Infection-homing nanosystems as antibacterial therapeutics-delivery platforms

作为抗菌治疗传递平台的感染归巢纳米系统

• 批准号: 10205961
• 负责人: SANGEETA N. BHATIA
• 金额: $ 78.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205961
• 关键词: Address; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Bacteriophages; Binding; Biodistribution; Biological; Cell Wall; Cells; Clinic; Clinical; Clinical Trials; Confocal Microscopy; Cytoplasm; Data; Development; Dose; Drug Formulations; Drug Kinetics; Drug Modelings; Drug Targeting; Drug resistance; Elements; Engineering; Event; Failure; Formulation; Goals; Gram-Negative Bacteria; Hepatic; Histopathology; Home; Homing; Hydrophobicity; In Vitro; Individual; Infection; Infectious Skin Diseases; Invaded; Kidney; Kinetics; Label; Lead; Libraries; Life; Mammalian Cell; Membrane; Metabolic; Modeling; Morbidity - disease rate; Mus; Muscle; Muscle Fibers; Nano delivery; Nosocomial Infections; Operative Surgical Procedures; Organ; Patients; Penetration; Peptide Antibiotics; Peptides; Performance; Phage Display; Pharmaceutical Preparations; Plasma; Pneumonia; Predisposition; Property; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Recovery; Research; Resistance to infection; Sampling; Silicon; Site; Skin; Small Interfering RNA; Staphylococcus aureus; Staphylococcus aureus infection; Surface; System; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Treatment Efficacy; Vancomycin; bactericide; base; clinical application; cytotoxic; cytotoxicity; dosage; gastrointestinal; improved; in vivo; interest; lead candidate; macrophage; mortality; mouse model; nanoformulation; nanoparticle; nanosystems; nanotechnology platform; pneumonia model; prevent; receptor; resistance mechanism; screening; side effect; small molecule; standard care; tool; uptake

PROJECT SUMMARY Staphylococcus aureus and Pseudomonas aeruginosa are the leading causes of hospital-acquired infections and contribute significantly to morbidity and mortality [3, 4]. Standard treatment of infection entails repetitive high-dose administrations of antibiotics, but the treatment is often rendered ineffective due to poor delivery to sites of infection and drug resistance mechanisms preventing antibiotic access to intracellular drug targets (e.g. the drug-impermeable cell wall in gram-negative P. aeruginosa) [5, 6]. Skin infections that have invaded down to the muscles and fibers are also difficult-to-reach by free-antibiotic formulations and require surgical treatment [7]. The obstacles we tackle in this proposal are: (1) loss of antibiotics to non-infected tissues; (2) rapid clearance of small molecule antibiotics by renal and gastrointestinal clearance; (3) poor penetration of drugs past the bacterial cell wall. We hypothesize that loading antibiotics into longer-circulating nanovehicles that will home to sites of infection and subsequently facilitate drug uptake into cells/bacteria of interest can overcome the abovementioned challenges. Here, we propose to develop such nanoplatforms through three major aims. In Aim 1, we will use in vivo phage display to identify peptides that will home to the bacteria of interest and/or infected tissue. We will focus specifically on S. aureus and P. aeruginosa infections in models of deep skin (invasion in muscles and fibers) infection and pneumonia in mice. In the event that direct bacteria- targeting proves to be difficult, we will also look at peptides that bind selectively to infected tissues and host cells surrounding the bacterial colonies, as well as macrophage-targeting peptides. As these peptides are to be conjugated to nanoparticle surfaces, we will then investigate the binding properties of the peptides in singular and multivalent forms. In Aim 2, we will engineer two nanoplatforms: (1) peptide-based agents that can selectively penetrate the bacterial membrane (i.e. peptide permeation agents) to which small molecule drugs will be tethered for increased uptake and (2) porous silicon nanoparticles (pSiNP) to load drugs that have poor delivery to sites of infection due to unfavorable physicochemical properties (hydrophobic, highly ionic, etc). These nanoplatforms will be targeted to sites of infection using peptides we have previously discovered or additional peptides to be identified in Aim 1. Model drugs with poor in vivo antibacterial activity will be loaded and optimal platforms selected based on drug loading, release kinetics, and cellular uptake for in vivo pharmacokinetics. In addition to individual pSi- and peptide-based nanoplatforms, we will develop a combined system in which bacteria-penetrating drug conjugates are loaded into targeted pSi nanoparticles with the goal of enhanced efficacy. Finally, Aim 3 will focus on the therapeutic performance of lead nanoplatform candidates in vivo. The goal of this aim is to demonstrate the biosafety and therapeutic efficacy (i.e. bacterial burden clearance, tissue recovery, improved survival) of the pSiNP and bacteria-penetrating nanosystems. This project will yield tools to actively target infected tissues as well as a strong set of nanoplatforms that can address many of the current barriers to in vivo antibacterial drug activity.

项目概要 金黄色葡萄球菌和铜绿假单胞菌是医院获得性感染的主要原因 并显着增加发病率和死亡率 [3, 4]。感染的标准治疗需要重复 抗生素的使用剂量很大，但由于抗生素输送不畅，治疗常常无效。 感染部位和耐药机制阻止抗生素进入细胞内药物靶点（例如， 革兰氏阴性铜绿假单胞菌中药物不可渗透的细胞壁）[5, 6]。皮肤感染已侵入下方 游离抗生素制剂也难以到达肌肉和纤维，需要进行手术 治疗[7]。我们在该提案中要解决的障碍是：（1）抗生素流失到非感染组织； (2) 通过肾脏和胃肠道快速清除小分子抗生素； (3)渗透力差 药物可以穿过细菌细胞壁。我们假设将抗生素装载到循环时间较长的纳米载体中 它将成为感染部位并随后促进药物吸收到感兴趣的细胞/细菌中 克服上述挑战。在这里，我们建议通过三个方面来开发这样的纳米平台 主要目标。在目标 1 中，我们将使用体内噬菌体展示来识别能够定位细菌的肽。 兴趣和/或感染的组织。我们将特别关注金黄色葡萄球菌和铜绿假单胞菌模型中的感染 小鼠深层皮肤（侵入肌肉和纤维）感染和肺炎。如果直接细菌- 事实证明靶向很困难，我们还将研究选择性结合受感染组织和宿主的肽 细菌菌落周围的细胞，以及巨噬细胞靶向肽。由于这些肽是 与纳米颗粒表面缀合，然后我们将研究肽在单一形式中的结合特性 和多价形式。在目标 2 中，我们将设计两个纳米平台：（1）基于肽的试剂，可以 选择性地渗透小分子药物的细菌膜（即肽渗透剂） 将被束缚以增加吸收和（2）多孔硅纳米粒子（pSiNP）以负载具有较差的药物 由于不利的理化特性（疏水性、高离子性等）而输送至感染部位。 这些纳米平台将使用我们之前发现或的肽来靶向感染部位 目标1中待鉴定的额外肽。将加载体内抗菌活性较差的模型药物 以及根据药物负载、释放动力学和体内细胞摄取选择的最佳平台 药代动力学。除了单独的基于 pSi 和肽的纳米平台外，我们还将开发一个组合的 该系统将细菌渗透性药物缀合物加载到目标 pSi 纳米颗粒中，其目标是 的功效增强。最后，目标 3 将重点关注领先纳米平台候选者的治疗性能 体内。该目标的目的是证明生物安全性和治疗功效（即细菌负荷） pSiNP 和细菌穿透纳米系统的清除、组织恢复、提高存活率。这 该项目将产生主动针对感染组织的工具以及一套强大的纳米平台，可以 解决了目前体内抗菌药物活性的许多障碍。