Abstract
In the biomedical field, gold nanoparticles (GNPs) have attracted the attention of the scientific community thanks to their high potential in both diagnostic and therapeutic applications. The extensive use of GNPs led researchers to investigate their toxicity, identifying stability, size, shape, and surface charge as key properties determining their impact on biological systems, with possible strategies defined to reduce it according to a Safe-by-Design (SbD) approach. The purpose of the present work was to analyze the toxicity of GNPs of various sizes and with different coating polymers on the developing vertebrate model, zebrafish. In particular, increasing concentrations (from 0.001 to 1 nM) of 6 or 15 nm poly-(isobutylene-alt-maleic anhydride)-graft-dodecyl polymer (PMA)- or polyethylene glycol (PEG)-coated GNPs were tested on zebrafish embryos using the fish embryo test (FET). While GNP@PMA did not exert significant toxicity on zebrafish embryos, GNP@PEG induced a significant inhibition of embryo viability, a delay of hatching (with the smaller size NPs), and a higher incidence of malformations, in terms of tail morphology and eye development. Transmission electron microscope analysis evidenced that the more negatively charged GNP@PMA was sequestered by the positive charges of chorion proteins, with a consequent reduction in the amount of NPs able to reach the developing embryo and exert toxicological activity. The mild toxic response observed on embryos directly exposed to GNP@PMA suggest that these NPs are promising in terms of SbD development of gold-based biomedical nanodevices. On the other hand, the almost neutral GNP@PEG, which did not interact with the chorion surface and was free to cross chorion pores, significantly impacted the developing zebrafish. The present study raises concerns about the safety of PEGylated gold nanoparticles and contributes to the debated issue of the free use of this nanotool in medicine and nano-biotechnologies.
Highlights
In recent years, the Safe-by-Design (SbD) approach has gained increasing importance for the development of new nanomaterials, including nanoformulated medicines [1]
From the data obtained on zebrafish embryos analyzed according to fish embryo test (FET), it seems evident that, while different sizes of gold nanoparticles (GNPs)@poly(isobutylene-alt-maleic anhydride) (PMA) do not exert significant toxicity on this developmental vertebrate model, the same NPs functionalized with polyethylene glycol (PEG) induce strong adverse effects, more or less evident from different FET endpoints according to their dimension and treatment concentration
The 6 nm NPs seem to be more effective than 15 nm NPs, taking into account hatching percentage and the occurrence of eye malformation, but a lower percentage of tail malformations was detected with these nanoparticles with respect to the higher-dimension ones
Summary
The Safe-by-Design (SbD) approach has gained increasing importance for the development of new nanomaterials, including nanoformulated medicines [1]. According to SbD, the biological hazard of the new nanomaterial needs to be determined at the earlier stage of the production process, in order to predict its potential adverse effect on human health and the environment. Among the many nanodevices developed for biomedical applications, gold nanoparticles (GNPs) have received great interest over the last 10 years for the management of cancer disease, due to their ability in diagnostic and/or therapeutic applications. In the context of an increasingly widespread development of GNPs for oncology, the issue of their biosafety is still today controversial, and many in vitro and in vivo toxicity studies have been performed over the past decade to elucidate the adverse impacts of gold-based nanoparticles [4,5]. Shape and size play a key role in the adverse impact of these nanomaterials [7,8] and, in a range between 1 and 15 nm, small-dimension NPs seem to exert more toxic effects than higher-dimension ones [9]
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