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Co-Delivery of Doxorubicin and Survivin shRNA-Expressing Plasmid Via Microenvironment-Responsive Dendritic Mesoporous Silica Nanoparticles for Synergistic Cancer Therapy

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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.

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Abbreviations

APTES:

(3-aminopropy) triethoxysilane

BET:

Brunauer-Emmett-Teller

CLSM:

Confocal laser scanning microscopy

CTAB:

Cetyltrimethylammonium bromide

DL:

Drug loading

DMEM:

Dulbecco’s modified eagle medium

DMSN:

Dendrimer mesoporous silica nanoparticles

DMSN@DOX:

DOX loaded DMSN nanoparticles

DMSN@DOX/pDNA:

iSur-pDNA loaded DMSN@DOX nanocomplexes

DOX:

Doxorubicin

FT-IR:

Fourier transform-infrared spectroscopy

FITC-pDNA:

FITC-labeled pDNA

IC50 :

Half maximal inhibitory concentration

iSur-pDNA:

Survivin shRNA-expressing plasmid

MTT:

Methyl thiazolyl tetrazolium

PBS:

Phosphate buffer solution

SAXS:

Small-angle X-ray scattering

SDS:

Sodium dodecyl sulfate

SL-IDMSN:

Schiff-base linked imidazole dendritic mesoporous silica nanoparticles

SL-IDMSN@DOX:

DOX loaded SL-IDMSN nanoparticles

SL-IDMSN@DOX/pDNA:

iSur-pDNA loaded SL-IDMSN@DOX nanocomplexes

TEA:

Triethanolamine

TEM:

Transmission electron microscopy

TEOS:

Tetraethyl orthosilicate

TIR:

Tumor inhibition ratio

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Acknowledgments and Disclosures

The authors are thankful for the financial support from the National Natural Science Foundation of China (No. 81273460).

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Authors and Affiliations

  1. State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Zhengxiong Li, Linlin Zhang, Cui Tang & Chunhua Yin

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  1. Zhengxiong Li
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  2. Linlin Zhang
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  3. Cui Tang
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  4. Chunhua Yin
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Correspondence to Cui Tang.

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Li, Z., Zhang, L., Tang, C. et al. Co-Delivery of Doxorubicin and Survivin shRNA-Expressing Plasmid Via Microenvironment-Responsive Dendritic Mesoporous Silica Nanoparticles for Synergistic Cancer Therapy. Pharm Res 34, 2829–2841 (2017). https://doi.org/10.1007/s11095-017-2264-6

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  • DOI: https://doi.org/10.1007/s11095-017-2264-6

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