NANOPHOTOSENSITIZERS FOR REGENERATIVE PHOTOTHERAPY OF TUMORS

 描述(申请人提供)：无机纳米颗粒(INP)表现出独特的性质，有利于它们在医学、工程、科学和技术方面的广泛应用。这些INP的大表面与体积比为多种药物和/或显像剂的附着提供了场所，用于治疗和成像各种人类疾病。蛋白质、核酸和脂类等生物实体的进一步结合使这些INPs在体内能够特异性地靶向所需的组织。最近的研究表明，一些INP的内在特性可以用于治疗效果，但通过NPs与细胞内细胞器、蛋白质或分子过程的相互作用自发刺激内在治疗效果是很难控制的，从而导致显著的门外毒性。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换能器的能力来实现。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)是一些在治疗人类疾病方面显示出希望的纳米级能量转换器。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对光的吸收进行精确的光疗。目前光治疗干预的两大局限性是用于激活光敏器的光的穿透性有限，这将治疗限制在浅层病变，以及频繁依赖氧气产生细胞毒性活性氧物种，这阻碍了在许多实体肿瘤中发现的低氧条件下的有效治疗。我们假设，通过深度无关的切伦科夫辐射对低辐射敏感的纳米光敏剂进行光激活，将以一种不依赖氧的方式产生细胞毒性自由基，从而实现有效的治疗。在这项建议中，我们将(1)合成和优化肿瘤靶向纳米光敏剂，以有效地进行疾病的时空治疗；(2)优化正交靶向放射性核素，以选择性地将切伦科夫辐射输送到病理细胞和组织。利用癌症动物模型，我们将确定切伦科夫辐射介导的纳米光疗的疗效。

 DESCRIPTION (provided by applicant): 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 taget 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.