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.

抽象的 - 寻常痤疮是美国最常见的皮肤病，影响多达 5000 万美国人 虽然痤疮在年轻人中很常见，但这种情况在成年人中变得越来越普遍， 尤其是女性——慢性青春期后痤疮影响着美国约 15% 的女性。 严重的痤疮给美国带来了巨大的医疗、心理和经济医疗负担 痤疮的形成是多因素的，但以皮脂腺 (SG) 为中心，皮脂腺是 皮肤真皮内的微观全分泌腺由特殊细胞（皮脂细胞）组成。 临床上常规治疗严重炎症性痤疮，分泌多种脂质组成的皮脂。 涉及局部和全身药物的组合，在几个月甚至几个月的时间内给药 这些包括局部和口服类视黄醇、抗生素，以及在某些情况下的激素治疗。 值得注意的是，光动力疗法（PDT）通常无效，并且存在副作用的风险。 PDT 涉及局部应用光敏剂，显示出皮肤病学的突破潜力。 (PS) 到受影响的皮肤区域时，这些药剂会产生大量的光。 细胞毒性单线态氧 (1O2) 会损害皮脂细胞，减少 SG 的大小和活性，并局部 消除细菌感染。然而，使用传统的 PDT 存在很大的皮肤损伤风险，因为 1O2 本质上会损害整个 SG 之外的成纤维细胞、上皮细胞和其他皮肤成分 受照射的皮肤区域会受到意外的光损伤，从而对皮肤结构和功能产生不利影响。 因此，由于这些显着的副作用，传统 PDT 的实用性受到限制。 为了解决这一限制，ACIS 正在开发智能 PDT (S-PDT) 平台，该平台将能够实现有针对性的、 对 SG 细胞进行可调治疗，同时不影响其他细胞类型。 下一代 PS 剂，旨在选择性地在 SG 和皮脂产生细胞中发挥活性 细菌感染部位，同时不会对周围健康组织造成损害，这减轻了方法。 通过小有机体中系统间交叉的可逆开/关切换，常见的光动力治疗局限性 分子，从而促进（在“开启”模式下）或抑制（在“关闭”模式下）单线态氧的产生。 该一期项目的目标如下：1）设计并合成可逆可切换的pH敏感PS 具有可调节的等电点和可调节的吸收最大值，以最佳深度渗透皮肤；2) 通过体外和离体测试（包括细胞摄取、 新合成材料在人体皮肤模型中的细胞毒性和 PDT 作用。 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开发。