Abstract
BackgroundThe increasing use of gold nanoparticles (AuNPs) in the field of neuroscience instilled hope for their rapid translation to the clinical practice. AuNPs can be engineered to carry therapeutics or diagnostics in the diseased brain, possibly providing greater cell specificity and low toxicity. Although there is a general enthusiasm for these tools, we are in early stages of their development. Overall, their brain penetrance, stability and cell specificity are critical issues that must be addressed to drive AuNPs to the clinic.ResultsWe studied the kinetic, distribution and stability of PEG-coated AuNPs in mice receiving a single injection into the cisterna magna of the 4th ventricle. AuNPs were conjugated with the fluorescent tag Cy5.5 (Cy5.5-AuNPs) to track their in vivo distribution. Fluorescence levels from such particles were detected in mice for weeks. In situ analysis of brains by immunofluorescence and electron microscopy revealed that Cy5.5-AuNPs penetrated the brain parenchyma, spreading in the CNS parenchyma beneath the 4th ventricle. Cy5.5-AuNPs were preferentially found in neurons, although a subset of resting microglia also entrapped these particles.ConclusionsOur results suggest that the ICM route for delivering gold particles allows the targeting of neurons. This approach might be pursued to carry therapeutics or diagnostics inside a diseased brain with a surgical procedure that is largely used in gene therapy approaches. Furthermore, this approach could be used for radiotherapy, enhancing the agent’s efficacy to kill brain cancer cells.
Highlights
The increasing use of gold nanoparticles (AuNPs) in the field of neuroscience instilled hope for their rapid translation to the clinical practice
Intra-carotid injection of AuNPs increases the penetrance of particles in the brain, their diffusion in the parenchyma is limited to few microns from the visible vessels [22]
Purified Cy5.5-AuNPs were stable for months when kept at 4 °C, without any trace of nanoparticles aggregation or Cy5.5. dye degradation as detected by Dynamic light scattering (DLS) and fluorescence measurements
Summary
Synthesis and characterization of Cy5.5‐AuNPs We recently developed a new method based on a Turkevich-modified ‘one-pot’ strategy to obtain large batches of functionalized AuNPs, that avoids the purification of intermediate citrate-stabilized nanoparticles [32]. We detected signals that were more robust when we scored FLI in isolated brains collected 5 days after the injection of particles (Additional file 3: Figure S3A). We calculated Au concentrations in brain explants obtained from mice receiving ICM injection of Cy5.5AuNPs. The Cy5.5-injected group was not included in this experiment since we reasoned that FR signals were close to background levels as shown in the previous experiment (Fig. 3d). Ex‐vivo localization of Cy5.5‐AuNPs in ICM injected brains We investigated the uptake of Cy5.5-AuNPs in fixed brains sections, sampling brains from mice sacrificed 30 days after ICM delivery of Cy5.5-AuNPs. Using confocal microscope, we acquired Cy5.5 and Au fluorescence in order to increase the signal to noise ratio, the signal specificity, and to provide a better estimation of Cy5.5AuNPs distribution [38].
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