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

• 批准号: 7890520
• 负责人: Jayanth Panyam
• 金额: $ 37.53万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/7890520
• 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; 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; Regimen; Research; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid Arthritis; Site; Temporal Arteritis; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Treatment Efficacy; 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

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）：由细胞内细菌病原体沙眼衣原体和肺炎衣原体引起的人类感染是一个巨大的卫生保健问题。这些病原体的感染与产生和/或加重几种慢性疾病有关，并且这些衣原体感染中的一些已被证明是抗生素治疗难治的。治疗效果的缺乏是由于在某些情况下感染衣原体的代谢率减弱，以及通过将这些药物正常递送至衣原体驻留在宿主细胞胞质中的内含物可实现的适度细胞内浓度。本文概述的研究的主要治疗目标是开发一种方法，通过该方法可以以有效浓度以靶向方式将抗生素或其他治疗剂递送至细胞内衣原体包涵体，而对宿主细胞或感染组织没有毒性。我们的初步研究表明，衣原体感染引起宿主细胞叶酸受体（FAR）的表达增加，并且叶酸缀合的纳米颗粒可以提供一种将治疗剂细胞内递送至衣原体感染的细胞的新颖且高效的手段。所提出的研究的工作假设是，感染沙眼衣原体或肺炎衣原体的宿主细胞可以通过纳米颗粒介导的靶向递送有效浓度的已知对活动性衣原体感染有效的抗生素来清除活动性或持续性感染的生物体。我们进一步假设，纳米颗粒促进的交付将需要减少治疗材料的量，这可能会产生显着的医疗保健成本降低。为了实现这一目标，将处理三个具体目标。在目标一，我们将确定表达的时间过程中的相关面板的人类宿主细胞培养和沙眼衣原体感染的小鼠模型中的沙眼衣原体感染后，叶酸受体，并确定宿主细胞和细胞质包涵体膜之间的叶酸受体的本地化。在目标二中，我们将确定在体外感染后的什么时间点递送这些纳米颗粒是最有效的，以及通过纳米颗粒向感染细胞递送抗生素是否有效清除沙眼衣原体感染。此外，使用荧光显微镜，我们将研究纳米粒子在感染和未感染细胞中的细胞内运输，以了解纳米粒子靶向包涵体的机制。在第三个目标中，使用体内成像，分子遗传学和定量分析方法，我们确定是否FAR靶向递送纳米颗粒抗生素到衣原体感染的小鼠体内清除滑膜感染。如果成功，这项研究的结果将提出一种新的基于纳米技术的治疗方案，用于有效治疗一个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，包括炎性关节炎、输卵管阻塞导致异位妊娠和宫颈癌（沙眼衣原体）;肺炎衣原体与动脉粥样硬化、炎性关节炎和颞动脉炎等密切相关。拟议的研究预计将对人类健康产生积极影响，因为预计它将导致开发一种治疗持续性衣原体感染的有效方法。