Stable cationic bacteriochlorins for antimicrobial photodynamic therapy

描述（由申请人提供）：本提案描述了一项突破性的发展，涉及化学设计和合成稳定的细菌氯分子以进行光动力治疗。这些新型光敏剂（PS）在光谱的近红外区域具有非常强的吸收带，其中组织穿透性最大，并且产生活性氧的三重态激发态的产率很高。这些极具前景的新型PS的首选应用是优先杀死感染性微生物和治疗局部感染。大多数用于癌症和其他疾病光动力治疗（PDT）的PS都是基于四吡啶核，因为它们能够被恶性细胞或肿瘤积累。现有PS的主要限制是缺乏合适的近红外吸收，因为深红色/近红外的光提供最深的组织穿透。含有两个吡咯环的细菌氯（四吡咯）在？？-吡咯-位)由于其强的近红外吸收性而成为理想的PS，但迄今为止，它们具有极端的不稳定性（由于自发脱氢生成氧化产物）和缺乏合成可调性。最近在分子设计和化学合成方面的一场革命为稳定、多功能、近红外强吸收的细菌氯打开了大门。无毒染料和无害光的组合被称为抗菌PDT，可以有效地杀死病原体（包括致病微生物中的多种抗生素耐药性），并且可以有效地用于对抗感染，前提是PS对细菌在宿主组织中表现出选择性。据认为，多阳离子PS分子不仅最适合结合和渗透多种微生物，而且在将PS直接引入感染区域的情况下，对微生物的选择性优于哺乳动物细胞。在这个提议中，七种阳离子细菌氯将被设计、合成，并在体外测试对广谱致病微生物的PDT活性。这两种性能最好的细菌氯将在潜在致命伤口感染的小鼠模型中进行测试，并通过生物发光成像进行监测。

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.