Ultrasound mediated delivery of drugs and genes to solid tumors

Abstract

It has long been shown that therapeutic ultrasound can be used effectively to ablate solid tumors, and a variety of cancers are presently being treated in the clinic using these types of ultrasound exposures. There is, however, an ever-increasing body of preclinical literature that demonstrates how ultrasound energy can also be used non-destructively for increasing the efficacy of drugs and genes for improving cancer treatment. In this review, a summary of the most important ultrasound mechanisms will be given with a detailed description of how each one can be employed for a variety of applications. This includes the manner by which acoustic energy deposition can be used to create changes in tissue permeability for enhancing the delivery of conventional agents, as well as for deploying and activating drugs and genes via specially tailored vehicles and formulations.

Sonoluminescence and acoustic emission spectra at different stages of cavitation zone development

“…This interest is motivated by the promising results obtained during the study of ultrasonically induced biological effects including, I) enhanced cell membrane permeability which improves the delivery of small compounds, macromolecules and other therapeutics into cells and tissues, i.e. sonoporation [6][7][8][9]; II) DNA-mediated transfection [10,11]; III) tumour growth reduction [12,13], and IV) the activation of specific compounds triggering antitumor or antimicrobial activity [14][15][16][17]. It is believed that cavitation plays an important role in these bio-effects.…”

“…It is believed that cavitation plays an important role in these bio-effects. Three types of ultrasound action on biological cells have been identified [6][7][8][9][10][11][12][13][14][15][16][17][18]; damping viability, reversible cell damage (sonoporation) and irreversible damage/cytotoxicity. It is possible that these types of action derive from the different properties that cavitation displays under different conditions, meaning that the monitoring and control of cavitation is therefore an important factor in the successful use of ultrasound in medicine and biology.…”

Pulsed focused ultrasound exposures enhance locally administered gene therapy in a murine solid tumor model

“…However, by providing the exposures in pulsed mode (pFUS) using duty cycles that are typically 5% or 10%, the rate of energy deposition can be substantially lowered, where cooling can also occur between the pulses. As a result, temperature elevations may be just a few degrees Celsius (and hence non-destructive), allowing for more delicate, non-thermal mechanisms to occur (Frenkel, 2008). pFUS exposures have demonstrated the ability to noninvasively enhance the delivery of a variety of systemically administered agents to solid tumors, including small molecules (Poff et al, 2008), plasmid DNA (Dittmar et al, 2005), monoclonal antibodies (Khaibullina et al, 2008), and nanoparticles (Dittmar et al, 2005;Frenkel et al, 2006).…”

“…More recently, these exposures were shown to enhance the distribution of locally administered nanoparticles in skeletal muscle (Hancock et al, 2009). The manner by which this enhancement occurs is generally thought to be mediated by non-thermal mechanisms of ultrasound (e.g., acoustic cavitation and acoustic radiation forces), where these can generate effects that transiently increase the effective pore size of a tissue, and hence its permeability (Frenkel, 2008). In the present study, investigations were carried out to determine if combining pFUS exposures with intratumoral injection of plasmid DNA encoding for a therapeutic gene could lead to enhanced tumor growth inhibition in a murine solid tumor model.…”

Interplay Between Mechanochemistry and Sonochemistry

“…It is generally considered that ultrasound waves change the permeability properties of liposome membranes due to transient cavitation, where the collapse of air bubbles near the lipid membrane creates pores that alter the orientation and hydrophobicity of the lipid structure [98]. Drug delivery via acoustically sensitive liposomes is also largely influenced by the content and structure of the lipid systems.…”