College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Biomaterials. 2013 Dec;34(37):9638-47. doi: 10.1016/j.biomaterials.2013.08.058. Epub 2013 Sep 6.
Here, we report hyaluronyl reduced graphene oxide (rGO) nanosheets as a tumor-targeting delivery system for anticancer agents. Hyaluronyl-modified rGO nanosheets were prepared by synthesizing cholesteryl hyaluronic acid (CHA) and using it to coat rGO nanosheets, yielding CHA-rGO. Compared with rGO, CHA-rGO nanosheets showed increased colloidal stability under physiological conditions and improved in vivo safety, with a survival rate of 100% after intravenous administration of 40 mg/kg in mice. The doxorubicin (Dox) loading capacity of CHA-rGO was 4-fold greater than that of rGO. Uptake of Dox by CD44-overexpressing KB cells was higher for CHA-rGO than for rGO, and was decreased in the presence of hyaluronic acid through competition for CD44 receptor binding. After intravenous administration in tumor-bearing mice, CHA-rGO/Dox showed higher tumor accumulation than rGO/Dox. The in vivo antitumor efficacy of Dox delivered by CHA-rGO was significantly increased compared with free Dox or rGO/Dox. In CHA-rGO/Dox-treated mice, tumor weights were reduced to 14.1% ± 0.1% of those in untreated mice. Our findings indicate that CHA-rGO nanosheets possess greater stability, safety, drug-loading capacity, and CD44-mediated delivery of Dox than rGO nanosheets. These beneficial properties of CHA-rGO improved the distribution of Dox to tumors and facilitated the cellular uptake of Dox by CD44-overexpressing tumor cells, resulting in enhanced anticancer effects.
在这里，我们报告了透明质酸还原氧化石墨烯（rGO）纳米片作为抗癌药物的肿瘤靶向递药系统。通过合成胆固醇透明质酸（CHA）并将其用于包裹 rGO 纳米片，制备了透明质酸修饰的 rGO 纳米片，得到 CHA-rGO。与 rGO 相比，CHA-rGO 纳米片在生理条件下表现出更高的胶体稳定性和改善的体内安全性，在小鼠中静脉注射 40mg/kg 后存活率为 100%。CHA-rGO 的阿霉素（Dox）载药量是 rGO 的 4 倍。CD44 过表达 KB 细胞对 CHA-rGO 的 Dox 摄取高于 rGO，并且通过与 CD44 受体结合竞争，透明质酸的存在降低了 Dox 的摄取。在荷瘤小鼠中静脉给药后，CHA-rGO/Dox 在肿瘤中的积累高于 rGO/Dox。与游离 Dox 或 rGO/Dox 相比，CHA-rGO 递送的 Dox 的体内抗肿瘤功效显著增加。在 CHA-rGO/Dox 治疗的小鼠中，肿瘤重量减少到未治疗小鼠的 14.1%±0.1%。我们的研究结果表明，CHA-rGO 纳米片比 rGO 纳米片具有更大的稳定性、安全性、载药能力和 CD44 介导的 Dox 递药。CHA-rGO 的这些有益特性改善了 Dox 向肿瘤的分布，并促进了 CD44 过表达肿瘤细胞对 Dox 的细胞摄取，从而增强了抗癌效果。
