NANOPHOTOSENSITIZERS FOR REGENERATIVE PHOTOTHERAPY OF TUMORS

用于肿瘤再生光疗的纳米光敏剂

• 批准号: 10164004
• 负责人: Samuel Achilefu
• 金额: $ 45.07万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164004
• 关键词: A549; Address; Animal Cancer Model; Animal Model; Antioxidants; Biodistribution; Biological; Carbon; Cell model; Cells; Cherenkov Radiation; Clinical; Dependence; Disease; Endoscopes; Engineering; Enzymes; Excretory function; Exhibits; Free Radicals; Glucose; Harvest; Hydroxyl Radical; Hypoxia; Image; In Transferrin; Intervention; Kidney; Label; Lesion; Light; Lipids; Liver; Magnetic Resonance Imaging; Magnetism; Mediating; Medicine; Methods; Molecular; Nucleic Acids; Organ; Organelles; Oxidation-Reduction; Oxygen; PUVA Photochemotherapy; Pathologic; Penetration; Pharmaceutical Preparations; Photosensitization; Photosensitizing Agents; Phototherapy; Positron; Positron-Emission Tomography; Precision therapeutics; Process; Prodrugs; Proliferating; Property; Proteins; Quantum Dots; Radiation; Radioisotopes; Radiolabeled; Reactive Oxygen Species; Science; Singlet Oxygen; Site; Solid Neoplasm; Source; Surface; TFRC gene; Technology; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Transducers; Transferrin; Treatment Efficacy; Ultraviolet Rays; absorption; alternative treatment; analog; cancer cell; cancer therapy; cell type; cellular imaging; cytotoxic; cytotoxicity; effective therapy; free radical oxygen; human disease; imaging agent; improved; in vivo; light dosimetry; nano; nanomaterials; nanoparticle; nanoscale; neoplastic cell; optical imaging; overexpression; photoactivation; receptor; regenerative; spatiotemporal; therapy outcome; titanium dioxide; treatment optimization; tumor; uptake

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.

摘要 无机纳米粒子（INPs）具有独特的性质，有利于其多样化的应用 在医学、工程、科学和技术方面。大的表面积与体积比， INPs提供了用于附着多种药物和/或成像剂的位点， 各种人类疾病的成像。生物实体如蛋白质的进一步缀合， 核酸和脂质赋予这些INPs在体内对所需组织的特异性靶向。最近 研究表明，一些INPs的内在特性可以用于治疗， 结果，但通过相互作用的内在治疗效果的自发刺激 具有细胞内细胞器、蛋白质或分子过程的NP难以控制，导致 明显脱靶毒性。另一种治疗方法可以通过利用 一些INPs作为有效的纳米级能量转换器的能力。量子点， 上转换NP、碳纳米材料和光催化NP，如二氧化钛 纳米颗粒是一些纳米级能量转换器，在治疗中显示出希望 人类疾病。这些纳米光敏剂的优异的氧化还原性质提供了高性能。 时空控制和精确光疗。两大局限 目前的光疗干预是有限的光穿透用于激活 光敏剂，这限制了治疗浅病变，并经常依赖于氧气 以产生细胞毒性活性氧，这妨碍了根据本发明的有效治疗。 在许多实体瘤中发现的缺氧条件。 我们假设，低辐射敏感的纳米光敏剂的光活化，通过 与深度无关的切伦科夫辐射将在氧- 独立的方式进行有效的治疗。在本建议中，我们将（1）综合和优化 用于疾病的有效时空治疗的肿瘤靶向纳米光敏剂;和（2） 优化正交靶向放射性核素，以选择性地递送切伦科夫辐射， 病理细胞和组织。使用癌症的动物模型，我们将确定 切伦科夫辐射介导的纳米光疗。

项目成果

Utilizing the Multiradionuclide Resolving Power of SPECT and Dual Radiolabeled Single Molecules to Assess Treatment Response of Tumors.

• DOI: 10.1007/s11307-015-0842-8
• 发表时间: 2015-10
• 期刊: Molecular imaging and biology
• 影响因子: 3.1
• 作者: Xu B;Shokeen M;Sudlow GP;Harpstrite SE;Liang K;Cheney PP;Edwards WB;Sharma V;Laforest R;Akers WJ;Achilefu S
• 通讯作者: Achilefu S

Breaking the depth dependency of phototherapy with Cerenkov radiation and low-radiance-responsive nanophotosensitizers.

• DOI: 10.1038/nnano.2015.17
• 发表时间: 2015-04
• 期刊: Nature nanotechnology
• 影响因子: 38.3

Monodispersed calcium carbonate nanoparticles modulate local pH and inhibit tumor growth in vivo.

• DOI: 10.1039/c5nr06162h
• 发表时间: 2016-07-07
• 期刊: Nanoscale
• 影响因子: 6.7
• 作者: Som A;Raliya R;Tian L;Akers W;Ippolito JE;Singamaneni S;Biswas P;Achilefu S
• 通讯作者: Achilefu S

Probing distance-dependent plasmon-enhanced near-infrared fluorescence using polyelectrolyte multilayers as dielectric spacers.

• DOI: 10.1002/anie.201308516
• 发表时间: 2014-01-13
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Gandra N;Portz C;Tian L;Tang R;Xu B;Achilefu S;Singamaneni S
• 通讯作者: Singamaneni S

Inactivation of multidrug-resistant bacteria and bacterial spores and generation of high-potency bacterial vaccines using ultrashort pulsed lasers.

• DOI: 10.1002/jbio.202100207
• 发表时间: 2022-03
• 期刊: Journal of biophotonics
• 影响因子: 2.8
• 作者: Tsen SD;Popovich J;Hodges M;Haydel SE;Tsen KT;Sudlow G;Mueller EA;Levin PA;Achilefu S
• 通讯作者: Achilefu S