Key Laboratory of Biomedical Polymers (The Ministry of Education), Department of Chemistry, Wuhan University, Wuhan, China.
Biomacromolecules. 2013 Feb 11;14(2):358-66. doi: 10.1021/bm3015297. Epub 2013 Jan 11.
In this paper, a facile strategy to develop graphene-based delivery nanosystems for effective drug loading and sustained drug release was proposed and validated. Specifically, biocompatible naphthalene-terminated PEG (NP) and anticancer drugs (curcumin or doxorubicin (DOX)) were simultaneously integrated onto oxidized graphene (GO), leading to self-assembled, nanosized complexes. It was found that the oxidation degree of GO had a significant impact on the drug-loading efficiency and the structural stability of nanosystems. Interestingly, the nanoassemblies resulted in more effective cellular entry of DOX in comparison with free DOX or DOX-loaded PEG-polyester micelles at equivalent DOX dose, as demonstrated by confocal microscopy studies. Moreover, the nanoassemblies not only exhibited a sustained drug release pattern without an initial burst release, but also significantly improved the stability of formulations which were resistant to drug leaking even in the presence of strong surfactants such as aromatic sodium benzenesulfonate (SBen) and aliphatic sodium dodecylsulfonate (SDS). In addition, the nanoassemblies without DOX loading showed negligible in vitro cytotoxicity, whereas DOX-loaded counterparts led to considerable toxicity against HeLa cells. The DOX-mediated cytotoxicity of the graphene-based formulation was around 20 folds lower than that of free DOX, most likely due to the slow DOX release from complexes. A zebrafish model was established to assess the in vivo safety profile of curcumin-loaded nanosystems. The results showed they were able to excrete from the zebrafish body rapidly and had nearly no influence on the zebrafish upgrowth. Those encouraging results may prompt the advance of graphene-based nanotherapeutics for biomedical applications.
本文提出并验证了一种简便的策略，用于开发基于石墨烯的递药纳米系统以实现有效药物负载和持续药物释放。具体而言，将生物相容性的萘端接聚乙二醇（NP）和抗癌药物（姜黄素或阿霉素（DOX））同时整合到氧化石墨烯（GO）上，导致自组装的纳米级复合物。研究发现，GO 的氧化程度对药物负载效率和纳米系统的结构稳定性有显著影响。有趣的是，与游离 DOX 或 DOX 负载的 PEG-聚酯胶束相比，纳米组装体导致 DOX 的细胞内摄取更加有效，这一点通过共聚焦显微镜研究得到了证明。此外，纳米组装体不仅表现出持续的药物释放模式而没有初始突释，而且即使在存在强表面活性剂如芳香族苯磺酸钠（SBen）和脂肪族十二烷基硫酸钠（SDS）的情况下，也能显著提高制剂的稳定性，使其能够抵抗药物泄漏。此外，未负载 DOX 的纳米组装体表现出可忽略不计的体外细胞毒性，而负载 DOX 的纳米组装体则对 HeLa 细胞表现出相当大的毒性。基于石墨烯的制剂中 DOX 介导的细胞毒性比游离 DOX 低约 20 倍，这很可能是由于复合物中 DOX 的缓慢释放所致。建立了斑马鱼模型来评估负载姜黄素的纳米系统的体内安全性。结果表明，它们能够迅速从斑马鱼体内排出，对斑马鱼的生长几乎没有影响。这些令人鼓舞的结果可能会促使基于石墨烯的纳米疗法在生物医学应用中的发展。
