Stable cationic bacteriochlorins for antimicrobial photodynamic therapy

用于抗菌光动力治疗的稳定阳离子菌绿素

基本信息

批准号：
7218167
负责人：
JONATHAN SIDNEY LINDSEY
金额：
$ 30万
依托单位：
NIRVANA PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7218167
关键词：
Acne Acute Aerosols Affect American Antibiotic Resistance Area Aspergillus fumigatus Bacteria Binding Biological Bioluminescence Burn Trauma Burn injury Candida albicans Candidiasis Cell Nucleus Cells Characteristics Charge Chemicals Chronic Class Communicable Diseases Complex Dentistry Depth Dermatology Development Disease Dyes Endocytosis Exhibits Focal Infection Gram-Negative Bacteria Gram-Positive Bacteria Head and neck structure Histocompatibility Testing Image In Vitro Infection Injection of therapeutic agent Invasive Investigation Klebsiella Lasers Legal patent Light Lighting Localized Malignant Neoplasms Mammalian Cell Marketing Methods Microbe Modeling Molecular Monitor Mycoses Nail plate Nature Numbers Ophthalmology Penetration Phase Photochemotherapy Photosensitizing Agents Pigments Pneumonia Porphyrins Positioning Attribute Principal Investigator Procedures Process Property Proteus mirabilis Pseudomonas aeruginosa Pyrroles Reactive Oxygen Species Research Sampling Singlet Oxygen Skin Staphylococcus aureus Streptococcus pyogenes Structure Surgical incisions Techniques Testing Tetrapyrroles Thinking Time Tissues Topical application Triplet Multiple Birth Wound Infection absorption antimicrobial bacteriochlorin base cancer cell cancer therapy chemical stability chemical synthesis chlorin commercialization dehydrogenation design fighting fungus interstitial killings methicillin resistant Staphylococcus aureus microbial microorganism mouse model novel pathogen programs size soft tissue triplet state tumor

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a breakthrough development involving the chemical design and synthesis of stabilized bacteriochlorin molecules to carry out photodynamic therapy. These novel photosensitizers (PS) have very intense absorption bands in the near-infrared region of the spectrum where tissue penetration is maximized and good yields of the triplet excited state that produces the reactive oxygen species. The first chosen application of these novel and highly promising PS is to preferentially kill infectious microorganisms and treat localized infections. Most PS that are under investigation for the photodynamic therapy (PDT) of cancer and other diseases are based on the tetrapyrrole nucleus, owing to their ability to be accumulated by malignant cells or tumors. A chief limitation of existing PS has been the lack of suitable near-IR absorption since light in the deep-red/near-IR offers the deepest tissue penetration. Bacteriochlorins (tetrapyrroles containing two pyrrole rings that are reduced at the??- pyrrole-positions) would be ideal PS due to their strong NIR absorption, but until now have suffered from extreme instability (due to spontaneous dehydrogenation to yield oxidized products) and a lack of synthetic tunability. A recent revolution in molecular design and chemical synthesis has opened the door to stable, versatile bacteriochlorins with strong absorptions in the NIR. The combination of non-toxic dyes and harmless light known as antimicrobial PDT can efficiently kill pathogens (including multi-antibiotic resistance amongst pathogenic microbes) and can be usefully employed to fight infections provided the PS shows selectivity for bacteria over host tissue. It is thought that polycationic PS molecules not only are optimal for binding and penetration of multiple classes of microorganism, but also show temporal selectivity for microbes over mammalian cells provided the PS is directly introduced into the infected area. In this proposal, seven types of cationic bacteriochlorins will be designed, synthesized, and tested for PDT activity against a broad spectrum of pathogenic microorganisms in vitro. The two best performing bacteriochlorins will then be tested in a mouse model of a potentially lethal wound infection and monitored by bioluminescence imaging.

描述（由申请人提供）：该提案描述了涉及化学设计和合成稳定的细菌氯肽分子以进行光动力疗法的突破性发展。这些新型的光敏剂（PS）在光谱的近红外区域中具有非常强烈的吸收带，其中组织渗透是最大化的，并且产生活性氧的三胞胎激发态的良好产量。这些新型且高度有希望的PS的第一个选择是优先杀死传染性微生物并治疗局部感染。大多数正在研究的癌症光动力疗法（PDT）和其他疾病的PS基于四吡咯核，这是因为它们通过恶性细胞或肿瘤积累的能力。现有PS的主要局限性是缺乏合适的近红外吸收，因为深红色/近IIR的光提供了最深的组织穿透。细菌氯蛋白（含有两个吡咯环在??-吡咯置位置降低的吡咯环）由于其强大的NIR吸收而成为理想的PS，但到目前为止一直遭受极端不稳定（由于自发脱氢以产生氧化产物而产生氧化产物）和缺乏合成可调性。分子设计和化学合成的最近革命为NIR中具有强吸收的稳定，多才多艺的细菌蛋白打开了大门。称为抗菌PDT的无毒染料和无害的光的结合可以有效地杀死病原体（包括病原体微生物中的多抗生物抗生素耐药性），并且可以用来有效地用来对抗感染，前提是PS在宿主组织上表现出对细菌的选择性。据认为，多阳化PS分子不仅是多种微生物的结合和穿透最佳的，而且只要PS直接引入感染区域，也表现出对微生物对哺乳动物细胞的时间选择性。在此提案中，将设计，合成并测试七种类型的阳离子细菌氯蛋白，并在体外针对多种致病性微生物进行PDT活性。然后将在潜在的致命伤口感染的小鼠模型中测试两种表现最佳的细菌蛋白，并通过生物发光成像进行监测。