稀土上转换粒子-纳米金刚石多功能载药体系的构筑和性能研究

The visualization of drug delivery at target site has great significance for the individualized tumor therapy, but a single reagent or material cannot meet the requirements of real-time monitoring the drug-delivering process. To address the problem, a multifunctional drug-loaded nano-system was invented on the basis of the composite of rare earth upconversion nanoparticles (UCNPs) and nanodiamonds (NDs), where UCNPs served as imaging system due to the stable luminescence and near-infrared excitation, and NDs acted as drug-deliverying system because of their bio-compatibility, large surface area, and rich functional groups. Construction of the composite started with synthesis of high-quality upconversion nanocrystals. Subsequently, a core-shell nanostructure was fabricated by coating the UCNPs with nanodiamonds in the inverse microemulsion. The inner UCNPs can monitor the drug release and bio-distribution in cells. Meanwhile, the NDs in shell layer could achieve the pH-responsive release and initiative targeting at tumor area after conjugating with folate. Thus, this project synthesized multi-block materials for targeted drug delivery, triggered drug release, and real-time monitoring the therapeutic response, which opens a possibility for individualized medication and theranostic cancer therapy.

可视化靶向载药在肿瘤的个性化治疗中有重要意义，但是单一的试剂和材料尚不能满足给药过程实时成像的要求。针对这一问题，本项目利用纳米金刚石（ND）生物兼容性好、表面活性高的优势以及稀土上转换纳米粒子（UCNP）发光稳定、可被近红外光激发的特点，以纳米金刚石为药物载体、稀土上转换纳米粒子为成像系统设计并构建了UCNP-ND多功能复合载药体系。在制备高质量稀土上转换纳米晶体的基础之上，利用反乳液法将纳米金刚石修饰在上转换粒子表面形成UCNP-ND核壳型复合纳米材料。内层的稀土上转换发光材料用以跟踪和监测药物在细胞内的释放和分布情况，外层的纳米金刚石作为药物载体和功能化平台，嫁接叶酸分子后可实现对肿瘤细胞的主动靶向和pH驱动的药物释放。总之，本项目通过构建多功能复合载药体系解决了靶向载药、触发性释药和治疗效果实时监控的问题，为癌症的个体化给药和诊断治疗一体化的实现开辟了新的途径。

构建一种集生物成像与药物运输功能于一身的多功能纳米材料对于肿瘤的治疗具有重大意义。稀土材料具有优良的光学和磁学性能，这使其广泛应用于生物成像领域；纳米金刚石具有丰富的表面官能团、大的比表面积，能够容易地嫁接药物分子以及复合其他纳米材料，在抗癌药物运输以及构建多功能诊疗平台上具有重要的应用价值。本项目在获得分散性良好的羧基化纳米金刚石以及发光性能优异的稀土纳米材料的基础之上，通过共价连接的方法制备了一系列纳米金刚石-稀土复合纳米材料；通过调节稀土离子种类可同时实现荧光/磁性多模式成像，能够在细胞和活体小动物层面进行了生物成像；该复合物对抗癌药物阿霉素具有较高的负载率，体外试验显示可实现pH刺激响应的药物控制释放；细胞毒性试验表面单纯的复合物对细胞存活无明显影响，负载药物后较药物单体具有增强的癌细胞杀伤效果。此外，利用纳米金刚石1332 cm-1处的拉曼信号在细胞层面实现了拉曼成像；修饰光敏剂二氢卟吩e6后可对癌细胞进行光动力杀伤。以上结果表明，所合成的纳米金刚石-稀土纳米复合材料具有生物成像、药物运输、癌细胞杀伤等多种功能，为将来肿瘤的个性化精准治疗所遇到的难题提供了一种有效的解决方案。