UV-emitting nanoparticles as novel radiation sensitizers targeting hypoxic cells

发射紫外线的纳米颗粒作为针对缺氧细胞的新型辐射敏化剂

• 批准号: 9344815
• 负责人: Martin Purschke
• 金额: $ 30万
• 依托单位: RADIATION MONITORING DEVICES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-03 至 2018-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344815
• 关键词: Alpha Cell; Biochemical; Cancer Patient; Cell Communication; Cell Death; Cell Hypoxia; Cell Survival; Cells; Clinical; Collaborations; Country; DNA; DNA Damage; Deposition; Development; Diagnostic; Dose; Effectiveness; Electrons; Elements; Employee Strikes; Gadolinium; General Hospitals; Goals; High-LET Radiation; Human Biology; Hypoxia; In Vitro; Income; Irradiated tumor; Light; Linear Energy Transfer; Link; Literature; Lutetium; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Massachusetts; Mediating; Metabolism; Modeling; Nuclear; Optics; Oxygen; Particle Size; Phase; Photons; Prostate; Radiation; Radiation Monitoring; Radiation therapy; Radiation-Sensitizing Agents; Radioresistance; Radiosensitization; Reaction; Recurrence; Relapse; Resistance; Roentgen Rays; Solid Neoplasm; Systemic Therapy; Techniques; Technology; Testing; Therapeutic; Tissues; Treatment outcome; Tumor Tissue; Ultraviolet Rays; anticancer research; cancer cell; cancer therapy; cell killing; comparative; exhaustion; experimental study; improved; ionization; irradiation; killings; light effects; malignant breast neoplasm; medical schools; minimally invasive; molecular imaging; monitoring device; nanoparticle; neoplastic cell; novel; particle; preclinical study; radiation resistance; research and development; research facility; skin disorder; therapy outcome; tumor

Project Summary/Abstract Radiation therapy is one of the primary therapeutic techniques for treating cancer. Nearly two-thirds of all cancer patients will receive radiation therapy during their illness, with an average of 29 radiation treatment episodes. Although largely effective, radiation therapy, like other forms of cancer treatment, has difficulty killing hypoxic regions within solid tumors. Cellular hypoxia is associated with radiotherapy resistance, resulting in the incomplete killing of cancer cells, and leading to recurrence and relapse. Thus, developing techniques to target the hypoxic core of tumors is a major goal of cancer research. Nearly 40% of all breast cancers and 50% of locally advanced breast cancers are hypoxic, and their altered metabolism is strongly linked to resistance to radiotherapy and systemic therapy. In prostate cancer, hypoxia is associated with early biochemical relapse after radiotherapy and also with local recurrence in the prostate gland. A variety of approaches are being used to enhance the efficacy of radiation therapy and reduce dose. These include the use of nanoparticles to enhance the radiosensitization of tumor tissue, reversing radiation resistance in tumor tissue, and increasing the radioresistance of healthy tissue. In this proposed effort, we will develop a new technique that enhances radiation treatment by using a sensitizer that both increases the energy deposited locally within the tumor and generates UV photons in the vicinity of the DNA in cancer cells. Our sensitizer consists of scintillating nanoparticles that emit UV radiation, capable of both directly damaging the DNA in hypoxic cancer cells. In addition, these particles will be composed of high atomic number elements with much higher radiation stopping power than the low atomic number elements that make up tissue. This will enhance the efficacy of the high-energy X-rays used in radiation treatment by down converting the X-ray photon energy into lower energy X-rays and particles, which have a much higher energy deposition rate (linear energy transfer, LET). We have performed a preliminary experiment, which gave encouraging results showing an increase in cell death using the LuPO4 scintillating nanoparticles. In Phase I of this effort, we will model photon transport and energy conversion, for both X-rays and UV photons, and experimentally demonstrate the effectiveness of the concept in vitro. In Phase II, we will develop size homogenous nanoparticles suitable for use in exhaustive in vitro cell experiments and preclinical studies.

项目总结/摘要 放射治疗是治疗癌症的主要治疗技术之一。近三分之二的 所有癌症患者在患病期间将接受放射治疗，平均29次放射治疗 情节。虽然很大程度上有效，放射治疗，像其他形式的癌症治疗，有困难， 杀死实体瘤内的缺氧区域。 细胞缺氧与放射治疗抵抗有关，导致对癌症的不完全杀死 细胞，并导致复发和复发。因此，开发针对肿瘤缺氧核心的技术 是癌症研究的主要目标。近40%的乳腺癌和50%的局部晚期乳腺癌 缺氧，其代谢改变与对放射治疗和全身治疗的抵抗密切相关。 在前列腺癌中，缺氧与放疗后早期生化复发有关，也与局部复发有关。 前列腺内复发。 各种各样的方法被用来提高放射治疗的疗效和减少剂量。 这些包括使用纳米颗粒来增强肿瘤组织的放射增敏作用，逆转辐射 增强肿瘤组织的抗辐射能力，提高健康组织的抗辐射能力。 在这项提议的努力中，我们将开发一种新技术，通过使用 敏化剂既增加了肿瘤内局部沉积的能量，又在肿瘤内产生UV光子。 癌细胞中的DNA附近。我们的敏化剂由发射紫外线的纳米粒子组成， 能够直接破坏缺氧癌细胞的DNA。此外，这些颗粒将 由高原子序数元素组成，其辐射阻止能力比低原子序数元素高得多。 组成组织的元素。这将提高用于治疗的高能X射线的功效 通过将X射线光子能量向下转换为较低能量的X射线和粒子的放射治疗， 具有高得多的能量沉积速率（线性能量传递，LET）。我们已经进行了初步的 该实验给出了令人鼓舞的结果，显示使用LuPO 4稀释的细胞死亡增加 纳米粒子 在第一阶段，我们将模拟X射线和紫外线的光子传输和能量转换 光子，并在体外实验证明了这一概念的有效性。在第二阶段，我们将开发 尺寸均匀的纳米颗粒适合用于详尽的体外细胞实验和临床前研究。

项目成果

Fabrication and characterization of UV-emitting nanoparticles as novel radiation sensitizers targeting hypoxic tumor cells.

• DOI: 10.1016/j.optmat.2018.04.033
• 发表时间: 2018-06
• 期刊: Optical Materials
• 影响因子: 3.9
• 作者: M. Squillante;T. Jüstel;R. Anderson;C. Brecher;Daniel Chartier;J. Christian;Nicholas Cicchetti;S. Espinoza;D. McAdams;Matthias Müller;Brooke Tornifoglio;Yimin Wang;M. Purschke