Biodegradable Nanoparticles for Targeted Antibiotic Delivery

用于靶向抗生素递送的可生物降解纳米颗粒

基本信息

批准号：
7728645
负责人：
Jayanth Panyam
金额：
$ 39.19万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-10 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7728645
关键词：
Acute Address Affect Anatomy Ankle Antibiotic Therapy Antibiotics Arthritis Atherosclerosis Attenuated Bacteria Cells Chlamydia Chlamydia Infections Chlamydia trachomatis Chlamydophila pneumoniae Chronic Disease Communities Confocal Microscopy Cytoplasm Cytoplasmic Inclusion Data Developed Countries Developing Countries Development Disease Distant Ectopic Pregnancy Fluorescence Microscopy Folate Folic Acid Goals Health Health Care Costs Healthcare Healthcare Systems Home environment Human Image In Vitro Infection Inflammation Knee Lead Location Malignant neoplasm of cervix uteri Mediating Membrane Metabolic Methods Microscopy Molecular Genetics Mucous Membrane Mus Nanotechnology Organelles Organism Pharmaceutical Preparations Pneumonia Protein Isoforms Refractory Research Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis Site Temporal Arteritis Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Treatment Efficacy Treatment Protocols Tubal Occlusion Work analytical method base effective therapy folate-binding protein genital infection in vivo insight mouse model nanoparticle novel particle pathogen public health relevance receptor expression respiratory response targeted delivery trafficking

项目摘要

DESCRIPTION (provided by applicant): Human infections by the intracellular bacterial pathogens Chlamydia trachomatis and C pneumoniae present an enormous health care problem. Infections by these pathogens have been associated with engendering and/or exacerbating several chronic diseases, and some of these Chlamydial infections have proved to be refractory to antibiotic therapy. The lack of therapeutic efficacy results from the attenuated metabolic rate of infecting chlamydiae under some circumstances, in combination with the modest intracellular concentrations achievable by normal delivery of such drugs to the inclusions within which chlamydiae reside in the host cell cytoplasm. The major therapeutic goal of the studies outlined here is to develop a means by which antibiotics or other therapeutic agents can be delivered in a targeted manner to the intracellular Chlamydial inclusion at effective concentrations, without toxicity to the host cell or infected tissue. Our initial studies indicate that Chlamydial infection elicits increased expression of host cell folic acid receptors (FAR), and that folic acid-conjugated nanoparticles may provide a novel and highly effective means of intracellular delivery of therapeutic agents to Chlamydia- infected cells. The working hypothesis underlying the studies proposed is that host cells infected with either C trachomatis or C pneumoniae can be cleared of actively- or persistently-infecting organisms via nanoparticle-mediated targeted delivery of effective concentrations of antibiotics known to work against active Chlamydial infections. We further hypothesize that nanoparticle-facilitated delivery will require reduced amounts of therapeutic materials, which could engender significant health care cost reductions. To pursue that end, three Specific Aims will be addressed. In Aim One, we will define the time-course of expression of folate receptors following C trachomatis infection of a relevant panel of human host cells in culture and in a mouse model of C trachomatis infection, and define the localization of folic acid receptors between the host cell and cytoplasmic inclusion membranes. In Aim Two, we will determine at what time point post-in vitro infection delivery of those nanoparticles is most effective, and whether delivery of antibiotics to infected cells by nanoparticles is effective in clearing C trachomatis infection. In addition, using fluorescence microscopy, we will study the intracellular trafficking of nanoparticles in infected and uninfected cells to understand the mechanism of nanoparticle targeting to inclusions. In Aim Three, using in vivo imaging, molecular genetics, and quantitative analytical methods, we determine if FAR targeted delivery of nanoparticle antibiotics to Chlamydia-infected mice clears synovial infection in vivo. If successful, results of this research will suggest a novel nanotechnology-based therapeutic regimen for effective treatment of an important health care problem. PUBLIC HEALTH RELEVANCE: Chlamydiae are associated with several chronic diseases, including inflammatory arthritis, tubal occlusion leading to ectopic pregnancy, and cervical cancer (C trachomatis); C pneumoniae has been compellingly associated with atherosclerosis, inflammatory arthritis, and temporal arteritis, among several others. The proposed research is expected to positively affect human health, because, it is expected to lead to the development of an effective approach for the treatment of persistent Chlamydial infections.

描述（由申请人提供）：细胞内细菌病原体沙眼衣原体和C肺炎的人类感染带来了巨大的医疗保健问题。这些病原体的感染与激发和/或加剧了几种慢性疾病有关，事实证明，其中一些衣原体感染对抗生素疗法是难治性的。缺乏治疗疗效是由于在某些情况下感染衣原体的代谢率，以及通过正常递送此类药物向衣原体居住在宿主细胞细胞质量中的纳入纳入的纳入的衰减率。此处概述的研究的主要治疗目标是开发一种手段，抗生素或其他治疗剂可以以有效浓度的细胞内衣原体包容性以有效的浓度，而不会对宿主细胞或感染组织毒性。我们的初步研究表明，衣原体感染会引起宿主细胞叶酸受体（FAR）的表达增加，并且叶酸偶联的纳米颗粒可能会提供一种新型且高效的细胞内治疗剂向衣原体感染细胞的方法。提出的研究的基础假设是，感染了Crachomatis或C肺炎感染的宿主细胞可以通过纳米粒子介导的靶向靶向赋予有效浓度的抗生素的靶向递送，从而积极或持续感染的生物，已知可用于抗活性的疗法的疗法。我们进一步假设，纳米颗粒的交付将需要减少治疗材料，这可能会导致大量的医疗保健成本降低。为了追求这一目标，将解决三个具体目标。在目标一个中，我们将在培养物和C沙眼感染的小鼠模型中定义叶酸受体感染后叶酸受体的表达时间。在目标二中，我们将确定这些纳米颗粒的体外感染输送的时间最有效，以及通过纳米颗粒向感染细胞的抗生素是否有效地清除C c沙眼感染。此外，使用荧光显微镜，我们将研究受感染和未感染细胞中纳米颗粒的细胞内运输，以了解纳米颗粒靶向夹杂物的机制。在AIM三中，使用体内成像，分子遗传学和定量分析方法，我们确定纳米颗粒抗生素的靶向范围是否靶向递送到衣原体感染的小鼠中是否会在体内清除滑膜感染。如果成功的话，这项研究的结果将表明一种新型的基于纳米技术的治疗方案，以有效治疗重要的医疗保健问题。公共卫生相关性：衣原体与几种慢性疾病有关，包括炎症性关节炎，导致异位妊娠的输卵管闭塞和宫颈癌（C Trachomatis）； C肺炎与动脉粥样硬化，炎症性关节炎和颞动脉炎等等。拟议的研究预计将对人类健康产生积极影响，因为预计将导致开发一种有效治疗持续性衣原体感染的方法。