Ultrasound-mediated cavitation does not decrease the activity of small molecule, antibody or viral-based medicines

Abstract

The treatment of cancer using nanomedicines is limited by the poor penetration of these potentially powerful agents into and throughout solid tumors. Externally controlled mechanical stimuli, such as the generation of cavitation-induced microstreaming using ultrasound (US), can provide a means of improving nanomedicine delivery. Notably, it has been demonstrated that by focusing, monitoring and controlling the US exposure, delivery can be achieved without damage to surrounding tissue or vasculature. However, there is a risk that such stimuli may disrupt the structure and thereby diminish the activity of the delivered drugs, especially complex antibody and viral-based nanomedicines. In this study, we characterize the impact of cavitation on four different agents, doxorubicin (Dox), cetuximab, adenovirus (Ad) and vaccinia virus (VV), representing a scale of sophistication from a simple small-molecule drug to complex biological agents. To achieve tight regulation of the level and duration of cavitation exposure, a “cavitation test rig” was designed and built. The activity of each agent was assessed with and without exposure to a defined cavitation regime which has previously been shown to provide effective and safe delivery of agents to tumors in preclinical studies. The fluorescence profile of Dox remained unchanged after exposure to cavitation, and the efficacy of this drug in killing a cancer cell line remained the same. Similarly, the ability of cetuximab to bind its epidermal growth factor receptor target was not diminished following exposure to cavitation. The encoding of the reporter gene luciferase within the Ad and VV constructs tested here allowed the infectivity of these viruses to be easily quantified. Exposure to cavitation did not impact on the activity of either virus. These data provide compelling evidence that the US parameters used to safely and successfully delivery nanomedicines to tumors in preclinical models do not detrimentally impact on the structure or activity of these nanomedicines.

Vaccination into the Dermal Compartment: Techniques, Challenges, and Prospects

“…More recently, ultrasound-mediated cavitation has been shown to enhance drug penetration and extravasation in cancer therapy by providing a convective stimulus to push the drug into and throughout solid tumours [ 274 , 275 ]. Notably, this happens without damage to the structure or activity of the drug [ 276 , 277 ].…”

Gas-stabilizing nanoparticles for ultrasound imaging and therapy of cancer

“…Chemical cavitation effects such as ROS generation, on the other hand, could break chemical bonds or oxidize molecules. Thus, to understand if the cavitation events generated by nanocups can decrease the effectiveness of therapeutics, Myers et al [ 105 ] treated a variety of small molecules, macromolecules, and viruses, including doxorubicin, cetuximab, adenovirus, and enveloped viral vectors with unfocused 0.5 MHz ultrasound pulses with PNP of 1.5 MPa in the presence of nanocups. Their results did not show any detectable decrease in the efficacy of any of the tested therapeutics when exposed to cavitation.…”

Colloids, nanoparticles, and materials for imaging, delivery, ablation, and theranostics by focused ultrasound (FUS)

“…For instance, mechanical and chemical effects induced by acoustic cavitation may denature or aggregate proteins or change the molecular structures by breaking down the covalent bonds, reducing the double bonds and so on. Myers et al, studied the impact of cavitation events induced by gas stabilizing nanocups on the activity of a small molecule (doxorubicin, Dox), an antibody (cetuximab) and non-enveloped (adenovirus, Ad) and enveloped (VV) viral vectors 198. They did not detect any activity loss for any of the materials tested in in vitro conditions.…”