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. 2010 Dec;27(12):2556-68.
doi: 10.1007/s11095-010-0245-0. Epub 2010 Aug 21.

Enhanced gene and siRNA delivery by polycation-modified mesoporous silica nanoparticles loaded with chloroquine

Shanta Raj Bhattarai  1 , Elayaraja Muthuswamy, Amit Wani, Michal Brichacek, Antonio L Castañeda, Stephanie L Brock, David Oupicky
Affiliations

Enhanced gene and siRNA delivery by polycation-modified mesoporous silica nanoparticles loaded with chloroquine

Shanta Raj Bhattarai et al. Pharm Res. 2010 Dec.

Abstract

Purpose: To prepare mesoporous silica-based delivery systems capable of simultaneous delivery of drugs and nucleic acids.

Methods: The surface of mesoporous silica nanoparticles (MSN) was modified with poly(ethylene glycol) (PEG) and poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA) or poly(2-(diethylamino)ethylmethacrylate) (PDEAEMA). The particles were then loaded with a lysosomotropic agent chloroquine (CQ) and complexed with plasmid DNA or siRNA. The ability of the synthesized particles to deliver combinations of CQ and nucleic acids was evaluated using luciferase plasmid DNA and siRNA targeting luciferase and GAPDH.

Results: The results show a slow partial MSN dissolution to form hollow silica nanoparticles in aqueous solution. The biological studies show that polycation-modified MSN are able to simultaneously deliver CQ with DNA and siRNA. The co-delivery of CQ and the nucleic acids leads to a significantly increased transfection and silencing activity of the complexes compared with MSN not loaded with CQ.

Conclusion: PEGylated MSN modified with polycations are promising delivery vectors for combination drug/nucleic acid therapies.

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Figures

Fig. 1
Fig. 1
TEM images and size distribution determined from TEM of the studied particles. From top to bottom: MSN, PMSN, PDMAEMA-PMSN, PDEAEMA-PMSN (insets: HRTEM showing porous structure of the particles).
Fig. 2
Fig. 2
MSN dissolution. TEM images of MSN acquired after 24 h incubation of 0.5 and 2 mg/mL MSN in DMEM, TRIS, and deionized water.
Fig. 3
Fig. 3
MSN dissolution. The content of soluble silicic acid was determined by silicomolybdic acid assay after 24 incubation of MSN in deionized water, DMEM, and TRIS.
Fig. 4
Fig. 4
Chemical structure of the polycations used for surface modification of MSN.
Fig. 5
Fig. 5
DNA condensation by PEG-coated MSN (PMSN), PEG- and polycation-coated MSN (PDMAEMA-PMSN, PDEAEMA-PMSN) and free polycations (PDMAEMA, PDEAEMA). DNA condensation was determined by ethidium bromide exclusion assay using luciferase plasmid DNA and PDMAEMA-based (top) or PDEAEMA-based (bottom) particles (RFU: relative fluorescence units normalized to ethidium bromide/DNA fluorescence).
Fig. 6
Fig. 6
Hydrodynamic size and zeta potential of polymer-modified MSN and their DNA complexes. (particle:DNA w:w ratio 20).
Fig. 7
Fig. 7
Kinetics of chloroquine release from polymer-modified MSN and their DNA complexes. (particle:DNA w:w ratio 20).
Fig. 8
Fig. 8
Toxicity of DNA (top) and siRNA (bottom) complexes of polymer-modified MSN with and without CQ in B16F10 cells.
Fig. 9
Fig. 9
Transfection activity of luciferase plasmid DNA complexes of polymer-modified MSN with and without CQ in B16F10 cells.
Fig. 10
Fig. 10
Effect of externally added CQ on the transfection activity of polymer-modified MSN and free polycations in B16F10 cells. (complexes with polycation-PMSN were made at w:w 20 and complexes with free polycations at the corresponding total polycation concentration).
Fig. 11
Fig. 11
Gene silencing by siRNA complexes of polymer-modified MSN. Luciferase silencing in transiently transfected cells using CQ-loaded PDMAEMA-PMSN particles (particle:siRNA w:w ratio 20) in B16F10 cells.
Fig. 12
Fig. 12
Silencing of endogenous GAPDH expression by siRNA complexes of PDMAEMA-PMSN.
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