Molecular Imaging to Study Radio-Protection by Cerium Oxide Nanoparticles

 描述（由申请人提供）：沿着化疗和手术，放射治疗（RT）是癌症的主要治疗选择。它是全世界5000多万癌症幸存者治疗计划的一个组成部分。即使随着适形图像引导治疗的进步，RT仍然受到对正常组织损伤的限制。短期和长期的副作用都与RT有关，包括贫血、胃肠道不适、皮肤刺激、组织纤维化，甚至继发性癌症。这些损害了RT期间许多患者的生活质量。RT通过产生自由基杀死细胞，从而破坏细胞的自由基清除保护机制，导致DNA损伤。作为一种预防措施，抗氧化剂药物已被发现可以补充细胞的自由基清除和减少RT副作用。这些药物都有自己的副作用，它们是否也能保护肿瘤组织尚不清楚，这导致了对它们使用的争议。由稀土元素铈的氧化物制成的氧化铈纳米颗粒（CONPs）可能是一种新型的潜在治疗剂，用于其作为RT的正常组织的保护剂的应用。CONPs已被用作工业催化剂，以其独特的氧化还原化学而闻名，并且最近已被研究用于其生物医学应用。C 0 NP已经证明保护细胞免受由炎症、氧化和辐射损伤产生的自由基的影响，具有最小的剂量相关毒性。已经表明，CONP不能保护癌细胞免受辐射损伤，尽管对这种辐射保护损失的机制知之甚少。该项目试图通过尝试发现肿瘤微环境（TME），特别是低pH和缺氧对CONP的辐射防护特性的影响来显着增加对这些机制的理解。pH和缺氧是本研究的重点，因为CONP在较低pH下失去其氧化还原性质，并且TME的缺氧条件对自由基产生和肿瘤放射抗性至关重要，并且还可能影响CONP在肿瘤组织中的反应。已在体内研究了CONP的作用，但缺乏在临床模拟治疗条件下的机制研究。本提案将采用多种方式 分子影像学和适形影像引导的放射治疗，以更好地理解自发性结肠癌小鼠模型中CONP的放射保护作用的潜在机制。分子成像将包括放射性标记的C 0 NP（rC 0 NP）的SPECT- /PET-CT成像以测量摄取和药代动力学，而MRI和断层光声成像（TPA）将用于确定体内pH和氧梯度。[18F]FDG PET成像将用于监测肿瘤生长和肿瘤/正常组织对RT的反应。比较正常/肿瘤组织对rCONPs摄取和体内pH/O2条件的反应，并进行体外交叉验证，将揭示它们之间的相互关系。这种方法 这些研究的结果与临床上可用的结果相当，这些研究的信息可能有助于加速CONP转化为RT临床试验。

 DESCRIPTION (provided by applicant): Along with chemotherapy and surgery, radiation therapy (RT) is a leading treatment option for cancer. It is an element in the treatment plan of over 50 million cancer survivors worldwide. Even with advances in conformal image guided therapies, RT is still limited by damage to normal tissues. Both short and long term side effects have been associated with RT, including anemia, gastrointestinal distress, skin irritation, tissue fibrosis, and even secondary cancer. These compromise the quality of life for many patients during RT. RT kills cells through free radical generation that overwhelms cells' radical scavenging protective mechanisms, leading to DNA damage. As a preventive measure, antioxidant drugs have been discovered that can supplement cells' radical scavenging and reduce RT side effects. These drugs have their own side effects and whether they also protect tumor tissue is unclear, leading to controversy over their use. Cerium oxide nanoparticles (CONPs), made from an oxide of the rare-earth element cerium, may be a novel potential therapeutic for their application as protectors of normal tissue from RT. CONPs have been used as industrial catalysts, are well known for their unique redox chemistry, and have recently been investigated for their biomedical applications. CONPs have demonstrated protection of cells from free radicals produced by inflammatory, oxidative, and radiation damage, with minimal dose related toxicity. It has been shown that CONPs do not protect cancer cells from radiation damage, though the mechanisms of this loss of radio-protection are poorly understood. This project attempts to significantly increase understanding of these mechanisms by attempting to discover the effects of the tumor microenvironment (TME), specifically low pH and hypoxia, on CONPs' radio-protective properties. pH and hypoxia are the focus of this study because CONPs lose their redox properties at lower pHs, and the hypoxic conditions of the TME are critical to radical production and tumor radio-resistance and may also affect how CONPs react in tumor tissue. The effects of CONPs have been studied in vivo, but there is a lack of mechanistic studies under clinically simulating treatment conditions. This proposal will utilize multi-modality molecular imaging and conformal image guided RT to better understand the underlying mechanisms of CONPs' radio- protection in a spontaneously induced colon cancer mouse model. Molecular imaging will consist of SPECT- /PET-CT imaging of radiolabeled CONPs' (rCONPs) to measure uptake and pharmacokinetics, while MRI and tomographic photoacoustic imaging (TPA) will be used to determine in vivo pH and oxygen gradients. [18F]FDG PET imaging will be used to monitor tumor growth and tumor/normal tissue response to RT. Comparing the normal/tumor tissue response to the rCONPs' uptake and the pH/O2 conditions in vivo, with in vitro cross validation, will reveal how they are interrelated. The methods of this project are comparable to those available in the clinic and information from these studies may help accelerate CONP translation into RT clinical trials.