Photodynamic Therapy of Localized Infections

局部感染的光动力疗法

• 批准号: 6683897
• 负责人: MICHAEL R HAMBLIN
• 金额: $ 17.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6683897
• 关键词: Escherichia coli; Proteus; Pseudomonas aeruginosa; Staphylococcus aureus; antibiotics; bacterial disease; burns; charge coupled device camera; combination therapy; drug resistance; gram negative bacteria; gram positive bacteria; inflammation; laboratory mouse; lasers; luminescence; microorganism culture; neutropenia; nonhuman therapy evaluation; photosensitizing agents; phototherapy; urinary tract infection; virulence; wound infection

DESCRIPTION (provided by applicant): The overall goal of this proposal is to explore a novel photochemical method for killing antibiotic resistant pathogenic bacteria in localized models of 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. PDT has the advantage of dual selectivity in that the PS can be targeted to its destination cell or tissue, and in addition the illumination can be spatially directed to the lesion. PDT has previously been used to kill pathogenic microorganisms in vitro, but until now this has not been accomplished in animal models of infection. We have developed a novel method of targeting PS conjugates to both Gram (+) and Gram (-) pathogenic bacteria that can produce up to 6 logs of killing in vitro, while in vivo it increases the selectivity of the treatment for bacteria while sparing host tissue. This is based on the covalent attachment of the PS chlorin e6 to polycationic delivery vehicles such as poly-L-lysine, that increases the selective binding to bacteria and enables the PS to penetrate the cell walls of Gram (-) bacteria to gain access to sensitive intracellular sites. Multi-antibiotic resistant strains are as easily killed as wild-type strains. We have generated preliminary data using luminescent bacteria and a low-light imaging camera, that PDT will kill both Gram (-) species (Escherichia coli and Pseudomonas aeruginosa) and Gram (+) species Staphylococcus aureus) in vivo in animal models of both early and established infections. In the case of the invasive P. aeruginosa mice are cured of an otherwise fatal infection. 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 project will seek to explore the determinants of PDT for localized infections. Four specific aims will focus on optimizing the treatment in different mouse models of early, acute and chronic infections, comprising excisional wounds, established soft tissue infection, chronic abscesses, burns and urinary tract infections. Since one of the advantages of PDT is its rapidity compared to traditional antibiotic therapy, we will also study the use of PDT to quickly reduce the bacterial burden in the infection, followed by antibiotics to eliminate the residual bacteria.

描述（由申请人提供）：该提案的总体目标是探索一种新型的光化学方法，用于杀死局部感染模型中的抗生素抗生素致病细菌。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。 PDT具有双重​​选择性的优点，因为PS可以靶向其目的地细胞或组织，此外，可以将照明定向于病变。 PDT先前已被用于在体外杀死病原性微生物，但直到现在，在感染动物模型中尚未完成。我们已经开发了一种新的方法，将PS偶联物靶向克（+）和革兰氏（ - ）致病细菌，该方法可产生多达6个在体外杀死的日志中，而在体内会增加细菌的选择性，同时释放宿主组织。这是基于PS氯蛋白E6与多阳离子递送车（如多赖赖氨酸）的共价附着，从而增加了与细菌的选择性结合，并使PS能够穿透革兰氏（ - ）细菌的细胞壁以获取敏感细胞内部位。多抗生素抗性菌株与野生型菌株一样容易杀死。我们已经使用发光细菌和低光成像摄像机生成了初步数据，PDT将在早期和既定的感染动物模型中杀死革兰氏（ - ）物种（ - - - ）物种（ - - - ）物种（ - ）物种（ - ）物种（ - ）物种（ - ）种类（ - ）物种（ - - ）物种（ - - ）物种（ - - ）物种（ - - ）物种（ - ）和gram（+）物种（+）物种（+）葡萄球菌。在侵入性铜绿假单胞菌的情况下，小鼠治愈了原本致命的感染。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。该项目将寻求探索局部感染的PDT的决定因素。四个特定的目的将重点侧重于在早期，急性和慢性感染的不同小鼠模型中优化治疗，其中包括移植性伤口，已建立的软组织感染，慢性脓肿，烧伤和尿路感染。由于与传统的抗生素疗法相比，PDT的优势之一是它的速度迅速，因此我们还将研究PDT快速减轻感染中细菌负担的使用，然后是消除残留细菌的抗生素。