Photodynamic Therapy of Localized Infections

局部感染的光动力疗法

基本信息

批准号：
7568228
负责人：
MICHAEL R HAMBLIN
金额：
$ 35.27万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7568228
关键词：
Abscess Acute Animal Model Animals Antibiotic Resistance Antibiotics Area Aspergillus fumigatus Bacteria Bacterial Infections Bacterial Luciferases Binding Biological Bioluminescence Burn injury Candida albicans Cell Death Cell Line Cell Wall Cells Cessation of life Charge Chronic Clinical Combined Modality Therapy Destinations Dyes Effectiveness Energy Transfer Engineering Fluorescence Focal Infection Funding Generations Goals Gram-Negative Bacteria Grant Green Fluorescent Proteins Hydrogen Peroxide Hydroxyl Radical Image Imaging Techniques In Vitro Infection Invaded Investigation Laboratories Lesion Life Light Lighting Lipids Lysine Mammalian Cell Measures Mediating Methods Microbe Modeling Molecular Motivation Mouse Strains Mus Mycoses Nucleic Acids Oxygen Penetration Pharmaceutical Preparations Photochemotherapy Photosensitizing Agents Phototoxicity Prevalence Procedures Process Production Proteins Pseudomonas aeruginosa Reactive Oxygen Species Reporting Research Role Route Sepsis Singlet Oxygen Site Staphylococcus aureus Superoxides Surgical wound System Technology Testing Time Tissues Topical Antibiotic Toxic effect Vertebral column Virulence Factors Virus Visible Radiation Work Wound Infection Yeasts amino group antimicrobial cancer cell cell killing cell type chlorin e6 clinical practice cytotoxic design extracellular fluorescence imaging fungus in vivo killings microbial microbicide mouse model novel pathogen pathogenic bacteria prevent public health relevance resistant strain synergism triplet state

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to continue to explore a novel photochemical method for killing antibiotic resistant pathogenic bacteria or fungi in models of localized infection. Photodynamic therapy (PDT) employs a non-toxic dye termed a photosensitizer (PS) and low intensity visible light, which in the presence of oxygen produce cytotoxic species that damage proteins, lipids and nucleic acids and kill cells. PDT has the advantage of dual selectivity in that the PS can be targeted to its destination cell type or tissue, and in addition the illumination can be spatially directed to the area of infection. In the previous funding period we established that polycationic delivery vehicles such as poly-L-lysine could be conjugated to PS such as chlorin(e6), and these molecular delivery vehicles for PS increased the selective binding to bacteria and enabled the PS to penetrate the cell walls of Gram (-) bacteria to dramatically potentiate light-mediated killing.. We used luminescent bacteria and a low-light imaging camera to demonstrate that PDT will kill both Gram (-) species (eg Pseudomonas aeruginosa) and Gram (+) species (eg Staphylococcus aureus) in vivo in animal models of wounds, burns and deep established infections. Localized PDT may have an additional advantage in that it is also possible to inactivate secreted extracellular virulence factors that pathogenic bacteria use to establish infections and invade tissue. This competing renewal will seek to explore new ways of increasing the potency and applicability of antimicrobial PDT. Four specific aims will focus on (1) studying the photochemical mechanisms of photodynamic inactivation of microbes (that may be very different from cancer cells) with the aim of devising simple combination treatments; (2) investigating the new discovery that low non-toxic concentrations of hydrogen peroxide dramatically potentiate antimicrobial PDT by orders of magnitude; (3) synthesizing and testing a third generation polycationic PS conjugates with quaternized amino groups that retain cationic character under all conditions; (4) testing the above treatments in mouse models of acute or chronic wounds and burns infected with pathogenic bacteria (P. aeruginosa or S. aureus), together with an entirely new model of spectrally resolved fluorescence imaging of GFP Candida albicans or Aspergillus fumigatus growing in traumatic lesions in various strains of mice. These avenues of research are expected to suggest simple procedures to optimize antimicrobial PDT and hasten its wide introduction into clinical practice. PUBLIC HEALTH RELEVANCE The alarming rise in prevalence of antibiotic resistance amongst pathogenic bacteria has led to worries that previously treatable infections could soon be incurable. Traumatic or surgical wounds and burns are common sites of infection that can progress to sepsis and death if they fail to be controlled by antibiotics. Photodynamic therapy (PDT) involves a combination of non- toxic dyes and harmless visible light that in combination produce highly toxic reactive oxygen species. If the dye is targeted to the bacterial cell PDT can be a highly effective local antimicrobial therapy with little damage to host tissue. This application seeks to determine the optimum parameters for antimicrobial PDT and will look at new synergistic combination therapies.

描述（由申请人提供）：该提案的总体目标是继续探索一种新型的光化学方法，用于杀死局部感染模型中杀死抗生素的致病细菌或真菌。光动力疗法（PDT）采用一种称为光敏剂（PS）和低强度可见光的无毒染料，在存在氧气的情况下会产生细胞毒性物种，损害蛋白质，脂质和核酸和杀死细胞。 PDT具有双重选择性的优点，因为PS可以靶向其目的地细胞类型或组织，此外，可以将照明定向于感染区域。 In the previous funding period we established that polycationic delivery vehicles such as poly-L-lysine could be conjugated to PS such as chlorin(e6), and these molecular delivery vehicles for PS increased the selective binding to bacteria and enabled the PS to penetrate the cell walls of Gram (-) bacteria to dramatically potentiate light-mediated killing.. We used luminescent bacteria and a low-light imaging camera to demonstrate该PDT在伤口，烧伤和深厚的感染的动物模型中，在体内杀死了克（例如铜绿假单胞菌）和革兰氏（例如金黄色葡萄球菌）。局部PDT可能具有附加优势，因为还可以使病原细菌用来建立感染并入侵组织的分泌细胞外毒力因子失活。这种竞争性更新将寻求探索增加抗菌PDT效力和适用性的新方法。四个具体目标将重点放在（1）研究微生物光动力失活的光化学机制（可能与癌细胞大不相同），目的是设计简单的组合处理；（2）研究了新发现，即低毒性的过氧化氢通过数量级急剧增强抗菌PDT；（3）合成和测试第三代多阳离子PS与在所有条件下保留阳离子特征的Quaternizatized氨基共轭的共轭；（4）在急性或慢性伤口的小鼠模型中测试上述处理，并烧伤被致病性细菌（铜绿假单胞菌或金黄色葡萄球菌）感染，以及全新的频谱分辨出的荧光成像的新模型，这些模型是GFP念珠菌念珠菌的荧光成像，或者在各种薄膜中生长的曲菌。这些研究途径有望提出简单的程序，以优化抗菌PDT并加速其对临床实践的广泛引入。公共卫生相关性抗生素耐药性在致病细菌中的患病率令人震惊，这导致担心以前可治疗的感染很快可能是无法治愈的。创伤性或手术伤口和烧伤是常见的感染部位，如果不受抗生素的控制，它们可能会发展为败血症和死亡。光动力疗法（PDT）涉及非毒性染料和无害可见光的组合，结合产生了剧毒的活性活性氧。如果将染料靶向细菌细胞PDT，则可能是一种高效的局部抗菌治疗，对宿主组织造成的损害很小。该应用程序旨在确定抗菌PDT的最佳参数，并将研究新的协同组合疗法。