pH Sensitive Complex Hydrogels for Protein Drug Release

描述(由申请人提供)：这是一份竞争性续签申请，申请RO1 EB000246-17，用于继续我们的研究，利用一系列具有独特性质的新型生物聚合物络合载体和先进的控制释放系统，对药物、多肽和蛋白质经粘膜传递的基本理解进行研究。成功的蛋白质药物口服给药系统可能导致新疗法的开发，提高患者的依从性和疗效。我们团队开发了一种新型的聚合物络合水凝胶，它由聚乙二醇链接枝在聚甲基丙烯酸主链上组成。这些新系统此后被命名为P(MAA-g-EG)，作为胰岛素、降钙素和生长激素的口服载体显示出极大的前景。先前的研究已经证实，这些系统很有希望成为口服胰岛素的候选药物。然而，除了胰岛素之外，我们最近的工作和注意力现在集中在提高口服蛋白质的生物利用度的持续策略上。在这个相互竞争的更新方案中，我们打算采用的方法包括：(I)开发进一步的策略来保护GI管腔中的蛋白质；(Ii)加强蛋白质通过GI管腔的运输；以及(Iii)通过增强生物黏附来增加上小肠的滞留时间。虽然之前已经研究过一些使用胰岛素的策略取得了一定的成功，但在这项工作中，我们将寻求新的策略，这些策略可能会比我们之前的胰岛素研究取得重大进展。此外，我们打算进一步开发这些络合水凝胶，用于口服其他治疗蛋白，如降钙素和生长激素。 与公众健康相关：人们普遍认为，由于胃肠道的保护性质和胃肠道中酶的广泛蛋白分解活性，口服胰岛素、降钙素和生长激素等蛋白质药物是不可能的。我们已经开发了一种新型的络合水凝胶系统，该系统经过精心设计，可以保护胃肠道中的蛋白质药物，并增强药物进入血液的运输。成功的蛋白质药物口服给药系统可能导致新疗法的开发，提高患者的依从性和疗效。

DESCRIPTION (provided by applicant): This is a resubmission of a competing renewal proposal of grant RO1 EB000246-17 for the continuation of our studies on the fundamental understanding of transmucosal delivery of drugs, peptides and proteins using a series of novel biopolymeric complexation carriers with unique properties and in advanced controlled release systems. It has generally been believed that peptides and proteins such as insulin cannot be administered via the oral route because of their degradation by the proteolytic enzymes in the gastrointestinal tract and their extremely slow rate of transport across the mucosal membrane. A successful oral delivery system for protein drugs could lead to the development of new therapeutics with increased patient compliance and efficacy. Our group has developed a new class of polymeric complexation hydrogels comprised of poly (ethylene glycol) (PEG) chains grafted on poly (methacrylic acid) (PMAA) backbone chain. The new systems, henceforth designated as P (MAA-g-EG), have shown extreme promise as oral delivery vehicles for insulin, calcitonin, and growth hormone. Prior studies have established that these systems are promising candidates for oral delivery of insulin. Yet, our more recent work and attention is now focused on continued strategies for enhancing the bioavailability of oral delivered proteins, in addition to insulin. The methodologies we intend to pursue in this competing renewal proposal include: (i) developing further strategies for protection of the protein in the GI lumen; (ii) enhancing transport of the proteins across the GI lumen; and (iii) increasing the residence times in the upper small intestine through enhanced bioadhesion. While some strategies have been previously investigated with moderate success using insulin, in this work, we will pursue novel strategies that may provide significant advances over our prior studies with insulin. Additionally, we intend to further develop these complexation hydrogels for oral delivery of other therapeutic proteins such as calcitonin and growth hormone. PUBLIC HEALTH RELEVANCE: There is a general scientific belief that oral delivery of protein drugs such as insulin, calcitonin, and growth hormone is impossible due to the protective nature of the GI tract and extensive proteolytic activity of enzymes in the GI tract. We have developed a novel, complexation hydrogel system that has been engineered to protect the protein drugs in the GI tract and enhance transport of the drugs into the bloodstream. A successful oral delivery system for protein drugs could lead to the development of new therapeutics with increased patient compliance and efficacy.