Continuously Variable Protein Delivery Using a Photoactivated Depot

项目摘要 胰岛素等药物的给药需要连续可变的输送。这是因为 血糖本身是连续变化的，胰岛素需求量与血糖水平平行。 血液中的葡萄糖。临床上唯一允许连续可变输送的方法是 治疗性蛋白质如胰岛素是一个泵。泵可以改变治疗递送，但它们以一定的速率这样做。 高成本：药物储存器所在的患者外部的物理连接，以及 在病人体内，药物吸收将最终发生。这种连接在 胰岛素泵的情况是套管或针，其可能被移位、卷曲、钩住、感染， 最重要的是，在植入后迅速地被生物污染。这导致了变量和不可预测的 交付.相反，我们正在开发光活化仓库或PAD方法，并将其应用于 使用胰岛素。通过PAD方法，将含有胰岛素的材料注射到皮肤中，就像 正常的胰岛素，但保持不活动，直到光源是体外刺激 通过皮肤注射材料，并用光来释放胰岛素。我们的第一代PAD设计 将胰岛素通过光裂解接头连接到聚合物上。当LED发出的光脉冲亮起时， 这种物质，胰岛素被释放，释放的量与光量成正比。我们 已经证明，这些材料在糖尿病动物中起作用，释放胰岛素并减少血液中的 葡萄糖尽管取得了这一成功，但这些第一代材料的性能使它们成为 不适合人类使用。具体地说，用于确保胰岛素停留在 注射部位占材料的> 90%，这意味着存在的总胰岛素小于 人类功效所需要的东西。此外，低密度的胰岛素意味着， 光裂解也是不够的。正因为如此，我们提出了多种方法来解决 这些问题在具体目标1中，我们正在创造多种新的PAD材料，消除聚合物 我们的第一代材料所需的，并在这样做创造更高密度的材料， 是90%的胰岛素在Specific Aim 2中，我们正在整合新的光切割连接器， 使用更高波长的光来制造胰岛素。这将增加到达的光量。 由于较长波长的光穿透组织， 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，我们期望创造一个 一种新的革命性方法，可连续可变蛋白质输送， 侵入性，并最大限度地密切配合治疗与病人的要求。 相关性 这项工作的成功完成将创造一种新的胰岛素给药方法， 有效地消除了通常所需的大部分注射或泵的需要， 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。

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.