Abstract
Silica nanoparticles (SiO(2)) 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 SiO(2) further provides new opportunities for their applications in nanomedicine. Concerns however remain about the potential toxic effects of SiO(2) upon exposure to biological systems. In the present study, the acute toxicity of SiO(2) of systematically varied geometry, porosity, and surface characteristics was evaluated in immune-competent mice when administered intravenously. Results suggest that in vivo toxicity of SiO(2) was mainly influenced by nanoparticle porosity and surface characteristics. The maximum tolerated dose (MTD) increased in the following order: mesoporous SiO(2) (aspect ratio 1, 2, 8) at 30-65 mg/kg < amine-modified mesoporous SiO(2) (aspect ratio 1, 2, 8) at 100-150 mg/kg < unmodified or amine-modified nonporous SiO(2) at 450 mg/kg. The adverse reactions above MTDs were primarily caused by the mechanical obstruction of SiO(2) in the vasculature that led to congestion in multiple vital organs and subsequent organ failure. It was revealed that hydrodynamic sizes of SiO(2) post-protein exposure had an important implication in relating SiO(2) 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 SiO(2) to minimize in vivo toxicity and provides a critical guideline in selecting SiO(2) as the appropriate system for nanomedicine applications.