Abstract
Ultrasound stimulated microbubbles (USMB) are being investigated for their potential to promote the uptake of anticancer agents into tumor tissue by exploiting their ability to enhance microvascular permeability. At sufficiently high ultrasound transmit amplitudes it has also recently been shown that USMB treatments can, on their own, induce vascular damage, shutdown blood flow, and inhibit tumor growth. The objective of this study is to examine the antitumor effects of ‘antivascular’ USMB treatments in conjunction with chemotherapy, which differs from previous work which has sought to enhance drug uptake with USMBs by increasing vascular permeability. Conceptually this is a strategy similar to combining vascular disrupting agents with a chemotherapy, and we have selected the taxane docetaxel (Taxotere) for evaluating this approach as it has previously been shown to have potent antitumor effects when combined with small molecule vascular disrupting agents. Experiments were conducted on PC3 tumors implanted in athymic mice. USMB treatments were performed at a frequency of 1 MHz employing sequences of 50 ms bursts (0.00024 duty cycle) at 1.65 MPa. USMB treatments were administered on a weekly basis for 4 weeks with docetaxel (DTX) being given intravenously at a dose level of 5 mg/kg. The USMB treatments, either alone or in combination with DTX, induced an acute reduction in tumor perfusion which was accompanied at the 24 hour point by significantly enhanced necrosis and apoptosis. Longitudinal experiments showed a modest prolongation in survival but no significant growth inhibition occurred in DTX–only and USMB-only treatment groups relative to control tumors. The combined USMB-DTX treatment group produced tumor shrinkage in weeks 4–6, and significant growth inhibition and survival prolongation relative to the control (p<0.001), USMB-only (p<0.01) and DTX-only treatment groups (p<0.01). These results suggest the potential of enhancing the antitumor activity of docetaxel by combining it with antivascular USMB effects.
Highlights
Microbubbles (MBs) are systemically injected encapsulated micron sized (1–10 microns) bubbles that oscillate in response to incident ultrasound and are currently in clinical use as diagnostic contrast agents
This study has demonstrated a pronounced enhancement of the antitumor activity of docetaxel through its combination with ultrasound stimulated microbubbles (USMB) treatments
The combined effects were significantly higher than both the individual treatment groups and were achieved under conditions where the USMBs induced antivascular effects
Summary
Microbubbles (MBs) are systemically injected encapsulated micron sized (1–10 microns) bubbles that oscillate in response to incident ultrasound and are currently in clinical use as diagnostic contrast agents. When MBs are employed under therapeutic ultrasound exposure levels, it is well established that their oscillations are capable of increasing the permeability of microvessels and thereby enhancing the extravasation of molecules, nanoparticles and therapeutic agents [1,2] These effects have been explored in a range of tissue types and the results to date suggest the considerable potential of this approach as a means of augmenting the local delivery of therapeutic agents in the treatment of a range of diseases. With the exception of brain tumors, where the blood-brain-barrier presents a significant drug delivery obstacle, it must be considered that in many circumstances the penetration of antitumor agents into tumor tissue is not inhibited by their inability to extravasate from the bloodstream Rather, issues such as elevated interstitial fluid pressure levels and their uptake and sequestration in perivascular regions will limit the transport and distribution of anticancer agents within tumor tissue [13]. It is of interest to consider possible alternative approaches for employing USMBs in conjunction with anticancer agents that do not rely upon the enhancement of extravasation from the vascular compartment
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