siRNA Delivery with Chitosan: Influence of Chitosan Molecular Weight, Degree of Deacetylation, and Amine to Phosphate Ratio on in Vitro Silencing Efficiency, Hemocompatibility, Biodistribution, and in Vivo Efficacy
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Abstract
Chitosan (CS) shows in vitro and in vivo efficacy for siRNA delivery but with contradictory
findings for incompletely characterized systems. For understanding which parameters
produce effective delivery, a library of precisely characterized chitosans was produced
at different degrees of deacetylation (DDAs) and average molecular weights (Mn). Encapsulation
and transfection efficiencies were characterized in vitro. Formulations were selected
to examine the influence of Mn and N:P ratio on nanoparticle uptake, metabolic activity,
genotoxicity, and in vitro transfection. Hemocompatibility and in vivo biodistribution
were then investigated for different Mn, N:P ratios, and doses. Nanoparticle uptake
and gene silencing correlated with increased surface charge, which was obtained at
high DDA and high Mn. A minimum polymer length of ∼60-70 monomers (∼10 kDa) was required
for stability and knockdown. In vitro knockdown was equivalent to lipid control with
no metabolic or genotoxicity. An inhibitory effect of serum on biological performance
was dependent on DDA, Mn, and N:P. In vivo biodistribution in mice show accumulation
of nanoparticles in kidney with 40-50% functional knockdown.
[1
]Department
of Chemical Engineering, ‡Institute of Biomedical Engineering,
and §Department
of Electrical
Engineering, Polytechnique Montreal, Montreal, Quebec H3T 1J4, Canada