NANOPHOTOSENSITIZERS FOR REGENERATIVE PHOTOTHERAPY

用于再生光疗的纳米光敏剂

• 批准号: 10317997
• 负责人: Samuel Achilefu
• 金额: $ 70.85万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-04 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317997
• 关键词: Adrenal Cortex Hormones; Affect; Award; Binding; Biological; Biological Availability; Bone Marrow; Bone Matrix; Bortezomib; CAR T cell therapy; Carbon; Cell Death; Cells; Cherenkov Radiation; Clinical Treatment; Clonal Expansion; Combined Modality Therapy; Complement; Complex; Coupled; Data; Disease; Disease-Free Survival; Dose; Drug Delivery Systems; Drug resistance; Encapsulated; Engineering; Environment; Event; Exhibits; Fluorine; Fracture; Funding; Glucose Transporter; Grant; Hematologic Neoplasms; Hematopoietic Neoplasms; High Dose Chemotherapy; Human; Hypoxia; Image; Immunomodulators; Immunosuppression; Intervention; Intravenous; Lesion; Light; Lipids; Liver; Lung; Malignant - descriptor; Malignant Bone Neoplasm; Malignant Neoplasms; Mediating; Medical; Medicine; Metals; Methods; Molecular; Monoclonal Antibodies; Multiple Myeloma; Nanotechnology; Natural regeneration; Nucleic Acids; Organelles; Osteolysis; Outcome; Oxidation-Reduction; Oxygen; Pathway interactions; Patients; Penetration; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Photosensitizing Agents; Phototherapy; Plasma; Process; Prodrugs; Production; Progression-Free Survivals; Property; Proteasome Inhibitor; Proteins; Quality of life; Quantum Dots; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reactive Oxygen Species; Relapse; Research; Residual Tumors; Resistance; Science; Seminal; Signal Pathway; Site; Solid Neoplasm; Source; Spleen; Stromal Cells; Supporting Cell; Surface; Technology; Testing; Therapeutic; Therapeutic Effect; Thrombocytopenia; Tissues; Toxic effect; Transducers; Transferrin; Treatment outcome; Ultraviolet Rays; absorption; base; bone; cancer cell; cancer imaging; cancer therapy; chemotherapy; clinically translatable; cytotoxic; effective therapy; field study; fluorodeoxyglucose; human disease; imaging agent; improved; in vivo; nano; nanomaterials; nanomedicine; nanoparticle; nanoparticle delivery; nanoscale; nanoscience; nanotechnology platform; nanotherapy; neurotoxicity; novel; prevent; regenerative; relapse patients; side effect; spatiotemporal; stem; systemic toxicity; therapy outcome; titanium dioxide; titanocene; treatment response; treatment strategy; tumor; tumor growth

ABSTRACT The excitement about nanomedicine stems from the potential application of nanoscience to solve challenging medical problems. Inorganic nanoparticles (iNPs) exhibit unique properties that favor their diverse application in medicine, engineering, science, and technology. The large surface-to-volume ratio of these iNPs provides sites for the attachment of multiple drugs or imaging agents for therapy and imaging of diverse human diseases. Further conjugation of biological entities, such as proteins, nucleic acids, and lipids, confers specific targeting of these iNPs to desired tissues in vivo. Recent studies have shown that the intrinsic properties of some iNPs can be harnessed for therapeutic outcomes. Still, spontaneous stimulation of intrinsic therapeutic effects through interactions of the NPs with intracellular organelles, proteins, or molecular processes is difficult to control, leading to significant off-target toxicity. An alternative therapeutic approach is to transform some iNPs into nanoscale energy transducers. Quantum dots, upconversion NPs, carbon nanomaterials, and photocatalytic NPs are some nanoscale energy transducers that have shown promise in the treatment of human diseases. The excellent redox properties of these nanophotosensitizers offer high spatiotemporal control and precision phototherapy upon absorption of light. Two major limitations of current phototherapeutic interventions are the limited penetration of light used to activate the photosensitizers, which confines therapy to shallow lesions, and the frequent reliance on molecular oxygen to generate cytotoxic reactive oxygen species, a condition that precludes the effective treatment under the hypoxic conditions found in many solid and hematologic tumors. Recently, we developed radionuclide stimulated therapy that leverages the interaction of Cerenkov radiation emitting radionuclides to stimulate the production of reactive oxygen species from photosensitizers. The spatiotemporal therapeutic effects of these interactions allow the treatment of diverse diseases without tissue depth limitation that affects light-based therapies. Supported by new concepts grounded in robust preliminary data, we propose to (1) explore new nanostrategies to overcome the impediment to delivering NPs to tumors, (2) disrupt the protective interactions of cancer with stromal cells to enhance treatment response, and (3) exert sustainable therapeutic effect via multidimensional combination therapy to achieve disease-free survival. At the completion of this study, we would develop new nanoplatforms for the treatment and imaging of cancer and bone lesions.

摘要 对纳米医学的兴奋源于纳米科学在解决 挑战医学问题。无机纳米颗粒(INP)表现出独特的性质，有利于其多样化 在医学、工程、科学和技术方面的应用。这些INP的大表面积体积比 提供多种药物或显像剂的附着点，用于治疗和成像不同的人类 疾病。生物实体的进一步结合，如蛋白质、核酸和脂类，赋予特定的 在体内将这些INPS靶向所需的组织。最近的研究表明，一些生物的内在属性 INPS可用于治疗效果。尽管如此，内在疗效的自发刺激 通过NPs与细胞内细胞器、蛋白质或分子过程的相互作用，很难 控制，导致严重的脱靶毒性。另一种治疗方法是将一些INP 变成纳米级的能量传感器。量子点、上转换纳米粒子、碳纳米材料和光催化 NPS是一些纳米级的能量换能器，在治疗人类疾病方面显示出了希望。这个 这些纳米光敏剂优异的氧化还原性能提供了高时空控制和精确度 光吸收后的光疗。当前光疗干预的两个主要局限性是 用于激活光敏剂的光的穿透性有限，这将治疗限制在浅层皮损，以及 经常依赖分子氧来产生细胞毒性的活性氧物种，这种情况 排除了在许多实体和血液肿瘤中发现的低氧条件下的有效治疗。 最近，我们开发了利用切伦科夫辐射相互作用的放射性核素刺激疗法。 放出放射性核素以刺激光敏剂产生活性氧物种。这个 这些相互作用的时空治疗效应允许在没有组织的情况下治疗各种疾病 影响光疗法的深度限制。以稳健的初步研究为基础的新概念的支持 数据，我们建议(1)探索新的纳米战略，以克服向肿瘤输送NPs的障碍， (2)破坏肿瘤与基质细胞的保护性相互作用，以增强治疗反应；(3)发挥 通过多维联合治疗获得可持续的治疗效果，以实现无病生存。 在这项研究完成后，我们将开发新的纳米平台用于癌症的治疗和成像 和骨骼损伤。