Yu Tian

Understanding the toxicity of silica nanoparticles (SiO(2)) on the cellular level is crucial for rational design of these nanomaterials for biomedical applications. Herein, we explore the impacts of geometry, porosity, and surface charge of SiO(2) on cellular toxicity and hemolytic activity. Nonporous Stöber silica nanospheres (115 nm diameter), mesoporous silica nanospheres (120 nm diameter, aspect ratio 1), mesoporous silica nanorods with aspect ratio of 2, 4, and 8 (width by length 80 × 200 nm, 150 × 600 nm, 130 × 1000 nm), and their cationic counterparts were evaluated on macrophages, lung carcinoma cells, and human erythrocytes. It was shown that the toxicity of SiO(2) is cell-type dependent and that surface charge and pore size govern cellular toxicity. Using inductively coupled plasma mass spectrometry, the cellular association of SiO(2) was quantitated with the association amount increasing in the following order: mesoporous SiO(2) (aspect ratio 1, 2, 4, 8) < amine-modified mesoporous SiO(2) (aspect ratio 1, 2, 4, 8) < amine-modified nonporous Stöber SiO(2) < nonporous Stöber SiO(2). Geometry did not seem to influence the extent of SiO(2) association at early or extended time points. The level of cellular association of the nanoparticles was directly linked to the extent of plasma membrane damage, suggesting a biological cause-and-effect relationship. Hemolysis assay showed that the hemolytic activity was porosity- and geometry-dependent for bare SiO(2) and surface-charge-dependent for amine-modified SiO(2). A good correlation between hemolytic activity and cellular association was found on a similar dosage basis. These results can provide useful guidelines for the rational design of SiO(2) in nanomedicine.

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.

The influence of size, surface charge and surface functionality of poly(amido amine) dendrimers and silica nanoparticles (SNPs) on their toxicity was studied in immunocompetent mice. After systematic characterization of nanoparticles, they were administered to CD-1 (caesarean derived-1) mice to evaluate acute toxicity. A distinct trend in nanotoxicity based on surface charge and functional group was observed with dendrimers regardless of their size. Amine-terminated dendrimers were fatal at doses >10 mg/kg causing haematological complications such as disseminated intravascular coagulation-like manifestations whereas carboxyl- and hydroxyl-terminated dendrimers of similar sizes were tolerated at 50-fold higher doses. In contrast, larger SNPs were less tolerated than smaller SNPs irrespective of their surface functionality. These findings have important implications in the use of these nanoparticles for various biomedical applications.