Pharmacokinetics of metallic nanoparticles

Abstract

Metallic nanoparticles (NPs) have been widely applied in the field of nanomedicine. A comprehensive understanding of their pharmacokinetics is crucial for proper risk assessment and safe biomedical applications. This review focuses on gold and silver (Ag) NPs, and briefly discusses iron oxide, titanium dioxide (TiO2 ), and zinc oxide NPs. Pharmacokinetics of metallic NPs depends on the particle type, size, surface charge, surface coating, protein binding, exposure route, dose, and species. Generally, blood half-life is shorter in rodents than in larger laboratory animals (e.g., rabbits or monkeys) and differs between intravenous and oral exposures. Oral, dermal, or inhalational absorption is low (≤5%), but may increase with smaller sizes, negative charge, and appropriate coatings. Metallic NPs can be distributed throughout the body, primarily accumulating in the liver, spleen, and lymph node due to nonspecific uptake by reticuloendothelial cells, and could remain in the body for ≥6 months. Metallic NPs (≤100 nm) can cross the blood-brain barrier (BBB), favored by coating with BBB-permeable neuropeptides. Placental transfer depends on the stage of embryonic/placental maturation and surface composition, and may be enhanced by coating with biocompatible molecules (e.g., ferritin or polyethylene glycol). Renal and biliary excretion is generally low due to persistent accumulation in tissues, but renal elimination could be substantially increased with smaller sizes and specific coatings (e.g., glutathione). Physiologically based pharmacokinetic models for gold/dendrimer composite nanodevices, AgNPs, and TiO2 NPs have been developed in rats and the AgNP and TiO2 NP models have been extrapolated to humans to support risk assessment and nanomedicine applications.

Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles

“…The large differences in certain parameters (discussed further below) indicate that these biokinetics are highly dependent on properties of the NPs, as shown in numerous experimental studies. 7,16,42 A better understanding of the relationship between biokinetic parameters and NP properties requires experiments involving different doses and properties such as size, size distribution, charge, shape, agglomeration, and surface characteristics.…”

“…23,25,28 Several models for cellular NP uptake in vitro have been proposed, some of which suggest that the NPs are adsorbed to the cell surface prior to endocytosis. 16,[46][47][48] According to these models, the rate of this is faster than the rate of endocytosis, which depends on the accessibility and recirculation of appropriate receptors. Reported rates of endocytosis vary by more than three orders of magnitude and, in addition, adsorption can occur more than three orders of magnitude more rapidly than endocytosis itself.…”

Nanopharmaceuticals: Tiny challenges for the environmental risk assessment of pharmaceuticals

“…Further information on particle size and distribution, morphology (e.g., geometry, crystallinity), and surface properties (e.g., chemistry, reactivity, surface area) but also on agglomeration and dissolution behavior is needed for an adequate nanospecific ERA [24,25,26,27,28]. Because nanomaterials for medical purposes are often complex particles (e.g., composed of a core and coating [29]), detailed information on the composition of the compound is also of special importance. For nanomedicines that release small molecule ingredients, a traditional ERA should be conducted for the small molecule part and a nanospecific ERA for the remaining nano part.…”

“…Both processes might lead to a particle size above the nanosize range; however, agglomeration can be reversible, and nanosized particles could nevertheless be excreted or formed once they are back in the environment. Another process can occur for ion-forming nanoparticles [29]. Dissolution of ions is favored by the enhanced surface area or porosity of nanoparticles.…”

“…To increase biocompatibility, metallic nanoparticles are generally coated with polymers such as PEG, carbohydrates, or peptides [29]. One way to follow the pharmacokinetics of a medicinal nanoparticle consisting of a core and a coating is to use dually radiolabeled compounds.…”