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.
Increasing the radiation dose delivered to rectal cancers treated preoperatively can improve pathological response at the time of surgery and possibly even obviate the need for surgery but this has been challenging to implement in the clinic due to the limited radiation tolerance of the surrounding normal intestinal loops. Gold nanoparticles that preferentially accumulate in tumors offer the possibility to increase radiation dose within the tumor without damaging adjacent normal tissues. To amplify this radiation dose enhancement, we propose to advance clinical translation of a paradigm using gold nanoparticles that home to the tumor, get internalized by receptor-mediated endocytosis, disperse in the cytoplasm via co-administered pharmacological agents, and can be modeled by mathematical techniques that predict the biological consequences of tumor accumulation.
