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: 9311376
• 负责人: Jin Xie
• 金额: $ 49.23万
• 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 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311376
• 关键词: Adopted; Adverse effects; 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; Injectable; Label; Lead; Ligands; Light; Lipid Peroxidation; Lipid Peroxides; 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; killings; luminescence; malignant breast neoplasm; minimally invasive; mortality; nanoparticle; nanosystems; new technology; novel; novel therapeutics; pre-clinical; radioresistant; repaired; response; standard of care; stem; success; therapy outcome; tumor; uptake; virtual

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 光动力疗法(PDT)作为一种相对较新的肿瘤治疗方法已引起人们的广泛关注。光动力疗法 与放射治疗相比，具有更好的毒性特征。同时，它不会招致阻力，而且可以 适用于先前受过辐射的组织。然而，光动力疗法在临床上的应用一直非常有限。这是 这在很大程度上是由于其表面加权的治疗效果，这是光在组织中的穿透深度有限的结果。 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PDT或X-PDT，它可以 打破浅层侵彻限制。我们的策略是使用X射线，它具有很强的组织穿透能力， 作为触发光动力疗法的能源。我们技术的关键要素是一个集成的纳米系统，包括 闪烁体纳米颗粒核心和与闪烁体发射波长相匹配的光敏药物。 在X射线照射下，纳米粒子闪烁体起到换能器的作用，将X射线光子转换为可见光 光光子。可见光反过来通过光敏药物激活附近的药物，产生一种细胞毒 被称为单线态氧的物种。由于X射线的良好透过性，X-PDT可以从深部激活 纸巾。此外，还发现X-PDT本质上是PDT和放射治疗的结合。这导致了 协同治疗结果，使X-PDT能够在低辐射剂量下有效地杀死癌细胞，即使在 对放射治疗无效的癌细胞。这些特点使X-PDT成为一种吸引人的治疗方法 方法论。 本项目将利用X-PDT治疗非小细胞肺癌(NSCLC)，这是一项具有挑战性或 对于传统的光动力疗法是不可能的。非小细胞肺癌占所有肺癌病例的85%，被诊断为 每年有18.7万人。放射治疗通常与化疗同时进行，是治疗乳腺癌的标准治疗方法。 大多数患者。然而，这种治疗可能会引起严重的副作用，如中性粒细胞减少症和 三级食管炎。一旦复发，治疗选择就有限了，因为辐射已经给了 最大耐受量。因此，迫切需要一种有效且毒性较低的非小细胞肺癌治疗方法。它 预计X-PDT可通过相对低剂量、最小剂量的外照射有效地杀伤非小细胞肺癌 附带损害。 这一项目的成功将是范式的转变，打破了传统的肤浅的渗透教条 并开启了许多新的可能性。X-PDT在临床翻译、补充或治疗方面具有巨大潜力 取代目前的治疗方案用于非小细胞肺癌的治疗。虽然目前的研究重点是非小细胞肺癌，但 方法学可以很容易地扩展到其他类型的癌症的治疗，例如头颈癌， 乳腺癌和前列腺癌。