Murugan Baranya, Narashimhan Ramana Lakshmi, Gandhi Sakthivel, Sethuraman Swaminathan, Krishnan Uma Maheswari
Centre for Nanotechnology & Advanced Biomaterials, School of Chemical & Biotechnology, SASTRA University, Thanjavur 613 401, Tamil Nadu, India.
J Mater Chem B. 2013 Jul 28;1(28):3494-3505. doi: 10.1039/c3tb20415d. Epub 2013 Jun 10.
Specific release of drugs in the tumor microenvironment can significantly enhance the therapeutic efficiency. This work attempts to develop a mesoporous silica carrier that can selectively release drugs in the tumor microenvironment. Mesoporous silica nanoparticles (MCM-41) with spherical morphology were synthesized using the sol-gel method. The MCM-41 nanoparticles were then functionalized with 3-mercaptopropyltrimethoxysiliane (MPTMS), an organic thiol linker, through evaporation-induced self-assembly. Both unmodified and thiol-functionalized nanoparticles were characterized using electron microscopy, spectroscopy, thermogravimetry and surface area analysis. The mesoporous architecture of MCM-41 was used to load 5-fluorouracil (5-FU). The thiol functionalization enabled easy oxidation of the sulphydryl groups and formed disulphide cross-links, which was found to retard the drug release when compared to unmodified MCM-41. Addition of the reduced form of glutathione to the thiol-functionalized system was found to enhance the drug release through lysis of the disulphide links by reduction. The correlation between the amount of drug released and the disulphide cross-links was established by addition of reduced glutathione at alternate time points where a step-wise release profile was observed, thereby establishing the chemosensitivity of the thiol-functionalized MCM-41. Cell culture studies revealed that the cancer cells were more susceptible to the thiol-functionalized 5-FU loaded MCM-41 when compared with normal cells. The mechanism involves both membrane perturbation as well as high intracellular glutathione levels. These results indicate that this chemoswitchable system might be effective against cancer cells as they contain large amounts of reduced glutathione, demonstrating the potential of this carrier as a next generation 'smart' delivery system.
药物在肿瘤微环境中的特异性释放可显著提高治疗效果。本研究试图开发一种能在肿瘤微环境中选择性释放药物的介孔二氧化硅载体。采用溶胶-凝胶法合成了具有球形形态的介孔二氧化硅纳米颗粒（MCM-41）。然后通过蒸发诱导自组装，用有机硫醇连接剂3-巯丙基三甲氧基硅烷（MPTMS）对MCM-41纳米颗粒进行功能化修饰。使用电子显微镜、光谱学、热重分析和表面积分析对未修饰和硫醇功能化的纳米颗粒进行了表征。利用MCM-41的介孔结构负载5-氟尿嘧啶（5-FU）。硫醇功能化使得巯基易于氧化并形成二硫键交联，与未修饰的MCM-41相比，发现其可延缓药物释放。向硫醇功能化体系中添加还原型谷胱甘肽，发现可通过还原作用裂解二硫键来增强药物释放。通过在交替时间点添加还原型谷胱甘肽观察到逐步释放曲线，从而建立了药物释放量与二硫键交联之间的相关性，进而确定了硫醇功能化MCM-41的化学敏感性。细胞培养研究表明，与正常细胞相比，癌细胞对负载硫醇功能化5-FU的MCM-41更敏感。其机制包括膜扰动以及细胞内谷胱甘肽水平较高。这些结果表明，这种化学可切换系统可能对癌细胞有效，因为癌细胞含有大量还原型谷胱甘肽，证明了这种载体作为下一代“智能”递送系统的潜力。
