Nanotherapeutics for Ocular Infections

眼部感染的纳米疗法

基本信息

批准号：
9341333
负责人：
Michelle C Callegan
金额：
$ 35.77万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9341333
关键词：
Anti-Inflammatory Agents Anti-inflammatory Antibiotic Therapy Antibiotics Antitoxins Area Bacillus cereus Bacteria Bacterial Eye Infections Bacterial Model Biodistribution Blindness Cell Death Cell Survival Cell physiology Cells Clinical Communicable Diseases Cornea Cytoprotection Data Effectiveness Endophthalmitis Enterococcus faecalis Environment Experimental Models Eye Eye Infections Funding Future Goals In Vitro Infection Inflammation Keratitis Modeling Muller&apos s cell Mus Mutagenesis Nanotechnology Organism Outcome Pharmaceutical Preparations Physicians Positioning Attribute Research Retina Safety Sepsis Site Staphylococcus aureus Streptococcus pneumoniae Targeted Toxins Testing Therapeutic Therapeutic Agents Therapeutic Studies Therapeutic Uses Tissues Topical Antibiotic Toxin United States National Institutes of Health Virulence Vision Vision research Visual alpha Toxin base clinically relevant corneal epithelium design efficacy testing experimental study high risk improved in vivo ineffective therapies interest killings mouse model nanomedicine nanotherapeutic new therapeutic target novel ocular surface pathogen prevent programs public health relevance targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Ocular bacterial infections cause a significant number of cases of blindness worldwide. Efforts to prevent damage to delicate ocular tissues during infection rely on swift and proper use of therapeutics to rapidly kill organisms and arrest potentially damaging inflammation. Currently-used antibiotics can kill organisms, but the effectiveness of anti-inflammatory drugs is controversial. These drug classes do not target tissue-damaging toxins synthesized by bacteria at the site of infection. Pore-forming toxins (PFTs) are important, and often essential, to ocular virulence of the following Gram-positive ocular pathogens: Staphylococcus aureus, Streptococcus pneumoniae, Bacillus cereus, and Enterococcus faecalis. When PFTs are absent, ocular virulence is significantly decreased. Novel PFT-targeting therapeutics which neutralize toxins across species would provide coverage for the most common Gram-positive pathogens causing ocular surface (keratitis) and intraocular (endophthalmitis) infections. Toxin neutralization as an adjunct with antibiotics and anti-inflammatory agents would provide a significant improvement over current therapies that are ineffective against tissue-damaging toxins. Nanosponges have recently been developed which target Gram-positive PFTs. In vitro, nanosponges neutralize Gram-positive PFTs. In in vivo experimental models of sepsis and tissue infection, nanosponges neutralize toxins at the site of infection and reduce virulence. We hypothesize that nanosponges can effectively reduce the toxic activity of bacterial PFTs in the ocular environment, leading to use as a novel anti-toxi therapeutic with antibiotics for the treatment of intraocular and ocular surface infections. Preliminary data demonstrates the feasibility of testing our hypothesis. We show that nanosponges 1) neutralize PFTs of Gram-positive ocular pathogens, 2) do so in the presence of tears, vitreous, and antibiotics, 3) protect against toxic ocular cell death, and 4) are not toxic in/on mouse eyes. A critical barrier to clinical improvements in ocular bacterial infections is th absence of toxin- targeting. We will test nanosponges for PFT-neutralizing activity and efficacy with antibiotics against ocular pathogens causing keratitis (Aim 1) and endophthalmitis (Aim 2), and will also investigate their biodistribution following ocular application (Aim 3). If nanosponge are effective, the next step is to test nanosponges with more potent antibiotics and better anti-inflammatory agents. Testing of nanosponges in the treatment of ocular bacterial infections is high risk, but is novel, high-impact, translationally relevant, and will positively influence the ocular infectious disease field by identifying a novel anti-toxin therapy which may protect delicate tissues of the eye during infection. The proposed studies are a logical outgrowth of our ocular infection research program, and we are well positioned to contribute valuable information which will provide physicians with the best possible therapeutic options to preserve vision during ocular infections.

描述（由申请人提供）：眼部细菌感染导致全球范围内大量失明病例，目前，防止感染期间脆弱的眼部组织受损的努力依赖于迅速且正确地使用治疗方法来快速杀死微生物并阻止潜在的破坏性炎症。使用的抗生素可以杀死微生物，但抗炎药物的有效性存在争议，这些药物并不针对感染部位细菌合成的破坏组织的毒素。对于以下革兰氏阳性眼部病原体的眼部毒力至关重要，而且通常是必需的：金黄色葡萄球菌、肺炎链球菌、蜡状芽孢杆菌和粪肠球菌。当缺乏 PFT 时，中和毒素的新型 PFT 靶向疗法会显着降低。跨物种将覆盖引起眼表（角膜炎）和眼内的最常见革兰氏阳性病原体（眼内炎）感染作为抗生素和抗炎剂的辅助剂，与最近开发的针对革兰氏阳性 PFT 的现有疗法相比，纳米海绵具有显着的改善。在败血症和组织感染的体内实验模型中，纳米海绵可以中和感染部位的毒素并降低毒力。纳米海绵可以有效降低眼部环境中细菌 PFT 的毒性活性，从而可用作抗生素的新型抗毒疗法，用于治疗眼内和眼表感染。初步数据证明了检验我们的假设的可行性。纳米海绵 1) 中和革兰氏阳性眼部病原体的 PFT，2) 在泪液、玻璃体和抗生素存在的情况下发挥作用，3) 防止有毒眼部细胞死亡，以及4）在小鼠眼睛内/表面没有毒性。眼部细菌感染临床改善的一个关键障碍是缺乏毒素靶向性。我们将测试纳米海绵的 PFT 中和活性以及抗生素对引起角膜炎的眼部病原体的功效（目标 1）。）和眼内炎（目标 2），还将研究其在眼部应用后的生物分布（目标 3），如果纳米海绵有效，下一步是测试。纳米海绵具有更有效的抗生素和更好的抗炎剂，测试纳米海绵治疗眼部细菌感染的风险很高，但具有新颖性、高影响力、转化相关性，并将通过鉴定一种新的方法对眼部传染病领域产生积极影响。抗毒素疗法可以在感染期间保护眼睛的脆弱组织。拟议的研究是我们眼部感染研究计划的合理产物，我们有能力提供有价值的信息，为医生提供最佳的治疗选择。期间的视力眼部感染。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Toxoid Vaccination against Bacterial Infection Using Cell Membrane-Coated Nanoparticles.

使用细胞膜包被的纳米颗粒进行类毒素疫苗接种以预防细菌感染。

DOI：
10.1021/acs.bioconjchem.7b00692
发表时间：
2018-03-21
期刊：
Bioconjugate chemistry
影响因子：
4.7
作者：
Angsantikul P;Fang RH;Zhang L
通讯作者：
Zhang L

Broad-Spectrum Neutralization of Pore-Forming Toxins with Human Erythrocyte Membrane-Coated Nanosponges.

用人红细胞膜涂覆的纳米海绵广谱中和成孔毒素。

DOI：
发表时间：
2018-07
期刊：
影响因子：
10
作者：
Chen, Yijie;Chen, Mengchun;Zhang, Yue;Lee, Joo Hee;Escajadillo, Tamara;Gong, Hua;Fang, Ronnie H;Gao, Weiwei;Nizet, Victor;Zhang, Liangfang
通讯作者：
Zhang, Liangfang

Erythrocyte membrane-coated nanogel for combinatorial antivirulence and responsive antimicrobial delivery against Staphylococcus aureus infection.

红细胞膜涂层纳米凝胶，用于针对金黄色葡萄球菌感染的组合抗毒力和响应性抗菌药物递送。

DOI：
发表时间：
2017-10-10
期刊：
影响因子：
0
作者：
Zhang, Yue;Zhang, Jianhua;Chen, Wansong;Angsantikul, Pavimol;Spiekermann, Kevin A;Fang, Ronnie H;Gao, Weiwei;Zhang, Liangfang
通讯作者：
Zhang, Liangfang

Nanoparticle-based local antimicrobial drug delivery.

基于纳米颗粒的局部抗菌药物输送。