Smart Photodynamic Therapy for Acne by Reversibly Switchable Intersystem Crossing in Pure Organic Materials

通过纯有机材料中的可逆可切换系间交叉来治疗痤疮的智能光动力疗法

• 批准号: 10483461
• 负责人: Dalar Bansal
• 金额: $ 25.86万
• 依托单位: ADVANCED CYTOMETRY INSTRUMENTATION SYS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483461
• 关键词: Acidity; Acne; Acne Vulgaris; Address; Adolescent; Adult; Adverse effects; Affect; American; Antibiotics; Area; Bacteria; Bacterial Infections; Biopsy; Cell Culture Techniques; Cell Line; Cells; Characteristics; Chemical Structure; Chemicals; Chronic; Clinical Treatment; Coupling; Cytoplasm; Data; Dependence; Dermatology; Dermis; Development; Duct (organ) structure; Environment; Epidermis; Epithelial; Exposure to; Female; Fibroblasts; Frequencies; Gland; Human; In Vitro; Inflammation; Inflammatory; Isoelectric Point; Lead; Lesion; Light; Lipids; Malignant Neoplasms; Measures; Medical; Microscopic; Modality; Modeling; Molecular; Molecular Conformation; Ocular orbit; Oral; PUVA Photochemotherapy; Penetration; Persons; Pharmaceutical Preparations; Phase; Photosensitizing Agents; Population; Process; Production; Retinoids; Risk; Sebaceous Glands; Sebum; Series; Singlet Oxygen; Site; Skin; Sodium Chloride; Solubility; Specificity; Spottings; Stains; Structure; Surface; System; Testing; Therapeutic Effect; Tissues; Topical application; Treatment Efficacy; Triplet Multiple Birth; United States; Validation; Vertebral column; Woman; absorption; base; care burden; cell type; cytotoxic; cytotoxicity; design; dosage; health care economics; hormone therapy; molecular modeling; next generation; nile red; novel; novel strategies; prototype; psychologic; side effect; skin damage; triplet state; uptake

Abstract – Acne vulgaris is the most common skin condition in the United States, affecting up to 50 million Americans annually. While acne is common in young people, this condition becomes increasingly widespread in adults, especially in females— chronic post-adolescent acne affects about 15 percent of women in the USA. Moderate to severe acne confers a tremendous medical, psychological, and economic health care burden on the US population. The development of acne is multifactorial, but centers around the sebaceous glands (SG), which are the microscopic holocrine glands within the skin dermis. SGs comprise specialized cells—sebocytes—that secrete a variety of lipids composing the sebum. Conventional clinical treatment of severe inflammatory acne involves a combination of topical and systemic drugs, administered over the course of several months or even years. These include topical and oral retinoids, antibiotics, and in some instances, hormonal therapy. Treatment is often ineffective and carries the risk of adverse side effects. Remarkably, photodynamic therapy (PDT) has shown breakthrough potential for dermatology. PDT involves topical application of agents called photosensitizers (PS) to the affected skin area. When exposed to specific wavelengths of light, these agents generate highly cytotoxic singlet oxygen (1O2 ) that damages sebocytes, reducing both the size and activity of SGs, and locally eliminates bacterial infections. However, use of conventional PDT includes a significant risk of skin damage as the 1O2 inherently damages fibroblasts, epithelium, and other skin components outside the SG in the entire irradiated skin area. The unintended photodamage has an adverse effect on skin structure and function and can potentially lead to cancer. Thus, the utility of conventional PDT is limited because of these significant side effects. To address this limitation, ACIS is developing a Smart PDT (S-PDT) platform will enable targeted and tunable treatment to cells of the SGs, while sparing other cell types. As part of this, ACIS is developing a next generation PS agent that is designed to be active selectively in the sebum producing cells of SGs and bacteria-infected sites, while causing no damage to the surrounding healthy tissue. This approach alleviates the common photodynamic therapy limitations via reversible on/off switching of intersystem crossing in small organic molecules, thereby boosting (in “on” mode) or suppressing (in “off” mode) singlet oxygen production. The Specific Aims of this Phase I project are as follows : 1) Design and synthesize a reversibly switchable pH-sensitive PS with tunable isoelectric point and tunable absorption maximum to penetrate the skin at the optimal depth; and 2) Demonstrate the viability of the S-PDT approach via in vitro and ex vivo tests, including cellular uptake, cytotoxicity, and PDT action of newly synthesized materials in human skin models. Successful completions of these aims will demonstrate the viability of the S-PDT platform and support further development in Phase II.

摘要- 寻常痤疮是美国最常见的皮肤病，影响多达5000万美国人 每年一次。虽然痤疮在年轻人中很常见，但这种情况在成年人中越来越普遍， 尤其是女性--美国约有15%的女性患有青春期后的慢性痤疮。中等 严重的痤疮给美国带来了巨大的医疗、心理和经济卫生保健负担 人口。痤疮的发生是多因素的，但集中在皮脂腺(SG)，皮脂腺是 皮肤真皮内的微小全分泌腺。SGS由特化细胞--皮脂细胞--组成 分泌组成皮脂的各种脂类。重症炎症性痤疮的常规临床治疗 涉及局部和全身药物的组合，在几个月甚至几个月的过程中给药 好几年了。这些包括外用和口服维甲酸、抗生素，在某些情况下，还包括激素治疗。治疗 通常是无效的，并带有不良副作用的风险。值得注意的是，光动力疗法(PDT)有 显示出皮肤科的突破性潜力。光动力疗法涉及局部应用称为光敏剂的药物 (PS)到受影响的皮肤区域。当暴露在特定波长的光下时，这些制剂会产生 细胞毒性单线态氧(1O2)，破坏皮脂细胞，降低SGS的大小和活性，以及局部 消除细菌感染。然而，使用传统的光动力疗法包括严重的皮肤损伤风险，因为 1O2固有地损害成纤维细胞、上皮和整个SG外的其他皮肤成分 受辐射的皮肤区域。意外的光损伤会对皮肤结构和功能产生不利影响，并可能 可能会导致癌症。因此，由于这些显著的副作用，传统的光动力疗法的应用受到了限制。 为了解决这一限制，ACIS正在开发一个智能PDT(S-PDT)平台，将使有针对性的和 对SGS的细胞进行可调处理，同时保留其他类型的细胞。作为这项工作的一部分，ACIS正在开发一种 新一代PS制剂被设计为在SGS和SGS的皮脂产生细胞中选择性地活跃 细菌感染部位，同时不会对周围的健康组织造成损害。这种方法缓解了 小型有机物系统间交叉可逆开关光动力治疗的局限性 分子，从而促进(在“开”模式下)或抑制(在“关”模式下)单线态氧的产生。具体的 本项目一期工程的目标如下：1)设计和合成一种可逆切换的pH敏感PS 具有可调等电点和可调吸收最大值以在最佳深度穿透皮肤；以及2) 通过体外和体外测试，包括细胞摄取，证明S光动力疗法的可行性， 新合成材料在人体皮肤模型中的细胞毒性和光动力作用。成功完成 这些目标将证明S-PDT平台的可行性，并支持第二阶段的进一步发展。