UV-emitting nanoparticles as novel radiation sensitizers targeting hypoxic cells

项目摘要/摘要 放射治疗是治疗癌症的主要治疗技术之一。近三分之二的人 所有癌症患者在患病期间都将接受放射治疗，平均29次放射治疗 剧集。尽管放射治疗大体上有效，但像其他形式的癌症治疗一样，它也有困难。 杀死实体瘤内的缺氧区。 细胞缺氧与放射抵抗有关，导致肿瘤的不完全杀伤。 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 是癌症研究的一个主要目标。近40%的乳腺癌和50%的局部晚期乳腺癌 是低氧的，他们的新陈代谢改变与抵抗放射治疗和系统治疗密切相关。 在前列腺癌中，低氧与放射治疗后早期生化复发以及局部复发有关。 前列腺癌复发。 目前正在使用各种方法来提高放射治疗的疗效和减少剂量。 这些措施包括使用纳米颗粒来增强肿瘤组织的放射增敏，逆转辐射 肿瘤组织中的辐射抗性，以及增加健康组织的辐射抗性。 在这项拟议的工作中，我们将开发一种新技术，通过使用 一种增敏剂，既能增加肿瘤局部沉积的能量，又能在肿瘤组织中产生紫外线光子 癌细胞中DNA的附近。我们的感光剂由发射紫外线辐射的闪烁纳米颗粒组成， 都能直接损伤缺氧癌细胞的DNA。此外，这些粒子将被 由高原子序数元素组成，具有比低原子序数元素高得多的辐射阻挡能力 对构成组织的元素进行编号。这将增强高能X射线在 通过将X射线光子能量向下转换为较低能量的X射线和粒子进行放射治疗，这 有更高的能量沉积率(线性能量转移，LET)。我们已经进行了初步的 实验，给出了令人鼓舞的结果，表明使用LuPO4闪烁增加了细胞死亡 纳米粒子。 在这项工作的第一阶段，我们将对X射线和紫外线的光子传输和能量转换进行建模 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 大小均匀的纳米颗粒，适用于详尽的体外细胞实验和临床前研究。

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.