Abstract
Due to glioblastoma (GBM) being the most intractable brain tumor, the continuous improvement of effective treatment methods is indispensable. The combination of siRNA-based gene therapy and chemotherapy for GBM treatment has now manifested great promise. Herein, Gint4.T-siHDGF chimera-capped mesoporous silica nanoparticles (MSN) encapsulating chemotherapy drug temozolomide (TMZ), termed as TMSN@siHDGF-Gint4.T, is developed to co-deliver gene-drug siHDGF and TMZ for synergistic GBM therapy. TMSN@siHDGF-Gint4.T possesses spherical nucleic acid-like architecture that can improve the enzyme resistance of siHDGF and increase the blood-brain barrier (BBB) permeability of the nanovehicle. The aptamer Gint4.T of chimera endows the nanovehicle with GBM cell-specific binding ability. When administered systemically, TMSN@siHDGF-Gint4.T can traverse BBB and enter GBM cells. In the acidic lysosome environment, the cleavage of benzoic-imine bond on MSN surface leads to an initial rapid release of chimera, followed by a slow release of TMZ encapsulated in MSN. The sequential release of siHDGF and TMZ first allows siHDGF to exert its gene-silencing effect, and the downregulation of HDGF expression further enhances the cytotoxicity of TMZ. In vivo experimental results have demonstrated that TMSN@siHDGF-Gint4.T significantly inhibits tumor growth and extends the survival time of GBM-bearing mice. Thus, the as-developed TMSN@siHDGF-Gint4.T affords a potential approach for the combination treatment of GBM.