基于纳米二氧化硅的治疗诊断学药物研究

Advances in both nano-drug-delivery and diagnosis nanotechnology have pushed the merging of disease treatment and diagnosis, and have made nanoparticle-based theranostics a research hotspot. Theranostic nanomedicines can deliver drug with targeting, monitor the therapeutic response, and are expected to play an important role in the future personalized medicine. Peptide drugs have the merits of high specificity and low toxicity. The advances in genomics, proteomics and other biotechnologies show great promise for the development of peptide drugs for many diseases including cancer. However, the clinic use of peptide drugs is hampered by several problems such as the poor stability and low bioavailability. Reversible non-covalent encapsulation of peptide drugs by nanoparticle is an effective way to solve the above problems. For example, silica nanoparticles have been widely studied as safe drug carriers. However, due to the negative charge of silica nanoparticles, negatively-charged proteins are difficult to be encapsulated and easy to leak out. To solve this problem, we had previously developed a facile and general method to encapsulate proteins and peptides, including negatively-charged ones, in silica nanoparticles. In addition, we found that the green fluorescence protein encapsulated in silica nanoparticles shows substantial increase of fluorescence intensity and stabilities against denaturants, protease and high temperature, making the enhanced green fluorescence protein-encapsulated silica nanoparticle a potential robust fluorescence probe. Based on these advances, in this project, we are going to develop a nano-silica-based theranostic nanomedicine, by taking advantage of the high capacity of silica nanoparticle to simultaneously load peptide drugs, targeting groups and a safe fluorescent protein-based probe. The resulting silica nanoparticle-based theranostics nanomedicine is expected to be able to improve the stability and bio-availability of the peptide drugs, and provide targeting, releasing control, and monitoring of therapeutic response.

纳米技术的高速发展促进了治疗与诊断药物的融合和治疗诊断学的兴起。治疗诊断学纳米药物同时载带药物和探针，从而可以在治疗的同时监测其过程，是医疗个性化发展的方向。在当今医药市场上，多肽类药物因其高特异性、低毒副作用等优点，正扮演着越来越重要的角色。但多肽药物存在稳定性差、生物利用度低等问题。纳米载带是解决这些问题的有效途径，纳米二氧化硅是研究最多的纳米载带体系之一。我们前期发展了一种新颖的纳米二氧化硅包裹蛋白和多肽的技术，发现纳米二氧化硅包裹绿色荧光蛋白可以作为一种安全、稳定的高性能荧光探针。本项目拟在此基础上进一步发展相关技术，应用纳米二氧化硅同时载带多肽药物和近红外荧光蛋白，通过表面功能化实现靶向给药，通过载带的近红外荧光蛋白进行动物活体成像，以监测药物靶向性等治疗过程。在改善纳米二氧化硅进入动物体内的安全性基础上，将之在动物水平上推广应用，推动癌症多功能治疗诊断学纳米药物的开发和应用。

纳米治疗诊断学研究是纳米科技中一个快速发展的领域，具有广阔的应用前景。但目前该领域还有众多问题需要解决，包括纳米药物的稳定性、聚集状态以及载药效率，特别是纳米药物的生物安全性和靶向性效率。围绕这些问题，本课题发展了一种新的纳米二氧化硅包裹单个蛋白质的技术，制得的粒径小于10纳米的二氧化硅纳米粒子显示出优异的生物安全性，包裹近红外荧光蛋白质后可作为一种稳定性好、安全性好的优异荧光探针用于动物荧光成像。针对小二氧化硅纳米粒子合成、提纯、回收等方面的困难问题，我们发展了一种全新的纳米二氧化硅固相合成方法，该方法合成的二氧化硅纳米粒子都具有一个组氨酸标签，可以方便地对粒子进行提纯、回收、特异性功能化、甚至可控地可逆组装。应用我们发展的基于组氨酸标签的技术，我们还在小鼠模型上进行了纳米二氧化硅载带多肽药物的实验，显示出良好的控释效果。针对纳米药物与靶标蛋白特异性结合不强和靶向性不尽人意的问题，我们成功地在金纳米粒子表面通过精确控制功能化基团的构象，制备了一类全新的纳米人工抗体；这种人工抗体具有天然抗体一样的特异性，并更稳定，和抗原结合力更强，显示出广阔的生物医学应用前景，相关工作已在PNAS发表，并被F1000 Prime推荐。