纳米金刚石-Gd-As2O3复合药物抗肝癌效应的同步辐射研究

Based on the characteristics of nanodiamonds (NDs) including large specific surface area and high adsorption activity, the ND–Gd and ND-As2O3 interactions are investigated. On this basis, several groups of ND-Gd-As2O3 complexes with magnetic resonance imaging (MRI) function and tumor therapeutic activity are built. The distribution and metabolism of these ND complexes are investigated by MRI to screen out the one with optimal hepatic targeting. Human carcinoma cell lines and nude mice of human hepatocellular carcinoma via orthotopic implantation of histologically intact tissue are chosen as experimental models. Using the synchrotron phase-contrast X-ray imaging and hard X-ray fluorescence microscopy, as well as conventional methods for assessments of the pharmacological effects, the side effects, distribution, residence time and sustained-release effect of ND complexes and As2O3 are compared to reveal the anti-tumor mechanisms of ND complexes. Our results will promote the progress in the development of ND-based multifunctional anti-cancer drug delivery systems, open up new ideas for the application of As2O3 in tumor therapy, and provide basic research support for the development of novel anti-liver cancer drugs with high efficiency and low toxicity.

从纳米金刚石大的比表面积和高的吸附活性出发，研究纳米金刚石和Gd， As2O3的非共价相互作用。在此基础上构建多组同时具有核磁共振成像和肿瘤治疗活性的纳米金刚石-Gd-As2O3复合药物。使用核磁共振成像技术观察纳米金刚石复合药物的体内分布和代谢，筛选出肝肿瘤靶向最优的一组药物。选用离体人肝癌细胞模型和原位种植肝癌裸鼠模型，重点应用同步辐射X射线相衬CT成像和硬X射线荧光显微成像技术结合常规的药理药效评估方法，比较纳米金刚石复合药物和单纯药物的毒副作用，在肿瘤细胞和组织内的定位、分布，滞留时间和缓释效应，分析纳米金刚石复合药物的抗肿瘤机制。研究结果将推进纳米金刚石为载体的多功能抗肿瘤药物的研究进展，开创As2O3在恶性肿瘤治疗应用中的新思路和新技术，为研制新一代高效低毒的抗肝癌药物提供基础研究的支撑。

基于纳米金刚石卓越的物理化学性质和良好的生物相容性，开展了一系列其在生物医学领域的应用研究。在纳米金刚石和三氧化二砷的相互作用研究中，意外发现纳米金刚石的加入可以在一定浓度范围内显著增加实体瘤细胞对砷剂药物的敏感性。基于此，选用离体人肝癌细胞模型和原位种植肝癌裸鼠模型，重点应用同步辐射X射线显微成像技术结合常规的药理药效评估方法，比较有无纳米金刚石情况下三氧化二砷在肿瘤细胞和组织内的浓度以及定位和分布情况，评估药物的抗肿瘤效应。研究结果表明，纳米金刚石的加入可以显著提高低浓度砷剂药物的体内外抗肿瘤效应，而纳米金刚石本身具有很好的生物相容性。此外，拓展了纳米金刚石作为缓释型化疗药物顺铂细胞内输运载体的研究内容，证明了修饰的纳米金刚石可以显著提高顺铂药物的细胞摄取并介导缓慢的细胞内药物释放，从而长时间发挥抗肿瘤效应。还拓展了纳米金刚石作为缓释型免疫刺激药物体内输运载体的研究内容，证明构建的复合药物的免疫刺激效果大大好于数十倍剂量的临床药物，并且其在体内的活性持续时间长达两天，同时毒副作用很小。这些研究结果将大大推进纳米金刚石在生物医学领域应用的研究进展。