Construction of MIL-101 (Fe)/GO Composite Carrier and Suitability and Sustained-Release Characteristics for Co-Loading Luteolin and Matrine
-
摘要:
目的 探讨铁基金属有机框架材料MIL-101(Fe)与氧化石墨烯(GO)复合载体[MIL-101(Fe)/GO]共载2种抗肿瘤有效成分木犀草素和苦参碱的适宜性及体外释放性能。 方法 采用溶剂热法制备MIL-101(Fe)与MIL-101(Fe)/GO复合载体, 采用扫描电子显微镜分析(SEM)、X射线衍射分析(XRD)、比表面积及孔径结构分析(BET)、红外光谱分析(FT-IR)等方法进行结构表征, 采用CCK-8细胞实验考察2种载体的安全性, 采用体外溶出试验, 以HPLC法测定木犀草素与苦参碱在MIL-101(Fe)/GO中的载药量与释放量。 结果 扫描电镜结果可见制得的MIL-101(Fe)/GO复合载体为多面体晶型结构复合体系; 细胞活力实验结果表明, 2种载体对小鼠成纤维细胞未产生抑制。木犀草素与苦参碱在MIL-101(Fe)中的载药量分别为14.1%、10.63%, 在MIL-101(Fe)/GO中载药量分别为20.74%、14.1%;体外释放实验结果表明, 在pH=5的条件下, MIL-101(Fe)/GO在72 h内可释放出23.92%的木犀草素与32.07%的苦参碱, 而在pH=7.4的条件下, MIL-101(Fe)/GO在相同时间内可释放出8.84%的木犀草素与36.19%的苦参碱。 结论 MIL-101(Fe)/GO复合载体的载药量更高, 作为pH响应型复合载体, 可有效实现对木犀草素的酸性pH响应释放及其与苦参碱的缓慢释放, 为实现多药递送持久释放的抗肿瘤药物设计提供新的思路。 Abstract:OBJECTIVE To investigate the suitability and in vitro release performance of two antitumor active ingredients luteolin and matrine co-loaded with the composite carrier of iron fund organic frame material MIL-101(Fe) and graphene oxide (GO). METHODS MIL-101 (Fe) and MIL-101(Fe)/GO composite carriers were prepared by the solvothermal method. The structures were characterized by SEM, XRD, BET and FT-IR. CCK-8 cell experiments were used to investigate the safety of the two carriers. The drug loading and release of luteolin and matrine in the composite carrier were determined by HPLC. RESULTS The results of scanning electron microscopy showed that the MIL-101(Fe)/GO composite carrier was a polyhedral crystal structure composite system. The results of cell viability test showed that the two vectors did not inhibit mouse fibroblasts. The loading capacity of luteolin and matrine in MIL-101(Fe) were 14.1% and 10.63%, respectively; and the loading capacities of these two drugs in MIL-101(Fe)/GO were 20.74% and 14.1%, respectively. The results of in vitro release experiment showed that under the condition of pH=5, the complex carrier could release 23.92% luteolin and 32.07% matrine within 72 h, while under the condition of pH=7.4, the complex carrier could release 8.84% luteolin and 36.19% matrine within the same time. CONCLUSIONS MIL-101(Fe)/GO composite carrier has higher drug loading capacity. As a pH-responsive composite carrier, it can effectively achieve the acidic pH response release of luteolin and slow release with matrine, providing a new idea for the design of anti-tumor drugs with multi-drug delivery and sustained release. -
Key words:
- MIL-101(Fe) /
- graphene oxide /
- luteolin /
- matrine /
- drug co-loading /
- in vitro release
-
图 1 MIL-101(Fe)/GO复合体系的构建及载药示意图
Figure 1. Construction and drug loading diagram of MIL-101 (Fe)/GO composite system
图 2 扫描电子显微镜下MIL-101(Fe) 与MIL-101(Fe)/GO及两者载药后的微观图
注: A. MIL-101(Fe); B. MIL-101(Fe)/GO; C. MIL-101(Fe)/木犀草素/苦参碱; D. MIL-101(Fe)/GO/木犀草素/苦参碱
Figure 2. Micrographs of MIL-101(Fe) and MIL-101(Fe)/GO and drug loaded compounds under scanning electron microscopy
图 3 MIL-101(Fe)、MIL-101(Fe)/GO与GO的XRD谱图
Figure 3. XRD patterns of MIL-101(Fe), MIL-101(Fe)/GO and GO
图 4 MIL-101(Fe)与MIL-101(Fe)/GO的吸附-脱附等温曲线
注: A. MIL-101(Fe); B. MIL-101(Fe)/GO
Figure 4. Adsorption-desorption isotherm curves of MIL-101(Fe) and MIL-101(Fe)/GO
图 5 MIL-101(Fe)与MIL-101(Fe)/GO的孔径分布
Figure 5. Pore size distributions of MIL-101(Fe) and MIL-101(Fe)/GO
图 6 MIL-101(Fe)与MIL-101(Fe)/GO及两者载药后的红外光谱图
注: A. MIL-101(Fe); B. MIL-101(Fe)/GO
Figure 6. Infrared spectra of MIL-101(Fe) and MIL-101(Fe)/GO before and after drug loading
图 7 不同浓度的MIL-101(Fe)与MIL-101(Fe)/GO对成纤维细胞活力的影响
注：与MIL-101(Fe)空白组比较，*P < 0.05, * *P < 0.01; 与MIL-101(Fe)/GO空白组比较，#P < 0.05, ##P < 0.01。
Figure 7. Effects of MIL-101(Fe) and MIL-101(Fe)/GO at different concentrations on fibroblast viability
表 1 MIL-101(Fe)与MIL-101(Fe)/GO的比表面积与孔结构参数
Table 1. Specific surface area and pore structure parameters of MIL-101 (Fe) and MIL-101 (Fe)/GO
材料 BET比表面积/(m2·g-1) Langmuir表面积/(m2·g-1) 孔容/(cm3·g-1) 孔径/nm MIL-101(Fe) 487.485 527.306 0.344 2.819 MIL-101(Fe)/GO 292.930 307.173 0.268 3.657 
下载: 导出CSV
表 2 2种材料载药量(%)
Table 2. The drug load of two material(%)
载体组别 木犀草素 苦参碱 MIL-101(Fe) 14.68 10.63 MIL-101(Fe)/GO 20.74 14.10
下载: 导出CSV
-
[1] 张钦畅, 程海波, 余成涛, 等. 仙连解毒方对结直肠癌湿热瘀毒证模型小鼠肠道细胞类型的影响[J]. 中医杂志, 2022, 63(5): 461-467. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZYZ202205012.htmZHANG QC, CHENG HB, YU CT, et al. Effect of Xianlian Jiedu formula on intestinal cell types in colorectal cancer model mice with damp-heat stasis toxin pattern[J]. J Tradit Chin Med, 2022, 63(5): 461-467. https://www.cnki.com.cn/Article/CJFDTOTAL-ZZYZ202205012.htm [2] 王启娟, 沈卫星, 姜瑞阳, 等. 仙连解毒方维持肿瘤相关血管内皮细胞稳态抑制肿瘤血管新生的作用机制[J]. 中国实验方剂学杂志, 2022, 28(8): 86-92. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX202208011.htmWANG QJ, SHEN WX, JIANG RY, et al. Mechanism of Xianlian Jiedu prescription in maintaining cancer relative vascular endothelial cell homeostasis and inhibiting tumor neovascularization[J]. Chin J Exp Tradit Med Formulae, 2022, 28(8): 86-92. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX202208011.htm [3] 陶李蕙苹, 赖岳阳, 程海波, 等. 仙连解毒方对人结直肠癌细胞增殖及糖酵解的调控作用及机制[J]. 中国实验方剂学杂志, 2022, 28(8): 72-78. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX202208009.htmTAO LHP, LAI YY, CHENG HB, et al. Effect of Xianlian Jiedu prescription on proliferation and glycolysis of human colorectal cancer HCT-116 cells and mechanism[J]. Chin J Exp Tradit Med Formulae, 2022, 28(8): 72-78. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSFX202208009.htm [4] JIANG ZB, WANG WJ, XU C, et al. Luteolin and its derivative apigenin suppress the inducible PD-L1 expression to improve anti-tumor immunity in KRAS-mutant lung cancer[J]. Cancer Lett, 2021, 515: 36-48. doi: 10.1016/j.canlet.2021.05.019 [5] LIU Y, LANG TY, JIN BW, et al. Luteolin inhibits colorectal cancer cell epithelial-to-mesenchymal transition by suppressing CREB1 expression revealed by comparative proteomics study[J]. J Proteom, 2017, 161: 1-10. doi: 10.1016/j.jprot.2017.04.005 [6] QING WX, XING XY, FENG DF, et al. Indocyanine green loaded pH-responsive bortezomib supramolecular hydrogel for synergistic chemo-photothermal/photodynamic colorectal cancer therapy[J]. Photodiagnosis Photodyn Ther, 2021, 36: 102521. doi: 10.1016/j.pdpdt.2021.102521 [7] 姚薛超, 宁洪鑫, 黄欢, 等. 木犀草素制剂的研究进展[J]. 中草药, 2021, 52(3): 873-882. https://www.cnki.com.cn/Article/CJFDTOTAL-ZCYO202103032.htmYAO XC, NING HX, HUANG H, et al. Research progress on pharmaceutical preparation of luteolin[J]. Chin Tradit Herb Drugs, 2021, 52(3): 873-882. https://www.cnki.com.cn/Article/CJFDTOTAL-ZCYO202103032.htm [8] GE XY, WONG R, ANISA A, et al. Recent development of metal-organic framework nanocomposites for biomedical applications[J]. Biomaterials, 2022, 281: 121322. doi: 10.1016/j.biomaterials.2021.121322 [9] ZHANG HY, ZHANG J, LI Q, et al. Site-specific MOF-based immunotherapeutic nanoplatforms via synergistic tumor cells-targeted treatment and dendritic cells-targeted immunomodulation[J]. Biomaterials, 2020, 245: 119983. doi: 10.1016/j.biomaterials.2020.119983 [10] KARIMI ALAVIJEH R, AKHBARI K. Biocompatible MIL-101(Fe) as a smart carrier with high loading potential and sustained release of curcumin[J]. Inorg Chem, 2020, 59(6): 3570-3578. doi: 10.1021/acs.inorgchem.9b02756 [11] BHATTACHARJEE A, GUMMA S, PURKAIT MK. Fe3O4 promoted metal organic framework MIL-100(Fe) for the controlled release of doxorubicin hydrochloride[J]. Microporous Mesoporous Mater, 2018, 259: 203-210. doi: 10.1016/j.micromeso.2017.10.020 [12] XIE W, ZHOU FY, LI X, et al. A surface architectured metal-organic framework for targeting delivery: Suppresses cancer growth and metastasis[J]. Arab J Chem, 2022, 15(3): 103672. [13] SINGCO B, LIU LH, CHEN YT, et al. Approaches to drug delivery: Confinement of aspirin in MIL-100(Fe) and aspirin in the de novo synthesis of metal-organic frameworks[J]. Microporous Mesoporous Mater, 2016, 223: 254-260. [14] GHAREHDAGHI Z, RAHIMI R, NAGHIB SM, et al. Cu (Ⅱ)-porphyrin metal-organic framework/graphene oxide: Synthesis, characterization, and application as a pH-responsive drug carrier for breast cancer treatment[J]. J Biol Inorg Chem, 2021, 26(6): 689-704. [15] POORESMAEIL M, ASL EA, NAMAZI H. A new pH-sensitive CS/Zn-MOF@GO ternary hybrid compound as a biofriendly and implantable platform for prolonged 5-Fluorouracil delivery to human breast cancer cells[J]. J Alloys Compd, 2021, 885: 160992. [16] GU C, LU HG, QIAN ZH. Matrine reduces the secretion of exosomal circSLC7A6 from cancer-associated fibroblast to inhibit tumorigenesis of colorectal cancer by regulating CXCR5[J]. Biochem Biophys Res Commun, 2020, 527(3): 638-645. [17] GU YY, CHEN MH, MAY BH, et al. Matrine induces apoptosis in multiple colorectal cancer cell lines in vitro and inhibits tumour growth with minimum side effects in vivo via Bcl-2 and caspase-3[J]. Phytomedicine, 2018, 51: 214-225. [18] CHEN MH, GU YY, ZHANG AL, et al. Biological effects and mechanisms of matrine and other constituents of Sophora flavescens in colorectal cancer[J]. Pharmacol Res, 2021, 171: 105778. [19] 张清云. MOFs/GO复合材料的制备及其结构和性能研究[D]. 西安: 西安科技大学, 2020.ZHANG QY. Preparation of MOFs/GO composite materials and study on tructure properties[D]. Xi'an: Xi'an University of Science and Technology, 2020. [20] GORDON J, KAZEMIAN H, ROHANI S. MIL-53(Fe), MIL-101, and SBA-15 porous materials: Potential platforms for drug delivery[J]. Mater Sci Eng C, 2015, 47: 172-179. [21] LI ZC, LIU XM, JIN W, et al. Adsorption behavior of arsenicals on MIL-101(Fe): The role of arsenic chemical structures[J]. J Colloid Interface Sci, 2019, 554: 692-704. [22] MINH THANH HT, THU PHUONG TT, LE HANG PT, et al. Comparative study of Pb(Ⅱ) adsorption onto MIL-101 and Fe-MIL-101 from aqueous solutions[J]. J Environ Chem Eng, 2018, 6(4): 4093-4102. -
点击查看大图
计量
- 文章访问数: 175
- HTML全文浏览量: 12
- PDF下载量: 16
- 被引次数: 0
