Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines

Abstract

Inertial cavitation mediated by ultrasound has been previously shown to enable skin permeabilisation for transdermal drug and vaccine delivery, by sequentially applying the ultrasound then the therapeutic in liquid form on the skin surface. Using a novel hydrogel dosage form, we demonstrate that the use of sub-micron gas-stabilising polymeric nanoparticles (nanocups) to sustain and promote cavitation activity during simultaneous application of both drug and vaccine results in a significant enhancement of both the dose and penetration of a model vaccine, Ovalbumin (OVA), to depths of 500μm into porcine skin. The nanocups themselves exceeded the penetration depth of the vaccine (up to 700μm) due to their small size and capacity to 'self-propel'. In vivo murine studies indicated that nanocup-assisted ultrasound transdermal vaccination achieved significantly (p<0.05) higher delivery doses without visible skin damage compared to the use of a chemical penetration enhancer. Transdermal OVA doses of up to 1μg were achieved in a single 90-second treatment, which was sufficient to trigger an antigen-specific immune response. Furthermore, ultrasound-assisted vaccine delivery in the presence of nanocups demonstrated substantially higher specific anti-OVA IgG antibody levels compared to other transdermal methods. Further optimisation can lead to a viable, safe and non-invasive delivery platform for vaccines with potential use in a primary care setting or personalized self-vaccination at home.

Recent advances in ultrasound-based transdermal drug delivery

“…Cup-shaped polymeric nanoparticles have also been used in ultrasound-mediated transdermal delivery. 56 The nanocup consists of a single-cavity polymeric nanoparticle, which is ultrasound responsive and traps a bubble in its cavity. Ultrasound exposure to the nanocups generates cavitation activity, which causes active micropumping of the suspended components.…”

For Whom the Bubble Grows: Physical Principles of Bubble Nucleation and Dynamics in Histotripsy Ultrasound Therapy

“…Because of their relatively small size compared with microbubbles (100À500 nm vs. 0.6À10 mm) (Graham et al 2014), nanocups and droplets can efficiently penetrate leaky tumor vasculature (Kwan et al 2015). Other potential applications for nanocups include transdermal transport of vaccines (Bhatnagar et al 2016) and delivery of oncolytic vaccinia viruses (Myers et al 2016).…”

Novel approaches for the design, delivery and administration of vaccine technologies

“…This process involves the application of focused ultrasound to achieve expansion and collapse of gas bubbles which, in turn, creates microstreaming and shockwaves [159]. Sonophoresis has been used to either increase the permeability of the skin before topical application of the vaccine or as a method of concurrently applying both cavitation and vaccine, thereby actively pushing the vaccine particles into the skin [160,161]. The recent development of nano-sized polymeric cavitation nuclei (nanocups), capable of sustaining and promoting cavitation activity, provides a means of sustaining such delivery over extended periods [161,162].…”

“…Sonophoresis has been used to either increase the permeability of the skin before topical application of the vaccine or as a method of concurrently applying both cavitation and vaccine, thereby actively pushing the vaccine particles into the skin [160,161]. The recent development of nano-sized polymeric cavitation nuclei (nanocups), capable of sustaining and promoting cavitation activity, provides a means of sustaining such delivery over extended periods [161,162]. Indeed, when mixed with nanocups and exposed to ultrasound, the model antigen, ovalbumin, was delivered to depths of 500 µm and a specific anti-ovalbumin antibody response was raised [161].…”

“…The recent development of nano-sized polymeric cavitation nuclei (nanocups), capable of sustaining and promoting cavitation activity, provides a means of sustaining such delivery over extended periods [161,162]. Indeed, when mixed with nanocups and exposed to ultrasound, the model antigen, ovalbumin, was delivered to depths of 500 µm and a specific anti-ovalbumin antibody response was raised [161]. The major limitation of sonophoresis is the inability to deliver comparable amounts of antigen to that of a needle and syringe.…”