Rational translation of gold nanoparticle mediated radiosensitization tothe clinic

使用高原子序数（Z）元素作为肿瘤的放射增敏剂已经在文献中有很好的记载。 文学在过去的几十年里。特别地，金纳米颗粒（GNP），通常被定义为高Z金纳米颗粒。 具有小于100 nm的最长尺寸的结构，已经成为 在过去的15年里，同样的目的。GNP介导的放射增敏（GMR）的早期体内证明 作用基于GNP在肿瘤内的被动积累（“被动靶向”）。同时导致 由于GMR水平显著，这种方法通常需要临床上不太相关的辐射质量（低能量 千伏X射线）和临床上无法达到的（没有直接注射）金浓度（高达7毫克金， 肿瘤）。为了克服这些困难，我们一直在研究一种替代方法， “主动靶向”，这显示了一个有前途的前景，在短期内的临床翻译。该提案寻求 在开始行动之前， 关于GMR的临床翻译具体来说，我们的目标是确定GMR的分子机制，生物分布 GNP的临床翻译动力学，它们在肿瘤和细胞水平的命运，以及 GNP介导的剂量增强与GMR之间的相关性。尽管有大量的数据和出版物， 根据多年来积累的全球监测报告，在上述方面仍然存在严重的知识差距， 阻碍了GMR的临床转化。正如我们的初步数据所示，我们建议解决这些问题， 通过协调一致的多学科努力，解决GMR临床转化的关键问题。后 为了实现这一目标，GNP增强放射治疗（RT）的试点人体试验也将在 该项目用于治疗复发性直肠癌。总的来说，我们将追求三个具体目标， 为了实现这个项目的目标。(1)为了确定GMR的分子机制， GNP在体外和体内的生物分布/动力学，以及临床相关的放射增敏功效。 治疗方案，（2）使用高分辨率将GNP介导的剂量增强与GMR相关联 基于图像的细胞/组织模型和纳米级计算技术，以及（3）进行飞行员人体 GNP增强RT治疗既往放疗复发直肠癌的试验。最终，这个项目将奠定 为当前设想的RT范式的广泛应用奠定了基础， 肿瘤特异性RT，毒性较小。

The use of high atomic number (Z) elements as radiosensitizers of tumors has been well documented in the literature over the last few decades. In particular, gold nanoparticles (GNPs), typically defined as high-Z gold structures with the longest dimension smaller than 100 nm, have been the subject of active investigation for the same purpose for the past 15 years. Early in vivo demonstration of GNP-mediated radiosensitization (GMR) effect was based on passive accumulation of GNPs within tumors (“passive targeting”). While resulting in a remarkable level of GMR, this approach generally requires clinically less relevant radiation quality (low energy kilovoltage x-rays) and clinically unachievable (without direct injection) gold concentration (up to 7mg gold per gram of tumor). To overcome these difficulties, we have been investigating an alternative approach based on “active targeting” which shows a promising outlook for clinical translation in the near term. This proposal seeks to surmount the remaining challenges associated with our active targeting-based approach before embarking on clinical translation of GMR. Specifically, we aim to identify the molecular mechanism of GMR, biodistribution and kinetics of GNPs developed for clinical translation, their fate at the tumor and cellular levels, and the correlation between GNP-mediated dose enhancement and GMR. Despite abundant data and publications on GMR accumulated over the years, critical knowledge gaps still exist in terms of the aforementioned aspects, hindering clinical translation of GMR. As demonstrated in our preliminary data, we propose to address such issues that hold the key for clinical translation of GMR, through concerted multidisciplinary efforts. Upon achieving this goal, a pilot human trial of GNP-enhanced radiation therapy (RT) will also be conducted within this project for the management of recurrent rectal cancer. Overall, we will pursue three Specific Aims shown below to achieve the goals of this project. (1) To determine the molecular mechanism of GMR, the biodistribution/kinetics of GNPs in vitro and in vivo, and the radiosensitization efficacy in clinically relevant treatment scenarios, (2) To correlate GNP-mediated dose enhancement and GMR using high resolution image-based cell/tissue models and nanoscale computational techniques, and (3) To conduct a pilot human trial of GNP-enhanced RT for previously radiated recurrent rectal cancers. Ultimately, this project would lay the foundation for widespread applications of the currently envisioned RT paradigm that enables more potent and tumor-specific RT with less toxicity.