化的，而胰岛素的需求量与 血液中的葡萄糖。临床上唯一一种允许连续可变给药的方法 像胰岛素这样的治疗性蛋白质是一个泵。泵可以改变治疗效果，但它们是在 高成本：患者外部的物理连接，即药物储存库所在的位置，以及 在患者体内，药物最终将在那里吸收。此连接位于 胰岛素泵的情况是插管或针头，它可能会移位、卷曲、卡住、感染和 最重要的是，植入后很快就会被生物污染。这导致了变数和不可预测 送货。相反，我们正在开发光活化仓库或PAD方法，并将其应用于 胰岛素的使用。通过垫片的方法，含有胰岛素的物质被注射到皮肤中，就像 普通胰岛素，但在体外的光源刺激之前保持不活跃 用光线通过皮肤注射物质以释放胰岛素。我们的第一代衬垫设计 通过光切接头将胰岛素连接到聚合物上。当来自LED的光脉冲点亮时 这种物质会释放胰岛素，释放的量与光线的量成正比。我们 已经证明，这些物质在糖尿病动物身上起到释放胰岛素和降低血液的作用 葡萄糖。尽管取得了这样的成功，这些第一代材料的性能使它们 不适合人类使用。具体地说，用来确保胰岛素保持在 注射部位构成了90%的物质，这意味着目前存在的总胰岛素少于 什么是人类功效所需要的。此外，胰岛素的低密度意味着 光分裂也是不够的。正因为如此，我们提出了多种方法来解决 这些问题。在特定的目标1中，我们正在创造多种新的衬垫材料，以消除聚合物 在我们的第一代材料中需要，在这样做的过程中创造出密度高得多的材料 是90%的胰岛素。在《特定目标2》中，我们加入了新的光切割链接器，它将发布 使用更高波长的光的胰岛素。这将增加到达 由于更长波长的光可以穿透组织，因此胰岛素的释放更容易 更容易。最后，在具体目标3中，我们正在仔细检查这些新材料的能力 控制糖尿病动物的血糖。通过执行这三个目标，我们预计将创建一个 一种新的革命性的连续可变蛋白质输送方法，将 侵入性，并最大限度地使治疗与患者需求紧密匹配。 -- -- 相关性： -- 这项拟议的工作计划的成功完成将创造一种新的治疗方法，以帮助管理胰岛素治疗。 它有效地消除了大多数正常情况下需要的注射，或者减少了泵的安装和使用的需要。 血糖的变化。这一趋势为进一步提高人们的生活质量和生活质量提供了潜在的途径。 依赖胰岛素维持生命的糖尿病患者的健康问题。

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.