Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
Department of Pharmaceutics, School of Pharmacy, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China.
Molecules. 2018 Nov 26;23(12):3082. doi: 10.3390/molecules23123082.
Targeted drug delivery to colon cancer cells can significantly improve the efficiency of treatment. We firstly synthesized carboxyl-modified mesoporous silica nanoparticles (MSN⁻COOH) via two-step synthesis, and then developed calcium leucovorin (LV)-loaded carboxyl-modified mesoporous silica nanoparticles based on galactosylated chitosan (GC), which are galectin receptor-mediated materials for colon-specific drug delivery systems. Both unmodified and functionalized nanoparticles were characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR), nitrogen sorption, and dynamic light scattering (DLS). Drug release properties and drug loading capacity were determined by ultraviolet spectrophotometry (UV). LV@MSN⁻COOH/GC had a high LV loading and a drug loading of 18.07%. In vitro, its release, mainly by diffusion, was sustained release. Cell experiments showed that in SW620 cells with the galectin receptor, the LV@MSN⁻COOH/GC metabolized into methyl tetrahydrofolic acid (MTHF) and 5-fluorouracil (5-FU)@MSN⁻NH₂/GC metabolized into FdUMP in vivo. MTHF and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) had combined inhibition and significantly downregulated the expression of thymidylate synthase (TS). Fluorescence microscopy and flow cytometry experiments show that MSN⁻COOH/GC has tumor cell targeting, which specifically recognizes and binds to the galectin receptor in tumor cells. The results show that the nano-dosing system based on GC can increase the concentrations of LV and 5-FU tumor cells and enhance their combined effect against colon cancer.
靶向递送至结肠癌细胞可以显著提高治疗效率。我们首先通过两步合成法合成了羧基修饰的介孔硅纳米粒子（MSN-COOH），然后基于半乳糖化壳聚糖（GC）开发了负载左旋亚叶酸钙（LV）的羧基修饰的介孔硅纳米粒子，这是用于结肠特异性药物传递系统的半乳糖受体介导的材料。未修饰和功能化的纳米粒子均通过扫描电子显微镜（SEM）、透射电子显微镜（TEM）、X 射线衍射（XRD）、傅里叶变换红外（FT-IR）、氮气吸附和动态光散射（DLS）进行了表征。通过紫外分光光度法（UV）测定了药物释放性质和载药量。LV@MSN-COOH/GC 具有高的 LV 负载量和 18.07%的载药量。体外，其释放主要通过扩散呈持续释放。细胞实验表明，在具有半乳糖受体的 SW620 细胞中，LV@MSN-COOH/GC 代谢为甲基四氢叶酸（MTHF），而 5-氟尿嘧啶（5-FU）@MSN-NH2/GC 代谢为体内 FdUMP。MTHF 和 5-氟-2'-脱氧尿苷 5'-单磷酸（FdUMP）联合抑制并显著下调胸苷酸合成酶（TS）的表达。荧光显微镜和流式细胞术实验表明，MSN-COOH/GC 具有肿瘤细胞靶向性，可特异性识别并结合肿瘤细胞中的半乳糖受体。结果表明，基于 GC 的纳米给药系统可以增加 LV 和 5-FU 肿瘤细胞的浓度，并增强它们对结肠癌的联合作用。
