The Surprising in Vivo Instability of Near-IR-Absorbing Hollow Au–Ag Nanoshells

Abstract

Photothermal ablation based on resonant illumination of near-infrared-absorbing noble metal nanoparticles that have accumulated in tumors is a highly promising cancer therapy, currently in multiple clinical trials. A crucial aspect of this therapy is the nanoparticle size for optimal tumor uptake. A class of nanoparticles known as hollow Au (or Au–Ag) nanoshells (HGNS) is appealing because near-IR resonances are achievable in this system with diameters less than 100 nm. However, in this study, we report a surprising finding that in vivo HGNS are unstable, fragmenting with the Au and the remnants of the sacrificial Ag core accumulating differently in various organs. We synthesized 43, 62, and 82 nm diameter HGNS through a galvanic replacement reaction, with nanoparticles of all sizes showing virtually identical NIR resonances at ∼800 nm. A theoretical model indicated that alloying, residual Ag in the nanoparticle core, nanoparticle porosity, and surface defects all contribute to the presence of the plasmon resonance at the observed wavelength, with the major contributing factor being the residual Ag. While PEG functionalization resulted in stable nanoparticles under laser irradiation in solution, an anomalous, strongly element-specific biodistribution observed in tumor-bearing mice suggests that an avid fragmentation of all three sizes of nanoparticles occurred in vivo. Stability studies across a wide range of pH environments and in serum confirmed HGNS fragmentation. These results show that NIR resonant HGNS contain residual Ag, which does not stay contained within the HGNS in vivo. This demonstrates the importance of tracking both materials of a galvanic replacement nanoparticle in biodistribution studies and of performing thorough nanoparticle stability studies prior to any intended in vivo trial application.

Engineering Gold Nanotubes with Controlled Length and Near‐Infrared Absorption for Theranostic Applications

“…[25,26] After adding HAuCl 4 into the CTAB-Ag NR dispersion, the combined galvanic reaction (See the Reaction 1) and Kirkendall growth lead to the formation the Au NTs with hollow interiors and porous walls. [27,28] 3Ag (s) + AuCl 4 -(aq) → Au(s) + 3Ag that is, the ends of this NT are terminated by {111} facets, and the side surfaces are bounded by {100} facets, [29][30][31] providing further support for the above-mentioned morphological features observed from the real space TEM images of the Au NTs ( Figure 2B and D) and the diffraction patterns from X-ray diffraction (XRD) ( Figure S4). Further structural information of the Au NTs, (e.g.…”

“…[37] Furthermore, the reduced Ag content implies more Ag has been etched from the NTs, increasing the porosity and surface defects (as shown in Figure S7), which may also contribute to the observed redshift. [28,33,[38][39][40] …”

Colloidal Plasmonic Titanium Nitride Nanoparticles: Properties and Applications

“…However, this concrete step toward the improved clearance brings new questions such as the stability of the nanoparticle assembly and controllability of the biodegradation process. In another recent study, Goodman et al reported the instability of hollow Au-Ag nanoshells, which provide shell structures with dimensions smaller than 100 nm, during in-vivo applications [38]. Another approach to red-shift the plasmonic resonance is to engineer the nanoparticle aspect ratio.…”

“…The broader resonance peak obtained from TiN nanoparticles is another advantage that relaxes the restrictions on particle size dispersion. It should be noted that smaller nanoparticle dimensions are desirable due to many critical requirements including efficient cellular uptake and clearance of particles after treatment [1,37,38].…”

Impurity-Induced Plasmon Damping in Individual Cobalt-Doped Hollow Au Nanoshells

“…Conversely, nanoparticle size and geometry can be adjusted to maintain a constant plasmon resonance frequency in some plasmonic nanoparticles over a relatively large particle size range. (1) While much attention has been paid to the tuning of plasmon resonance energies, far fewer studies have examined mechanisms for controlling nanoparticle plasmon line widths and line shapes. For the dipolar plasmon mode of a metallic nanosphere, the line width changes with increasing nanoparticle size, a characteristic signature of a bright plasmon mode.…”