Effects of gold- and silver nanoparticles on the retina

Abstract: Over the past decade, a massive increase in the use of nanomaterials and nanoparticles (NPs) in both commercial and medical applications has occurred. Medical applications include advanced drug delivery vehicles, imaging and hyper thermic therapies. In retinal research, several nanomaterials have been explored in novel treatment approaches, ranging from metals, carbon, polymers and silica to biological materials such as lipids or lactic acid. NPs, especially, gain much attention as novel drug delivery vehicles due to their ability to cross the barriers of the eye including the cornea, conjunctiva and the blood-retinal barrier (BRB). This thesis focus on the two most commonly used nanomaterials; gold- and silver nanoparticles (AuNPs and AgNPs, respectively), both commonly used as the active component or as a carrier for a functional agent. AuNPs have desirable properties such as high chemical stability, well-controlled size and are easy to modify with various surface functionalization. AgNPs due to their antibacterial effects are often applied in wound disinfection, coatings of medical devices and prosthesis but also in many commercial products such as textiles, cosmetics and household gods. However, the literature is yet limited on the effect of AuNPs and AgNPs on the mammalian retina. Therefore, here we investigated the effect of AuNPs and AgNPs on the rodent retina using an ex vivo retina model. The retina is a well-organized laminar neural structure located at the back of the eye bulb. Sensory neurons, i.e. the photoreceptors, located in the outer nuclear layer of the retina, convert light to an electric signal that is transmitted through the bipolar cells and further to the retinal ganglion cells, which axons form the optic nerve that send the information from the retina to the brain for visual processing. All the neurons participating in this process are highly vulnerable to mechanical damage, changed levels of oxygen and nutrients as well as exposure to foreign factors. The immune cells of the central nervous system, also known as microglia cells, are located inside the retina and have the responsibility to sense pathological changes in their microenvironment. Any disturbances in the normal homeostasis will activate these cells which include increased proliferation, migration, phagocytosis and release of bioactive molecules.Here we characterized 20 nm and 80 nm of Ag- and AuNPs nanoparticles and show that the particles gain a defined protein corona upon entering a biological environment, here the explanted retina model system (Paper 1). With electron transmission microscope we further demonstrated that all NP types are able to translocate into all retinal neuronal layers unhindered. Moreover, we showed that the explanted retina model is a reliable and useful model for testing early prediction of NP-toxicity in the retina and report that low concentrations of 20 nm and 80 nm of Ag- and Au NPs have significant adverse effects on the retina (Paper 3). These effects were compared to the neurotoxicological effects induced by lipopolysaccharide administration, which is the most common way to mimic a bacterial infection (Paper 2). A range of typical pathological hallmarks were included in the analysis; micro- and macro morphological changes, macroglial activation, changes in microglia behavior, apoptosis and oxidative stress (Papers 2 & 3).Taken together, our results show that exposure to low doses of Au-and AgNPs causes neurotoxicity, similar to a LPS-induced pathological response in the retina. Our results, thus, suggest a careful assessment of candidate nanoparticles of any material to be used in neural systems, for therapeutic or other purposes.

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