The Fate and Toxicity of Raman-Active Silica-Gold Nanoparticles in Mice

Abstract

Raman spectroscopy is an optical imaging modality which analyses the Raman effect in which energy is exchanged between light and matter. Although Raman spectroscopy has been widely used for chemical and molecular analysis, its use in clinical applications has been hindered by the inherently weak nature of the Raman effect. Raman-silica-gold-nanoparticles (R-Si-Au-NPs) overcome this limitation by producing high Raman signals via Surface Enhanced Raman Scattering. Targeted polyethylene glycol (PEG)-ylated R-Si-Au-NPs (e.g. PEG-R-Si-Au-NPs labeled with an affibody which binds specifically to the epidermal growth factor receptor) are currently being designed to detect colorectal cancer after administration into the bowel lumen. With this approach, PEG-R-Si-Au-NPs are not expected to enter the systemic circulation and would be removed from the body via defecation. We examined the acute toxicity and biodistribution of core PEG-R-Si-Au-NPs after different routes of administration in mice. After intravenous administration, PEG-R-Si-Au-NPs were removed from the circulation by marcophages in the liver and spleen (i.e. the reticuloendothelial system). At 24 hours, PEG-R-Si-Au-NPs elicited a mild inflammatory response and an increase in oxidative stress in the liver, which subsided by 2 weeks. No evidence of significant toxicity was observed by measuring clinical, histological, biochemical or cardiovascular parameters for 2 weeks. Notably, after administration per rectum, we observed no significant bowel or systemic toxicity and no PEG-R-Si-Au-NPs were detected systemically. Although additional studies are required to investigate the long-term effects of PEG-R-Si-Au-NPs, these initial results support the idea that they can be safely used in living subjects, especially when administered rectally.

Effect of silica and gold nanoparticles on macrophage proliferation, activation markers, cytokine production, and phagocytosis in vitro

“…Gold and silica NPs are both relevant durable NPs to investigate as they have been proposed for use as drug delivery vehicles, imaging agents, and even active pharmaceutical ingredients. [25][26][27] As appropriate characterization has been repeatedly shown to be critical prior to toxicology evaluations, all NPs …”

Comprehensive spectral endoscopy of topically applied SERS nanoparticles in the rat esophagus

“…However, a spectral endoscope for comprehensive in vivo imaging of the esophagus has not been reported yet. Although recent studies have shown that SERS NPs applied topically in the rectum show no toxicity and result in negligible systemic uptake [36,37], the systemic toxicity of these NPs when orally administered is unknown and SERS NPs are not currently approved for administration in the human esophagus. Therefore, we are developing a device to image the rat esophagus.…”

A Raman-based endoscopic strategy for multiplexed molecular imaging

“…vs. i.v. in mice (18,22,45) These extensive toxicity studies, using over 120 mice, revealed that after i.r. administration, the Raman nanoparticles remained localized in the colon, with the majority clearing after 24 h. Additionally, the i.r.-administered Raman nanoparticles never crossed over into the systemic circulation, as opposed to the mice injected i.v., where the Raman nanoparticles quickly accumulated in the liver and spleen with prolonged/indefinite retention.…”

“…In this study, we have thoroughly assessed the usability and capability of our newly developed Raman endoscope to detect and multiplex an array of SERS nanoparticles within phantoms and on excised tissue samples. We have reported previously on functionalization of the SERS nanoparticles (12,13,18); although regulatory approval is pending for the topical administration of these particles in the human colon, we have been able to evaluate our Raman endoscope design extensively in patients. To advance this technology further and demonstrate the capability of the Raman endoscope, we simulated Raman signals by superimposing separately measured SERS spectra onto the intrinsic Raman signals obtained from patients during endoscopy.…”

“…Note that these results reflect the use of SERS nanoparticles at concentrations of ∼1 nM in volumes of 3 μL for each flavor used and that the sensitivity and specificity would presumably change at lower concentrations closer to the limit of detection (subpicomolar). However, to demonstrate the usability and multiplexing capabilities of the Raman endoscope, we chose a dose of ∼1 nM, which has been shown to be nontoxic when administered locally to the colon in mice (18,22) The sensitivity and specificity were also determined for each SERS flavor combination. More information is provided in Methods (Statistical Analysis) and SI Appendix, Fig.…”