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.

项目摘要 金黄色葡萄球菌和铜绿假单胞菌是医院获得感染的主要原因 并为发病率和死亡率做出了重大贡献[3，4]。感染的标准治疗需要重复 抗生素的高剂量施用，但由于交付不良，这种治疗通常是无效的 感染部位和耐药性机制，可防止抗生素进入细胞内药物靶标（例如 革兰氏阴性p。p.铜绿假单胞菌中的药物侵入细胞壁）[5，6]。侵入的皮肤感染 肌肉和纤维也很难通过自由抗生素的配方来触及，需要手术 治疗[7]。我们在该提案中要解决的障碍是：（1）对未感染组织的抗生素丧失； （2） 通过肾脏和胃肠道清除对小分子抗生素的快速清除； （3）渗透率不佳 超过细菌细胞壁的药物。我们假设将抗生素加载到长循环的纳米壳中 这将回到感染部位，随后促进药物吸收到感兴趣的细胞/细菌可以 克服上述挑战。在这里，我们建议通过三个 主要目标。在AIM 1中，我们将使用体内噬菌体显示器来识别将归入细菌的肽 兴趣和/或感染组织。我们将专门针对金黄色葡萄球菌和铜绿假单胞菌感染 深层皮肤（肌肉和纤维中的浸润）感染和小鼠的肺炎。如果直接细菌 - 靶向被证明很困难，我们还将研究与感染组织和宿主选择性结合的肽 细菌菌落周围的细胞以及靶向巨噬细胞的肽。因为这些肽是 结合到纳米颗粒表面，我们将研究肽在单数中的结合特性 和多价形式。在AIM 2中，我们将设计两个纳米板型：（1）基于肽的代理 选择性地穿透细菌膜（即肽渗透剂）小分子药物 将被束缚以增加摄取和（2）多孔硅纳米颗粒（PSINP），以加载较差的药物 由于不利的物理化学特性（疏水性，高离子等），传递到感染部位。 这些纳米植物形式将使用我们以前发现的肽或 在AIM 1中要鉴定的其他肽。将加载体内抗菌活性较差的模型药物 和基于药物加载，释放动力学和体内的细胞摄取选择的最佳平台 药代动力学。除了单个基于PSI-和肽的纳米板外形外，我们还将开发一个组合 将细菌穿透药物缀合物加载到目标的PSI纳米颗粒中的系统 增强功效。最后，AIM 3将重点介绍铅纳米板候选者的治疗性能 体内。该目标的目的是证明生物安全和治疗功效（即细菌负担 清除率，组织恢复，改善PSINP和细菌纳米系统的生存率）。这 项目将产生积极针对感染组织的工具，以及一组强大的纳米板形式 解决当前体内抗菌药物活性的许多障碍。