Influence of Geometry, Porosity, and Surface Characteristics of Silica Nanoparticles on Acute Toxicity: Their Vasculature Effect and Tolerance Threshold

Silica nanoparticles (SiO2) are widely used in biomedical applications such as drug delivery, cell tracking, and gene transfection. The capability to control the geometry, porosity, and surface characteristics of SiO2 further provides new opportunities for their applications in nanomedicine. Concerns however remain about the potential toxic effects of SiO2 upon exposure to biological systems. In the present study, the acute toxicity of SiO2 of systematically varied geometry, porosity, and surface characteristics was evaluated in immune-competent mice when administered intravenously. Results suggest that in vivo toxicity of SiO2 was mainly influenced by nanoparticle,porosity and surface characteristics. The maximum tolerated dose (MID) increased in the following order: mesoporous SiO2 (aspect ratio 1, 2, 8) at 30-65 mg/kg < amine-modified mesoporous SiO2 (aspect ratio 1, 2, 8) at 100-150 mg/kg < unmodified or amine-modified nonporous SiO2 at 450 mg/kg. The adverse reactions above MTDs were primarily caused by the mechanical obstruction of SiO2 in the vasculature that led to congestion in multiple vital organs and subsequent organ failure. It was revealed that hydrodynamic sizes of SiO2 post-protein exposure had an important implication in relating SiO2 physicochemical properties with their vasculature impact and resultant tolerance threshold, as the larger the hydrodynamic size in the presence of serum protein, the lower the MTD. This study sheds light on the rational design of SiO2 to minimize in vivo toxicity and provides a critical guideline in selecting SiO2 as the appropriate system for nanomedicine applications.