Gold Nanoparticle Coating Reduces Acoustic Pressure Threshold for Perfluorohexane Nanodroplet Vaporization: Potential Mechanisms and Therapy Implications

Ultrasound-induced vaporization of perfluorocarbon (PFC) nanodroplets can be used for triggered drug delivery. Nanodroplets of perfluorobutane (PFB) and perfluoropentane (PFP) can vaporize spontaneously at physiological temperature, which can cause off-target effects. Using high-boiling-point PFCs, such as perfluorohexane (PFH), can overcome this limitation. However, PFH requires higher peak negative pressures for vaporization, making its in vivo use challenging. We investigated the feasibility of reducing the vaporization pressure threshold by gold-coating lipid-encapsulated PFH nanodroplets (Au-PFH-ND). We synthesized PFH nanodroplets, and the gold-coating was confirmed by UV-visible spectra. The mass of gold per nanodroplet was 5.12×10^-4 pg. The size distribution peaked at 200 nm and had a mean concentration of 2×10¹⁰ droplets/ml. Au-PFH-ND demonstrated excellent stability over 8 weeks. Ultrasound imaging in vitro was used to determine the pressure threshold for nanodroplet vaporization upon exposure to 2 MHz ultrasound. The vaporization threshold for Au-PFH-ND (3.29 ± 0.93 MPa) was significantly lower than uncoated PFH nanodroplets (PFH-ND, 6.19 ± 1.25 MPa). Au-PFH-ND had a similar pressure threshold to uncoated PFP nanodroplets (PFP-ND, 2.81 ± 1.08 MPa). These findings show that the Au-PFH-ND can be vaporized at a similar ultrasound pressure as PFP-ND. Increasing pulse duration from 2 to 60 cycles enhanced vaporization of Au-PFH-ND, demonstrating the dominant role of a thermal mechanism. Even when accounting for the total ultrasound on-time and effective peak negative pressure, longer bursts (i.e., more cycles per burst) were more effective in inducing vaporization, consistent with the role of localized heating around the gold coating rather than a purely probabilistic effect. Additionally, inertial and stable cavitation emissions were quantified. Au-PFH-ND exhibited a marginally lower inertial cavitation threshold and similar second harmonic emissions than PFH-ND, suggesting that cavitation could also have played a role in reducing the pressure threshold. These findings are a step towards employing gold-coated PFC nanodroplets for multimodal drug delivery.