Developing cancer-specific, H2O2-activatable, and O2-evolving micelles encapsulating near-IR photosensitizers for phototherapy of breast cancer

项目摘要 光疗包括光动力疗法（PDT）和光热疗法（PTT）是一种替代疗法 一种基于光敏剂（PS）将光子能量转化为反应性能量的能力的癌症治疗模式， 氧物种（ROS，即单线态氧、超氧阴离子、羟基自由基等）或加热。PDT/PTT 处理具有特殊的选择性，因为处理只有当PS被活化时才有效。 光PDT/PTT具有非侵入性、由于快速愈合过程而很少或没有瘢痕形成的优点， 并且能够在门诊治疗病人。然而，目前可用的 基于卟啉的PS，例如不能被近红外（NIR）光激活，低ROS生成 在低氧实体瘤中的效率，对癌组织的低选择性，和持久的皮肤 光敏感性等限制了PDT在浅表肿瘤中的应用。为了解决这些问题，我们计划 将我们新开发的强近红外吸收PS BODIPY-Ir应用于PDT/PTT， 特异性靶向、H2 O2可活化和O2释放胶束，以在缺氧中有效产生ROS。我们 假设所提出的装载有吸收NIR的Ir（III）PS的胶束可以特异性地靶向肿瘤 并且被H2 O2活化，并有效地产生比H2 O2更有毒性的ROS形式，以改善PDT 缺氧效率。本项目将追求三个具体目标-目标1： NIR PS BODIPY-Ir进入H2 O2活化和O2释放胶束，用于癌症特异性靶向和高效 缺氧条件下活性氧的产生;并评价胶束的包封、释放、缺氧条件下活性氧的产生， 和在PBS溶液中的光热转换效率;目的2：评价体外生长抑制， 新一代BODIPY-Ir胶束PDT/PTT对乳腺癌细胞迁移和侵袭的影响;目的3： 评价抑制肿瘤生长和转移的体内治疗结果， BODIPY-Ir胶束PDT/PTT治疗。乳腺癌细胞系、MDA MB-231和4 T1以及肿瘤模型 Balb/c小鼠/4 T1将分别用于体外和体内检验我们的假设。我们的长期目标 是推进PDT/PTT模式，以获得更有效和更安全的三阴性癌症治疗。 乳腺癌包括美国原住民学生在内的12名本科生将接受这方面的培训。 项目参与的学生将参与本项目的所有科学方面，包括PS 合成、胶束形成和表征、生物物理学研究以及体外和体内研究 光生物学研究，从他们将在各种生物材料和生物医学广泛培训 研究实验室技能这些学生还将接受文献使用、数据收集和分析方面的培训， 科学写作和演示，时间管理和沟通/人际交往技能。更 重要的是，我们的培训将帮助学生成为独立的研究人员谁是关键的能力， 以创造性和有效的方式思考和解决具有挑战性的健康相关科学问题。

PROJECT SUMMARY Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is an alternative cancer treatment modality based on the ability of photosensitizers (PSs) to convert photon energy into reactive oxygen species (ROS， i.e. singlet oxygen, superoxide anion, hydroxyl free radical, etc.) or heat. PDT/PTT treatment has special selectivity because the treatment only becomes effective when the PS is activated by light. PDT/PTT has the advantages of noninvasiveness, little or no scarring due to the fast healing process, and being able to treat the patients in an outpatient setting. However, the drawbacks of currently available porphyrin-based PSs, such as the inability to be activated by near-IR (NIR) light, low ROS generation efficiency in hypoxic solid tumors, low selectivity for cancerous tissue, and long-lasting cutaneous photosensitivity, have limited the application of PDT to superficial tumors. To solve these problems, we plan to apply our newly developed strong NIR-absorbing PS BODIPY-Ir to PDT/PTT by encapsulating it into cancer specific targeting, H2O2-activatable, and O2-evolving micelles to efficiently produce ROS in hypoxia. We hypothesize that the proposed micelles loaded with the NIR-absorbing Ir(III) PS can specifically target tumors and be activated by H2O2 and efficiently generate more toxic forms of ROS than H2O2 to improve the PDT efficiency under hypoxia. Three Specific Aims will be pursued in this project - Aim 1: To encapsulate our NIR PS BODIPY-Ir into H2O2-activatable and O2-evolving micelles for cancer-specific targeting and efficient ROS generation in hypoxia; and to evaluate the micelle encapsulation, release, ROS generation in hypoxia, and photothermal conversion efficiency in PBS solutions; Aim 2: To evaluate the in vitro inhibition of growth, migration and invasion of breast cancer cells by new-generation BODIPY-Ir micelle PDT/PTT; Aim 3: To evaluate the in vivo therapeutic outcomes of inhibiting tumor growth and metastasis following new-generation BODIPY-Ir micelle PDT/PTT treatment. Breast cancer cell lines, MDA MB-231 and 4T1, and tumor model Balb/c mice/4T1 will be used to test our hypothesis in vitro and in vivo, respectively. Our long-term objective is to advance the PDT/PTT modality for a more effective and much safer cancer therapy of triple-negative breast cancer. Twelve undergraduate students including Native American students will be trained in this project. The participating students will be involved in all scientific aspects of this project, including PS synthesis, micelle formation and characterization, photophysical studies, and in vitro and in vivo photobiological studies, from which they will be extensively trained on various biomaterials and biomedical research lab skills. These students will also be trained on literature usage, data collection and analysis, scientific writing and presentation, time management, and communication / interpersonal skills. More importantly, our training will help students becoming independent researchers who are capable of critical thinking and solving challenging health-related scientific problems in a creative and effective manner.