Targeted Nanogel based Therapies for Chronic Recurrent Urinary Tract Infections

项目摘要 复发性尿路感染（鲁蒂）是最常见的细菌感染之一， 估计仅在美国就有268，000例。细菌如尿路致病性大肠杆菌（UPEC）遵循一个 多步骤的致病循环，其中细胞内细菌群落（生物膜）在细胞内建立 感染期间的尿道炎。条件致病菌铜绿假单胞菌也形成高度耐药 生物膜并感染长期插管的患者。目前的预防性抗生素治疗方案不能 进入尿道内的长寿细胞内细菌储库使得抗生素无效， 有助于抵抗。我们提出了一种治疗鲁蒂的新方法，其中靶向纳米凝胶具有高的 多种抗生素的装载可以经尿道递送到膀胱壁。我们最近发表了 其中证明了当共价缀合在细胞膜上时，细胞穿透肽CGCKRK 生物相容性丙烯酸纳米凝胶的表面，可以有效地结合和渗透裸露/受伤的小鼠 膀胱壁，并成功地将药物模拟物递送到鼠尿道内。基于体外 和体内初步收集的数据，我们已经详细介绍了一个项目计划，其中纳米凝胶网络， 穿透尿道，使抗生素的持续输送，以成功地治疗rUTIs， 精心设计的我们将通过1）合成具有增强能力的纳米凝胶来扩展我们的初步方法， 将治疗相关剂量的抗生素（环丙沙星和庆大霉素）封装并释放在 生理学相关的时间尺度和体外测试; 2）建立成功治疗鲁蒂的条件 在体内鼠感染模型中。描述的靶向膀胱递送系统的额外潜力 该建议是同时递送多种治疗剂，例如单一抗生素， 抗生素混合物或生物膜分散分子。描述了一种膀胱输送系统的开发， 也可用于推进其它膀胱病变的治疗。

PROJECT SUMMARY Recurrent urinary tract infections (rUTI) are among the most common bacterial infections, causing an estimated 268,000 cases in the US alone. Bacteria such as the uropathogenic Escherichia coli (UPEC) follow a multistep, pathogenic cycle in which intracellular bacterial communities (biofilms) are established within the urothelium during infection. The opportunistic pathogen Pseudomonas aeruginosa also forms highly resistant biofilms and infects chronically-catheterized patients. The inability of current prophylactic antibiotic regimens to access the long-lived intracellular bacterial reservoirs within the urothelium renders antibiotics inefficient while contributing to resistance. We propose a novel approach to treat rUTI in which targeted nanogels with high loading of multiple antibiotics can be delivered transurethrally to the bladder wall. We recently published results in which it was demonstrated that the cell penetrating peptide CGCKRK, when covalently conjugated on the surface of a biocompatible acrylic nanogel, can efficiently bind and penetrate the denuded/injured murine bladder wall in-vivo and successfully deliver a drug mimic within the murine urothelium. Based on the in vitro and in vivo preliminary data gathered, we have detailed a project plan in which nanogel networks that penetrate the urothelium to enable the sustained delivery of antibiotics to successfully treat rUTIs will be engineered. We will expand on our preliminary methods by 1) synthesizing nanogels with enhanced capacity to encapsulate and release therapeutically relevant doses of antibiotics (ciprofloxacin and gentamicin) in physiologically relevant timescales and tested in vitro and; 2) establish the conditions to successfully treat rUTI in an in-vivo murine infection model. Additional potential of the targeted bladder delivery systems described in this proposal is the ability to simultaneously deliver multiple therapeutics, such as a single antibiotic, an antibiotic cocktail or a biofilm dispersing molecule. The development of a bladder delivery system described here could also be used to advance treatments of other urinary bladder pathologies.