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

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。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， 特别是在女性中-在美国，慢性青春期后痤疮影响大约15%的女性。中度 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 人口痤疮的发展是多因素的，但中心周围的皮脂腺（SG）， 皮肤真皮内的微观全分泌腺。SG包括专门的细胞-皮脂腺细胞， 分泌各种脂质组成皮脂。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，在几个月甚至更长的时间内给药， 年这些包括局部和口服维甲酸，抗生素，在某些情况下，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） 在皮肤病学上有突破性的潜力PDT包括局部应用称为光敏剂的药物 (PS)受影响的皮肤区域。当暴露于特定波长的光时，这些试剂产生高度的 细胞毒性单线态氧（1 O2），损伤皮脂细胞，降低SG的大小和活性，并局部 消除细菌感染。然而，使用常规PDT包括皮肤损伤的显著风险， 1 O2固有地损伤成纤维细胞、上皮细胞和整个SG外的其他皮肤成分， 照射的皮肤区域。意外的光损伤对皮肤结构和功能具有不利影响， 可能导致癌症因此，由于这些显著的副作用，常规PDT的效用受到限制。 为了解决这一限制，货物预报信息系统正在开发一个智能PDT（S-PDT）平台， 对SG的细胞进行可调治疗，同时保留其他细胞类型。作为这项工作的一部分，货物预报信息系统正在开发一个 下一代PS剂，其被设计为在SG的皮脂产生细胞中选择性地具有活性， 细菌感染的部位，而不会对周围的健康组织造成损害。这一方法强调了 在小器官中通过系统间交叉的可逆开/关切换的常见光动力治疗限制 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 本课题第一阶段的主要工作如下：1）设计并合成一种可逆开关的pH敏感聚苯乙烯 具有可调的等电点和可调的吸收最大值，以在最佳深度穿透皮肤;以及2） 通过体外和离体试验证明S-PDT方法的可行性，包括细胞摄取， 细胞毒性和新合成材料在人体皮肤模型中的PDT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。

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.