Zhengxiong Li1, Linlin Zhang1, Cui Tang2, Chunhua Yin1. 1. State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai, 200438, China. 2. State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai, 200438, China. tangcui@fudan.edu.cn.
Abstract
PURPOSE: The present study is aimed at designing an appropriate co-delivery system for chemotherapeutic drugs and gene drugs with high loading capacity, on-demand release behaviors, efficient endosomal escape, and enhanced nucleic localization, thereby providing efficacious antitumor activity. METHODS: Schiff-base linked imidazole dendritic mesoporous silica nanoparticles (SL-IDMSN) were developed and employed to load doxorubicin (DOX) and survivin shRNA-expressing plasmid (iSur-pDNA) to form nanocomplexes. The nanoparticles were assessed by structural characterization, drug loading and release, cellular uptake, intracellular distribution, gene transfection, in vitro anti-proliferation of hepatoma cells, and in vivo tumor growth inhibition in H-22 tumor bearing mice. RESULTS: SL-IDMSN showed high loading capacity for both DOX and iSur-pDNA due to their hierarchical mesostructures. The cleavage of Schiff-base linkage on SL-IDMSN in the weakly acidic endosomes/lysosomes led to microenvironment-specific release of both DOX and iSur-pDNA. Meanwhile, the imidazole modification could trigger the efficient endosomal escape via proton sponge effect, thereby enhancing nuclear accumulation of iSur-pDNA and gene silencing efficiency. More importantly, these superior performances of SL-IDMSN resulted in their improved inhibitory effects on in vitro cancer cell proliferation and in vivo tumor growth. CONCLUSIONS: SL-IDMSN is a microenvironment-sensitive and biocompatible nanocarrier for the co-delivery of DOX and iSur-pDNA, which might be a promising carrier for co-delivery of chemotherapeutic drugs and gene drugs for synergistic cancer therapy.
PURPOSE: The present study is aimed at designing an appropriate co-delivery system for chemotherapeutic drugs and gene drugs with high loading capacity, on-demand release behaviors, efficient endosomal escape, and enhanced nucleic localization, thereby providing efficacious antitumor activity. METHODS:Schiff-base linked imidazole dendritic mesoporous silica nanoparticles (SL-IDMSN) were developed and employed to load doxorubicin (DOX) and survivin shRNA-expressing plasmid (iSur-pDNA) to form nanocomplexes. The nanoparticles were assessed by structural characterization, drug loading and release, cellular uptake, intracellular distribution, gene transfection, in vitro anti-proliferation of hepatoma cells, and in vivo tumor growth inhibition in H-22 tumor bearing mice. RESULTS: SL-IDMSN showed high loading capacity for both DOX and iSur-pDNA due to their hierarchical mesostructures. The cleavage of Schiff-base linkage on SL-IDMSN in the weakly acidic endosomes/lysosomes led to microenvironment-specific release of both DOX and iSur-pDNA. Meanwhile, the imidazole modification could trigger the efficient endosomal escape via proton sponge effect, thereby enhancing nuclear accumulation of iSur-pDNA and gene silencing efficiency. More importantly, these superior performances of SL-IDMSN resulted in their improved inhibitory effects on in vitro cancer cell proliferation and in vivo tumor growth. CONCLUSIONS: SL-IDMSN is a microenvironment-sensitive and biocompatible nanocarrier for the co-delivery of DOX and iSur-pDNA, which might be a promising carrier for co-delivery of chemotherapeutic drugs and gene drugs for synergistic cancer therapy.
Entities:
Keywords:
cancer therapy; co-delivery; nanoparticles; pH responsiveness
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