Nanoscintillator-based X-ray sensitizers to enable efficient NSCLC treatment with X-ray irradiation

基于纳米闪烁体的 X 射线敏化剂可通过 X 射线照射实现有效的 NSCLC 治疗

• 批准号: 9899249
• 负责人: Jin Xie
• 金额: $ 47.12万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899249
• 关键词: 3-Dimensional; Adopted; Animals; Area; Attention; Biodistribution; Biological Assay; Body Size; Body part; Cancer Etiology; Cells; Cetuximab; Characteristics; Clinic; Clinical; Clinical Oncology; Complement; DNA; DNA Damage; Development; Diagnosis; Disease; Dose; Elements; Energy-Generating Resources; Esophagitis; External Beam Radiation Therapy; Fluorescent Dyes; Formulation; Goals; Head and Neck Cancer; Histology; In Vitro; Individual; Label; Lead; Ligands; Light; Lipid Peroxidation; Low Dose Radiation; Mainstreaming; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Marriage; Maximum Tolerated Dose; Membrane Lipids; Methodology; Modality; Modeling; Monitor; Mus; Nanostructures; Nanotechnology; Neutropenic Fever; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; PUVA Photochemotherapy; Patients; Penetration; Persons; Pharmaceutical Preparations; Photons; Photosensitization; Photosensitizing Agents; Positron-Emission Tomography; Production; Protocols documentation; Radiation; Radiation therapy; Radioisotopes; Rattus; Refractory; Research; Resistance; Roentgen Rays; Series; Silicon Dioxide; Singlet Oxygen; Skin; Surface; System; Technology; Therapeutic procedure; Thick; Time; Tissues; Toxic effect; Transducers; Treatment Efficacy; Treatment Protocols; Treatment outcome; Visible Radiation; base; cancer cell; cancer invasiveness; cancer therapy; cancer type; cell killing; chemotherapy; clinical translation; conventional therapy; cytotoxic; image guided; interest; irradiation; luminescence; malignant breast neoplasm; minimally invasive; mortality; nanoparticle; nanosystems; new technology; novel; novel therapeutics; pre-clinical; radioresistant; repaired; response; side effect; standard of care; stem; success; therapy outcome; tumor; uptake; virtual; x-ray irradiation

Abstract Photodynamic therapy (PDT) has gained much attention as a relatively new cancer treatment modality. PDT has a favorable toxicity profile compared to radiotherapy. Meanwhile, it does not incur resistance, and can be applied to previously irradiated tissues. However, the use of PDT in the clinic has been very limited. This is largely due to its surface-weighted treatment efficacy, a result of limited penetration depth of light in tissues. Our long term objective is to develop a novel PDT derivative called X-ray induced PDT or X-PDT that can break the shallow penetration limitation. Our strategy is to use X-ray, which has great tissue penetration ability, as the energy source to trigger PDT. The key element of our technology is an integrated nanosystem, consisting of a scintillator nanoparticle core and photosensitizing drugs that match the scintillator’s emission wavelength. Upon X-ray irradiation, the nanoparticle scintillator functions as a transducer, converting X-ray photons to visible light photons. The visible photons, in turn, activate the near-by photosensitizing drugs to produce a cytotoxic species called singlet oxygen. Owing to the excellent transmittance of X-ray, X-PDT can be activated from deep tissues. Moreover, it was found that X-PDT is essentially a combination of PDT and radiotherapy. This leads to synergistic treatment outcomes, allowing X-PDT to efficiently kill cancer cells at low radiation doses, even for cancer cells that are refractory to radiotherapy. These characteristics make X-PDT an appealing treatment methodology. The present project will exploit X-PDT to treat non–small cell lung cancer (NSCLC), which is challenging or not possible for conventional PDT. NSCLC accounts for 85% of all lung cancer cases, and is diagnosed in 187,000 persons each year. Radiation, often concurrent with chemotherapy, is the standard of care for the majority of the patients. The treatment, however, may cause severe side effects such as neutropenic fever and Grade 3 esophagitis. Once recur, treatment options are limited since the radiation has been given to the maximum tolerated dose. Hence, there is an urgent need for an effective and less toxic treatment for NSCLC. It is expected that X-PDT can efficiently kill NSCLC through external radiation of relatively low doses with minimal collateral damage. Success of this project will be paradigm-shifting, breaking the shallow penetration dogma of conventional PDT and opening many new possibilities. X-PDT holds great potential in clinical translation, complementing or replacing current treatment regimens for NSCLC therapy. Although the current study is focused on NSCLC, the methodology can be easily extended to treatment of other cancer types, for instance head and neck cancer, breast cancer, and prostate cancer.

摘要 光动力学疗法（PDT）作为一种相对较新的癌症治疗方式受到了广泛关注。PDT 与放射疗法相比具有有利的毒性特征。同时，它不会引起阻力，并且可以 应用于先前照射的组织。然而，PDT在临床上的应用非常有限。这是 这主要是由于其表面加权的治疗功效，这是光在组织中的有限穿透深度的结果。 我们的长期目标是开发一种新的PDT衍生物，称为X射线诱导的PDT或X-PDT， 突破浅穿透限制。我们的策略是使用X射线，它具有很强的组织穿透能力， 作为能量源来触发光动力疗法我们技术的关键元素是一个集成的纳米系统， 闪烁体纳米颗粒核心和与闪烁体发射波长匹配的光敏药物。 在X射线照射时，纳米颗粒闪烁体用作换能器，将X射线光子转换为可见光。 光子可见光子反过来激活附近的光敏药物，产生细胞毒性 叫做单线态氧的物质。由于X射线具有良好的透射性，因此X-PDT可以从深部激活 组织中此外，发现X-PDT本质上是PDT和放射疗法的组合。这导致 协同治疗结果，允许X-PDT在低辐射剂量下有效杀死癌细胞，即使对于 对放射治疗无效的癌细胞。这些特点使X-PDT成为一种有吸引力的治疗方法 方法论 本项目将利用X-PDT治疗非小细胞肺癌（NSCLC），这是具有挑战性的， 这是传统PDT无法做到的。非小细胞肺癌占所有肺癌病例的85%， 每年18.7万人。放射治疗，通常与化疗同时进行，是治疗癌症的标准。 大多数患者。然而，这种治疗可能会引起严重的副作用，如贫血热， 3级食管炎。一旦复发，治疗选择是有限的，因为辐射已经给予了 最大耐受剂量因此，迫切需要有效且毒性较小的NSCLC治疗方法。它 预期X-PDT可以通过相对低剂量的外部辐射有效地杀死NSCLC， 附带伤害 这个项目的成功将是范式的转变，打破了传统的浅层渗透教条 PDT和开放许多新的可能性。X-PDT在临床翻译、补充或治疗方面具有巨大潜力。 取代目前的NSCLC治疗方案。虽然目前的研究集中在NSCLC， 该方法可以容易地扩展到其它癌症类型的治疗，例如头颈癌， 乳腺癌和前列腺癌。