NANOPHOTOSENSITIZERS FOR REGENERATIVE PHOTOTHERAPY OF TUMORS

摘要 无机纳米颗粒(INP)表现出独特的性质，有利于其广泛的应用 在医学、工程、科学和技术方面。它们的大表面积与体积比 INPS提供多种药物和/或显像剂的附着点，用于治疗和 对各种人类疾病进行成像。生物实体的进一步结合，例如蛋白质， 核酸和脂类赋予这些INPs在体内所需组织中的特异性靶向。近期 研究表明，某些INP的固有特性可用于治疗。 结果，但自发刺激的内在治疗效果通过相互作用 具有细胞内细胞器、蛋白质或分子过程的NPS很难控制，导致 严重偏离目标的毒性。另一种治疗方法可以通过利用 一些INP作为有效的纳米级能量转换器的能力。量子点， 上转换纳米粒子、碳纳米材料和光催化纳米粒子，如二氧化钛 纳米粒子是一些纳米级的能量转换器，在治疗中显示出了希望。 人类疾病。这些纳米光敏剂优异的氧化还原性能提供了高 对光的吸收进行时空控制和精密光疗。两个主要限制 目前的光治疗干预措施是有限的光穿透用于激活 将治疗局限于浅层皮损的光敏剂，以及对氧气的频繁依赖 产生细胞毒性的活性氧物种，这排除了有效的治疗 在许多实体肿瘤中发现的低氧状态。 我们假设低辐射敏感型纳米光敏剂通过 深度无关的切伦科夫辐射将在氧气中产生细胞毒性自由基- 以独立的方式进行有效治疗。在这个方案中，我们将(1)综合和优化 肿瘤靶向纳米光敏剂用于疾病的有效时空治疗；以及(2) 优化正交靶向放射性核素选择性地传输切伦科夫辐射到 病理细胞和组织。利用癌症的动物模型，我们将确定其疗效 切伦科夫辐射介导的纳米光疗。

Abstract 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 and/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, but 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 can be achieved by harnessing the ability of some INPs to serve as efficient nanoscale energy transducers. Quantum dots, upconversion NPs, carbon nanomaterials, and photocatalytic NPs such as titanium dioxide nanoparticles 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 photosentizers, which confines therapy to shallow lesions, and the frequent reliance on oxygen to generate cytotoxic reactive oxygen species, which precludes effective treatment under the hypoxic conditions found in many solid tumors. We hypothesize that photoactivation of low radiance-sensitive nanophotosensitizers via depth-independent Cerenkov radiation will generate cytotoxic free radicals in an oxygen- independent manner for effective therapy. In this proposal, we will (1) Synthesize and optimize tumor-targeting nanophotosensitizers for effective spatiotemporal therapy of diseases; and (2) optimize orthogonally targeted radionuclides for selective delivery of Cerenkov radiation to pathologic cells and tissue. Using animal models of cancer, we will determine the efficacy of Cerenkov radiation mediated nano-phototherapy.