A significant challenge to the clinical use of gold nanocrystals in humans is the reported toxicity from animal and <i>in vitro</i> cytotoxicity studies. The surface chemistry of nanomaterials has been well-characterized and found to contribute to the toxicity profile of these materials. Here we describe the surface chemistry characterization and the clean toxicity profile of clean-surfaced, faceted gold nanocrystals produced in water using a novel electrochemistry method.  Because these nanocrystals do not contain any capping agents, residual reactants, and/or stabilizing molecules, they exhibit improved toxicity and tolerability profiles compared to, for example, gold salts, when administered orally up to 90 mg/kg/day in animals and in doses up to 90mg/day in healthy adult volunteers. The surfaces of the gold nanocrystals have been interrogated with Time-of-Flight Secondary Ion Mass Spectrometry (TOF-SIMs), high-angle annular dark-field scanning transmission electron microscopy scanning tunneling electron microscopy (HAADF-STEM), and X-ray photoelectron spectroscopy (XPS).  These characterization data support the absence of any organic agents or oxides on the surfaces of the gold nanocrystals.  A 9-month chronic canine study with a four-week recovery concluded that the no-observed-adverse effect level (NOAEL) was the highest dose tested at 10 mg/kg/day, while a 6-month chronic rat study with 4-week recovery similarly concluded that the NOAEL was the highest dose tested at 40 mg/kg/day.  In a Phase 1, first-in-human healthy subject study, the incidence of treatment emergent adverse events (TEAEs) was comparable between the treatment and placebo groups after 21 days of once daily oral administration. All TEAEs were mild in severity with none being severe or resulting in treatment discontinuation.  All routine clinical laboratory assessments, vital signs, ECGs, and physical examinations did not reveal clinically notable findings.  Based on these results, we conclude that the absence of surface organic residues is critical to the safety and tolerability of nanotherapeutics.  This data represents the most comprehensive human drug safety profile to date for an orally administered clean surface gold nanocrystals.

Electrochemically grown, clean surfaced gold nanocrystals exhibit a very favorable safety profile in rodents, canines, and humans

256th National Meeting (2018)

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