Delivery of Chlorambucil Using an Acoustically-Triggered Perfluoropentane Emulsion

Abstract

Ultrasound-mediated delivery systems have mainly focused on microbubble contrast agents as carriers of drugs or genetic material. This study utilizes micron-sized, perfluoropentane (PFP) emulsions as carriers for chlorambucil (CHL), a lipophilic chemotherapeutic. The release of CHL is achieved via acoustic droplet vaporization (ADV), whereby the superheated emulsion is converted into gas bubbles using ultrasound. Emulsions were made using an albumin shell and soybean oil as the CHL carrier. The ratio of the PFP to soybean oil phases in the droplets, as well as the fraction of droplets that vaporize per ultrasound exposure were shown to correlate with droplet diameter. A 60-minute incubation with the CHL-loaded emulsion caused a 46.7% cellular growth inhibition, whereas incubation with the CHL-loaded emulsion that was exposed to ultrasound at 6.3 MHz caused an 84.3% growth inhibition. This difference was statistically significant (p < 0.01), signifying that ADV can be used as a method to substantially enhance drug delivery.

Scavenging dissolved oxygen via acoustic droplet vaporization

“…Larger droplets undergo a phase-transition more efficiently [10], but also have a higher probability of occluding pulmonary capillaries. Another limitation is the maximum concentration of droplets within the blood stream that can be tolerated by the body.…”

“…Micron-sized perfluorocarbon microbubbles created via ADV have been shown to occlude capillary beds and arterioles, which can facilitate embolotherapy in cancer treatment [3,7,8]. Previous studies have also demonstrated ADV-mediated delivery of chemotherapeutic drugs such as paclitaxel [9], chlorambucil [10], and doxorubicin [11] loaded in perfluorocarbon droplets. Thermal ablation of cancerous lesions has been enhanced using perfluorocarbon droplets as cavitation nuclei during high intensity focused ultrasound (HIFU) exposure [12][13][14].…”

Parallel generation of uniform fine droplets at hundreds of kilohertz in a flow-focusing module

“…Two such applications requiring many millions of droplets include site-specific therapeutics using oil-in-water droplets and next generation sequencing using water-in-oil droplets. In particular, the phase-change droplets in this study, at 9.8 lm in diameter, are amenable to intra-arterial administration 30 as gas embolotherapy (i.e., targeted vessel occlusion) agents for the treatment of various hypervascular cancers, as these droplets are stable at room temperature yet undergo rapid liquid-to-gas phase transition above a uniform acoustic or thermal activation threshold. 23 Using a more precise method to fabricate the channel geometries to be equal, the flow rate ratio could be increased in the dripping regime to stably generate smaller therapeutic droplets suitable for intravenous injection, 23,30 or sub-micron droplets for extravascular applications alongside medical ultrasound.…”

“…In particular, the phase-change droplets in this study, at 9.8 lm in diameter, are amenable to intra-arterial administration 30 as gas embolotherapy (i.e., targeted vessel occlusion) agents for the treatment of various hypervascular cancers, as these droplets are stable at room temperature yet undergo rapid liquid-to-gas phase transition above a uniform acoustic or thermal activation threshold. 23 Using a more precise method to fabricate the channel geometries to be equal, the flow rate ratio could be increased in the dripping regime to stably generate smaller therapeutic droplets suitable for intravenous injection, 23,30 or sub-micron droplets for extravascular applications alongside medical ultrasound. 31 The module presented here may also serve emerging methods in next generation sequencing, with the potential to dispense single DNA templates and primer (e.g., on a bead) into several hundreds of millions of small droplets within a quarter hour, facilitating the amplification and enrichment of single DNA templates with enhanced throughput and scalability yet reduced reagent consumption.…”

Monodisperse bubbles and droplets for medical applications

“…The severe side effects of the systemic injection of chemotherapeutic drugs on healthy tissue can potentially be lowered by encapsulation of the drug in phase-change droplets [187][188][189] . The droplets typically consist of a low boiling point perfluorocarbon oil, such as perfluoropentane (T b = 29 • C), and they do not spontaneously vaporize when injected in-vivo until the droplets are exposed to a high pressure ultrasound pulse 165,171 .…”