构建pH响应性中空介孔硅纳米复合材料用于肿瘤联合治疗

Construction of pH-responsive HMSN nanocomposites for combinatory therapy of tumor

摘要:

以正硅酸四乙酯为原料，合成直径约为100 nm的中空介孔二氧化硅（HMSNs）纳米颗粒作为药物载体，采用物理包埋法和原位还原KMnO4生成二氧化锰的方法实现对化疗药物阿霉素（DOX）和MnO2的有效负载。此外，利用肿瘤靶向性功能肽（PEG-R7-RGDS）末端的氨基与醛基修饰的HMSN（HMSN-CHO）形成席夫碱，合成pH响应性纳米载药系统（DOX/MnO2@HMSN-imide-PEG-R7-RGDS）。通过TEM，激光粒度仪，FTIR和XRD对合成材料形貌、粒径、结构和组成等进行表征。结果表明，合成的HMSNs呈球形中空结构。DOX/MnO2@HMSN-imide-PEG-R7-RGDS在模拟的肿瘤酸性环境（pH 5.0）中具有明显快于在模拟生理环境（pH 7.4）下的药物释放行为。此外，体外细胞实验结果表明，DOX/MnO2@HMSN-imide-PEG-R7-RGDS可以靶向进入宫颈癌细胞（HeLa）并快速释放DOX。与此同时，纳米载药颗粒中的MnO2和肿瘤细胞中高浓度谷胱甘肽（GSH）反应产生具有类芬顿反应效果的Mn2+。Mn2+与肿瘤细胞内过表达的H2O2反应生成·OH，发挥增强的化学动力学治疗。细胞毒性实验证明，化学动力学治疗与化疗相结合能对HeLa细胞产生很高的细胞毒性。

Abstract:

Hollow mesoporous silica nanoparticles (HMSN) with a diameter of about 100 nm were fabricated from tetraethyl orthosilicate. HMSN were used as drug nanocarrier to load chemotherapeutic drug doxorubicin (DOX) and manganese dioxide by physical embedding method and in situ reduction of KMnO4 to produce manganese dioxide. Then, a pH-responsive nano-drug delivery system (DOX/MnO2@HMSN-imide-PEG-R7-RGDS) was constructed by forming Schiff base between tamino group at the terminal of tumor-targeting functional peptide (PEG-R7-RGDS) and the aldehyde-modified nanoparticles (HMSN-CHO). The morphology, particle size, structure and composition of the nanomaterials were characterized by TEM, laser particle size analyzer, FTIR and XRD. The results showed that the synthesized spherical HMSN possessed hollow nanostructure. DOX/MnO2@HMSN-imide-PEG-R7-RGDS nanoparticles exhibited higher drugrelease rate under the simulated acidic tumor environment (pH 5.0) than that in the simulated physiological environment (pH 7.4). In addition, the results of in vitro cell experiments indicated that DOX/MnO2@HMSN-imide-PEG-R7-RGDS could target to cervical cancer cells (HeLa) and release DOX efficiently. At the same time, MnO2 in nanoparticles reacted with high concentration of glutathione (GSH) in tumor cells to produce Mn2+ with Fenton-like effect. Subsequently, Mn2+ would  catalyze endogenous H2O2 into highly toxic ·OH via Fenton-like chemistry. The cytotoxicity experiments revealed that the combination of chemodynamic therapy and chemotherapy of DOX/MnO2@HMSN-imide-PEG-R7-RGDS could produce high cytotoxicity against HeLa cells.