A limitation of microbubbles for both diagnostic and therapeutic applications is their relatively rapid clearance times, typically < 10 minutes. One solution to this is to use nanoscale droplets of volatile liquids that can be converted into microbubbles upon exposure to ultrasound. Their small size both significantly enhances their circulation time and also enables them to extravasate, for example in the leaky vasculature within a tumour.
Notwithstanding their significant potential, the development of nanodroplets still poses some considerable challenges. The conversion efficiency, i.e., the proportion of droplets undergoing a phase change for a given set of ultrasound exposure conditions is often very low. Thus either very high concentrations of nanodroplets or potentially damaging ultrasound intensities are required.
We therefore investigated the effect of loading perfluorocarbon nanodroplets with superparamagnetic solid nanoparticles to act as nucleation agents to promote phase transition thereby improving conversion efficiency. Using iron oxide particles also provides a means of imaging the droplets using magnetic resonance imaging (MRI) and manipulating the droplets using an external magnetic field which has been shown in previous work to be highly advantageous for drug delivery.
We first determined the effect upon the physical properties of the nanodroplets in terms of their size, surface charge, and stability under physiological conditions. Their response to ultrasound exposure was then examined to determine conversion efficiency, change in size and potential for image contrast enhancement under both ultrasound and MRI. Finally, delivery of a small molecule chemotherapy drug, paclitaxel, and small interfering ribonucleic acid (siRNA) to different cancer cell lines was investigated.
The nanodroplets were stable at 37oC over 10 days and showed a significantly higher conversion efficiency than a control droplet formulated without nanoparticles at 1 MHz and peak negative pressures < 500 kPa. They could be readily imaged at clinically safe concentrations using MRI and ultrasound and targeted using an externally applied magnetic field. Successful delivery of both paclitaxel and siRNA was demonstrated, with higher rates of cell death and transfection respectively achieved than with the control formulation.
Magnetic nanodroplets for targeted drug delivery