STTR Phase I: Developing a novel drug delivery system to enable an oral peptide based drug for kidney stones

该STTR项目的更广泛的影响/商业潜力是开发一种由肽负载的水凝胶纳米颗粒组成的新型药物递送系统，用于靶向和持续向肠道释放治疗肽。胃肠道系统和肠道微生物组已成为人类健康的关键驱动因素，为治疗食物过敏、真菌感染、炎症性肠病和高尿酸血症等疾病提供了新的机会。然而，需要一类新的药物系统来靶向这些疾病的局部生物学。第一个适应症是高尿酸和相关的复发性肾结石和肾脏疾病。在美国，草酸钙肾结石（KS）患者超过2700万（影响1/5的男性和1/11的女性），全球发病率甚至更高，KS是一种没有有效药物的医疗保健流行病。芝加哥大学最近的发现揭示了通过需要在肠道中局部作用的新型肽来治疗高尿酸的机会。因此，独特的肽负载水凝胶纳米颗粒药物递送系统可以为数百万高尿酸患者提供一流的治疗。更重要的是，该药物系统为其他困难的胃肠道疾病的口服、局部递送的肽治疗打开了大门，创造了实质性的医疗保健和经济收益。该STTR项目正在开发一种创新的药物递送系统，该系统由肽负载的水凝胶纳米颗粒（PLHN）组成，作为将新型肽递送到肠上皮的载体，最终使一流的口服药丸能够预防和治疗高尿症和相关的肾结石（KS）。一旦递送，纳米颗粒将粘附到肠粘膜并缓慢释放肽，刺激肠草酸盐分泌，从而降低血浆和尿草酸盐，从而防止KS形成。这种递送将使肽能够立即作用于肠上皮以诱导草酸盐分泌，然后被蛋白水解酶降解，模拟肽所来源的肠道细菌的行为。研究目标是：1.开发PLHN用于持续和局部递送肽至肠上皮。将定量肽释放动力学以确保4周的释放持续时间。2.表明PLHN，直肠给予灌肠剂和口服管饲法，将提供一个局部/持续的方式的肽到肠上皮细胞，他们将显着降低血浆和尿草酸盐在高血压和高尿酸小鼠的水平。与每天两次给药相比，每3天给药一次同样可以降低尿液和血浆草酸盐水平，这将证明可持续释放性。该奖项反映了NSF的法定使命，并且通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this STTR project is to develop a novel drug delivery system composed of peptide-loaded hydrogel nanoparticles for targeted and sustained therapeutic peptide release to the intestine. The gastrointestinal system and gut microbiome have emerged as critical drivers of human health, offering new opportunities to treat diseases such as food allergies, fungal infections, inflammatory bowel disease, and hyperoxaluria. However, a new class of drug systems are required to target the local biology of these diseases. The first indication pursued is hyperoxaluria and associated recurrent kidney stones and kidney diseases. With over ~27M calcium oxalate kidney stone (KS) patients in the U.S. (affecting 1 in 5 men and 1 in 11 women) and even higher global incidence, KS is a healthcare epidemic with no effective medication. Recent discoveries at the University of Chicago revealed the opportunity to treat hyperoxaluria through novel peptides that require local action in the intestine. Thus, a unique peptide-loaded hydrogel nanoparticle drug delivery system can enable a first-in-class therapeutic for the millions of patients with hyperoxaluria. More importantly, this drug system opens the door for additional orally administered, locally delivered, peptide therapeutics for other difficult gastrointestinal conditions, creating substantial healthcare and economic gains.This STTR project is developing an innovative drug delivery system consisting of peptide-loaded hydrogel nanoparticles (PLHN) as a vehicle to deliver novel peptides to the intestinal epithelium, ultimately enabling a first-in-class oral pill to prevent and treat hyperoxaluria and related kidney stones (KS). Once delivered, the nanoparticles will adhere to the intestinal mucosa and slowly release the peptides, stimulating intestinal oxalate secretion, thereby lowering plasma and urine oxalate and hence preventing KS formation. Such delivery will enable peptides to immediately act on the intestinal epithelium to induce oxalate secretion, before being degraded by proteolytic enzymes, mimicking the behavior of a gut bacteria, from which peptides were derived. Research objectives are: 1. Develop PLHN for sustained and localized delivery of peptides to the intestinal epithelium. Peptide release kinetics will be quantified to ensure a 4-week release duration. 2. Show that the PLHN, given rectally as enemas and orally by gavage, will deliver the peptides to the intestinal epithelium in a localized/sustained manner, and that they will significantly reduce plasma and urine oxalate levels in hyperoxalemic and hyperoxaluric mice. Showing dosing once every 3 days similarly reduces urine and plasma oxalate levels compared to twice daily dosing will demonstrate sustained releasability.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.