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.

Figure 1

A – a schematic representation showing how non-focused ultrasound exposures using a plane wave transducer (1) are used to treat superficially, whereas a concave tranducer (2), housed in a coupling bath of degassed water (DW), can be used to place the focal zone (FZ) of the beam deeper inside the body; B – tranducer head of a dual probe showing the concave bowl therapeutic transducer for producing a focused beam and the collinear imaging tranducer for treatment planning of the exposure. This device was modified from a Sonoblate 500 (Focus Surgery, Indianapolis, IN) and used for some of the preclinical studies described in this review [–,,–149,151,153,154,157, 163]; C – representative lateral and vertical B mode ultrasound scans of a subcutaneous tumor in a murine flank. The two long horizontal lines indicate the focal zone (FZ) of the transducer and the shorter vertical lines, the raster (treatment) points for the exposures. Four raster points are positioned in each view, producing a 4 × 4 raster pattern (right) for complete treatment of the tumor. Mice are treated in a bath of degassed water, and the tumor is positioned using a 3 dimensional stage during imaging. Because the depth of the tumor is less than the focal zone, rastering will occur in only 2 dimensions.

Figure 2

A schematic representation of the manner by which energy deposition from focused ultrasound exposures can act through various mechanisms to enhance the delivery or activity of drugs and genes. HSP – heat shock protein; LTSLs – low temperature sensitive liposomes; SDT – sonodynamic therapy; ECM – extracellular matrix.