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

• 批准号: 7429748
• 负责人: JONATHAN SIDNEY LINDSEY
• 金额: $ 29.97万
• 依托单位: NIRVANA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429748
• 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

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(申请人提供)：这项提案描述了一项突破性的发展，涉及到稳定的细菌素分子的化学设计和合成，以进行光动力疗法。这些新型光敏剂(PS)在光谱的近红外区具有非常强的吸收带，在那里组织穿透最大，并且产生活性氧物种的三重态激发态具有良好的产率。这些新颖且极具前景的PS的首选应用是优先杀灭感染微生物和治疗局部感染。大多数用于光动力疗法(PDT)治疗癌症和其他疾病的PS都是基于四聚吡咯核的，因为它们能够被恶性肿瘤细胞或肿瘤蓄积。现有PS的一个主要限制是缺乏合适的近红外吸收，因为在深红色/近红外中的光提供了最深的组织穿透。细菌氯(含有两个在？？-吡咯位被还原的吡咯环的四吡咯)将是理想的PS，因为它们具有很强的近红外吸收，但到目前为止一直存在极不稳定的问题(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在近红外光谱中具有强吸收的稳定、多功能的细菌素打开了大门。无毒染料和被称为抗菌PDT的无害光的组合可以有效地杀死病原体(包括致病微生物之间的多重抗生素耐药性)，并可有效地用于对抗感染，前提是PS对细菌显示出对宿主组织的选择性。人们认为，聚阳离子PS分子不仅对多种微生物的结合和渗透是最佳的，而且如果PS直接进入感染区域，微生物对哺乳动物细胞的时间选择性也是最好的。在这项提案中，将设计、合成七种类型的阳离子细菌素，并在体外测试其对广泛病原微生物的PDT活性。然后，将在潜在致命伤口感染的小鼠模型上测试这两种表现最好的细菌素，并通过生物发光成像进行监测。

项目成果

Molecular electronic tuning of photosensitizers to enhance photodynamic therapy: synthetic dicyanobacteriochlorins as a case study.

• DOI: 10.1111/php.12021
• 发表时间: 2013-05
• 期刊: Photochemistry and photobiology
• 影响因子: 3.3
• 作者: Yang E;Diers JR;Huang YY;Hamblin MR;Lindsey JS;Bocian DF;Holten D
• 通讯作者: Holten D

Stable synthetic bacteriochlorins for photodynamic therapy: role of dicyano peripheral groups, central metal substitution (2H, Zn, Pd), and Cremophor EL delivery.

稳定的用于光动力疗法的合成细菌蛋白：二氯外周组，中央金属取代（2H，Zn，PD）和Cremophor EL递送的作用。

• DOI: 10.1002/cmdc.201200351
• 发表时间: 2012-12
• 期刊: CHEMMEDCHEM
• 影响因子: 3.4
• 作者: Huang, Ying-Ying;Balasubramanian, Thiagarajan;Yang, Eunkyung;Luo, Dianzhong;Diers, James R.;Bocian, David F.;Lindsey, Jonathan S.;Holten, Dewey;Hamblin, Michael R.
• 通讯作者: Hamblin, Michael R.

Synthesis and evaluation of cationic bacteriochlorin amphiphiles with effective in vitro photodynamic activity against cancer cells at low nanomolar concentration.

• DOI: 10.1142/s108842461250126x
• 发表时间: 2013-01
• 期刊: Journal of porphyrins and phthalocyanines
• 影响因子: 1.5
• 作者: Sharma SK;Krayer M;Sperandio FF;Huang L;Huang YY;Holten D;Lindsey JS;Hamblin MR
• 通讯作者: Hamblin MR