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

Abstract

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 (MTD) 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.