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被很好地记录在 过去几十年的文学作品。特别是，金纳米颗粒(GNPs)，通常定义为高Z-金 最长尺寸小于100 nm的结构一直是积极研究的对象 在过去的15年里，同样的目的。GNP介导的放射增敏(GMR)的早期体内演示 作用是基于肿瘤内GNPs的被动积累(“被动靶向”)。同时导致了一个 显著的GMR水平，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金浓缩(每个金高达7毫克金 克肿瘤)。为了克服这些困难，我们一直在研究一种替代方法，该方法基于 “主动靶向”，显示了近期临床翻译的良好前景。这项提议旨在 在开始之前，克服与我们基于主动目标的方法相关的剩余挑战 关于GMR的临床翻译。具体地说，我们的目标是确定GMR的分子机制，生物分布 为临床翻译而开发的GNPs的动力学，它们在肿瘤和细胞水平上的去向，以及 GNP介导的剂量增强与GMR的相关性。尽管有大量的数据和出版物， 尽管全球监测系统多年来积累了大量经验，但上述各方面的关键知识差距仍然存在， 阻碍GMR的临床翻译。正如我们的初步数据所表明的那样，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临床翻译的关键问题。vt.在.的基础上 为了实现这一目标，还将在年内进行GNP增强放射治疗(RT)的试点人体试验 本项目用于治疗直肠癌复发。总体而言，我们将实现三个具体目标 以实现本项目的目标。(1)为了确定GMR的分子机制， GNPs在体内外的生物分布/动力学及临床相关放射增敏效应 治疗方案，(2)使用高分辨率将GNP介导的剂量增加和GMR联系起来 基于图像的细胞/组织模型和纳米级计算技术，以及(3)进行人体试验 GNP增强放疗治疗既往放疗后复发直肠癌的试验最终，这个项目将为 为当前设想的RT范例的广泛应用奠定了基础，该范例能够实现更强大的 肿瘤特异性RT，毒性小。

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.