Magnetic Graphene Oxide for Dual Targeted Delivery of Doxorubicin and Photothermal Therapy.
Magnetic Graphene Oxide for Dual Targeted Delivery of Doxorubicin and Photothermal Therapy.
复制标题
DOI：
10.3390/nano8040193
复制
发表时间：
2018-03-27
期刊：
影响因子：
--
通讯作者：
Chen JP
中科院分区：
文献类型：
--
作者：
Lu YJ;Lin PY;Huang PH;Kuo CY;Shalumon KT;Chen MY;Chen JP
为了开发一种pH敏感的双靶向磁性纳米载体，用于肿瘤的化学-光疗治疗，我们通过化学共沉淀法在氧化石墨烯（GO）上沉积Fe 3 O 4磁性纳米颗粒，制备了磁性氧化石墨烯（MGO）。用聚乙二醇（PEG）和西妥昔单抗（CET，表皮生长因子受体（EGFR）单克隆抗体）修饰MGO以获得MGO-PEG-CET。由于EGFR在肿瘤细胞表面高度表达，因此MGO-PEG-CET用于抗癌药物多柔比星（DOX）的双靶向递送。采用动态光散射、透射电镜、X射线衍射、傅里叶变换红外光谱、热重分析、超导量子干涉仪等对MGO-PEG-CET的物理化学性质进行了表征。载药实验表明，DOX吸附遵循Langmuir等温线，最大载药量为6.35 mg/mg，而DOX释放是pH依赖性的，在pH 5.5比pH 7.4释放更多的DOX。使用量子点标记的纳米载体和共聚焦显微镜，高EGFR表达的CT-26小鼠结肠直肠细胞对MGO-PEG-CET的细胞内摄取被证实比MGO更有效。这种细胞摄取可以通过与CET预孵育来抑制，这证实了MGO-PEG-CET的受体介导的内吞作用。磁靶向杀伤CT-26的体外实验通过磁导向MGO-PEG-CET/DOX实现，而光热效应可以通过近红外（NIR）激光照射MGO-PEG-CET在体内和体外证实。此外，生物相容性试验表明，MGO-PEG-CET对成纤维细胞没有细胞毒性，并引起最低限度的溶血。体外细胞毒性试验显示，MGO-PEG-CET/DOX对CT-26细胞的半数最大抑制浓度（IC 50）为1.48 µg/mL，低于MGO-PEG/DOX（2.64 µg/mL）。在结合NIR激光照射的光热治疗后，IC 50值可进一步降低至1.17 µg/mL。在BALB/c小鼠中使用皮下植入的CT-26细胞，体内抗肿瘤研究表明在第14天的相对肿瘤体积对于对照（生理盐水）为12.1，对于DOX为10.1，对于MGO-PEG-CET/DOX为9.5，对于MGO-PEG-CET/DOX +磁体为5.8，并且对于MGO-PEG-CET/DOX +磁体+激光为0.42。因此，MGO-PEG-CET/DOX双靶向给药系统可作为一种有效的抗肿瘤药物载体系统，其联合化疗和光热治疗的疗效是对照组的29倍。
To develop a pH-sensitive dual targeting magnetic nanocarrier for chemo-phototherapy in cancer treatment, we prepared magnetic graphene oxide (MGO) by depositing Fe3O4 magnetic nanoparticles on graphene oxide (GO) through chemical co-precipitation. MGO was modified with polyethylene glycol (PEG) and cetuximab (CET, an epidermal growth factor receptor (EGFR) monoclonal antibody) to obtain MGO-PEG-CET. Since EGFR was highly expressed on the tumor cell surface, MGO-PEG-CET was used for dual targeted delivery an anticancer drug doxorubicin (DOX). The physico-chemical properties of MGO-PEG-CET were fully characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction, Fourier transform Infrared spectroscopy, thermogravimetric analysis, and superconducting quantum interference device. Drug loading experiments revealed that DOX adsorption followed the Langmuir isotherm with a maximal drug loading capacity of 6.35 mg/mg, while DOX release was pH-dependent with more DOX released at pH 5.5 than pH 7.4. Using quantum-dots labeled nanocarriers and confocal microscopy, intracellular uptakes of MGO-PEG-CET by high EGFR-expressing CT-26 murine colorectal cells was confirmed to be more efficient than MGO. This cellular uptake could be inhibited by pre-incubation with CET, which confirmed the receptor-mediated endocytosis of MGO-PEG-CET. Magnetic targeted killing of CT-26 was demonstrated in vitro through magnetic guidance of MGO-PEG-CET/DOX, while the photothermal effect could be confirmed in vivo and in vitro after exposure of MGO-PEG-CET to near-infrared (NIR) laser light. In addition, the biocompatibility tests indicated MGO-PEG-CET showed no cytotoxicity toward fibroblasts and elicited minimum hemolysis. In vitro cytotoxicity tests showed the half maximal inhibitory concentration (IC50) value of MGO-PEG-CET/DOX toward CT-26 cells was 1.48 µg/mL, which was lower than that of MGO-PEG/DOX (2.64 µg/mL). The IC50 value could be further reduced to 1.17 µg/mL after combining with photothermal therapy by NIR laser light exposure. Using subcutaneously implanted CT-26 cells in BALB/c mice, in vivo anti-tumor studies indicated the relative tumor volumes at day 14 were 12.1 for control (normal saline), 10.1 for DOX, 9.5 for MGO-PEG-CET/DOX, 5.8 for MGO-PEG-CET/DOX + magnet, and 0.42 for MGO-PEG-CET/DOX + magnet + laser. Therefore, the dual targeting MGO-PEG-CET/DOX could be suggested as an effective drug delivery system for anticancer therapy, which showed a 29-fold increase in therapeutic efficacy compared with control by combining chemotherapy with photothermal therapy.
登录
查看更多内容
影响因子：
8
作者：
Chen JP;Yang PC;Ma YH;Tu SJ;Lu YJ
通讯作者：
Lu YJ
影响因子：
5.8
作者：
Li, You-Mei;Jiang, Tao;Zhuo, Ren-Xi
通讯作者：
Zhuo, Ren-Xi
DOI：
10.1016/j.nano.2012.11.009
发表时间：
2013-07-01
影响因子：
5.4
作者：
Kirui, Dickson K.;Khalidov, Ildar;Batt, Carl A.
通讯作者：
Batt, Carl A.
影响因子：
2.7
作者：
Hsu, Hao-Lung;Chen, Jyh-Ping
通讯作者：
Chen, Jyh-Ping
DOI：
10.1007/s00259-006-0361-6
发表时间：
2007-06-01
影响因子：
9.1
作者：
Cai, Weibo;Chen, Kai;Chen, Xiaoyuan
通讯作者：
Chen, Xiaoyuan