pH Sensitive Complex Hydrogels for Protein Drug Release

描述（由申请人提供）：这是对RO1 EB000246-17的竞争性续期申请的重新提交，以继续我们使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释系统对药物、肽和蛋白质的经黏膜递送的基本理解的研究。人们普遍认为，肽和胰岛素等蛋白质不能通过口服给药，因为它们在胃肠道中被蛋白水解酶降解，而且它们在粘膜上的转运速度极慢。一个成功的蛋白质药物口服给药系统可能会导致新的治疗方法的发展，提高患者的依从性和有效性。本课者组开发了一种由聚乙二醇（PEG）链接枝聚甲基丙烯酸（PMAA）主链组成的新型聚合物络合水凝胶。新的系统，从此被命名为P (MAA-g-EG)，作为口服给药胰岛素、降钙素和生长激素的载体显示出极大的希望。先前的研究已经确定，这些系统是口服胰岛素的有希望的候选者。然而，我们最近的工作和注意力现在集中在提高口服给药蛋白的生物利用度的持续策略上，除了胰岛素之外。我们打算在这一竞争性更新提案中采用的方法包括：(i)制定进一步保护胃肠道管腔中蛋白质的策略；（ii）增强蛋白质在胃肠道腔内的转运；（三）通过增强生物黏附，增加在上小肠的停留时间。虽然之前已经研究了一些使用胰岛素的策略，并取得了中等程度的成功，但在这项工作中，我们将寻求新的策略，这些策略可能会在我们之前的胰岛素研究中取得重大进展。此外，我们打算进一步开发这些络合水凝胶，用于口服递送其他治疗性蛋白质，如降钙素和生长激素。

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.