权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结