Antitumor Effects of Combining Docetaxel (Taxotere) with the Antivascular Action of Ultrasound Stimulated Microbubbles

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.

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

“…As noted, for all animals the ratio of non-linear contrast before and after ACT treatment is close to 1 over the time window investigated demonstrating that that ACT does not affect tumor vascular blood flow on a global level in any marked manner. It has earlier been reported that high intensity US in combination with microbubbles can reduce perfusion [21]. Compared to the current study, however, in [21] significantly higher MI and longer US pulses were applied.…”

“…It has earlier been reported that high intensity US in combination with microbubbles can reduce perfusion [21]. Compared to the current study, however, in [21] significantly higher MI and longer US pulses were applied. The lack of observed vascular effect shows that ACT treatment can be repeated several times in the same tumor.…”

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

“…However, in an effort to optimize biomechanical effects induced by Sonazoid™ microbubbles, the US Enhancement step for this group was performed by continuous insonation with 2.25 MHz and an MI of 0.4 for 5min and 45s. It is possible that this fairly strong and long regimen induce some kind of physiological response to shut down of the tumor vasculature, as has been reported elsewhere [24]. If so, this could prevent the drug penetrating tumor tissue and explain the lack of response in this group.…”

“…A subset of 5 animals were found dead one after day treatment, in which case they were included in the tumor growth data until that time point. Compared to similar studies [24], the number of unexplained fall outs are low in number, and these deaths are not considered to be treatment related. In the ACT+ABR group one animal, although its tumor was very small, was sacrificed in week 5 because of a necrotic tail at the ABR injection site.…”

Optimization of low-frequency low-intensity ultrasound-mediated microvessel disruption on prostate cancer xenografts in nude mice using an orthogonal experimental design

“…The anti-vascular effect of USMB is promising and reproducible (5,10,11,28). It has been demonstrated that thermal, mechanical, such as cavitation and other non-linear mechanisms, and sonochemical effects are likely to contribute to the anti-vascular activities of microbubbles (7).…”