Antitumor effects of combining metronomic chemotherapy with the antivascular action of ultrasound stimulated microbubbles

Abstract

Considerable effort is being directed toward investigating the use of ultrasound (US) stimulated microbubbles (MB) to promote the uptake of anticancer agents in tumors. In this study we propose and investigate a new method for combining therapeutic ultrasound with anticancer agents, which is to induce antivascular effects and combine these with an antiangiogenic treatment strategy, in this case metronomic chemotherapy. This is effectively a vascular targeting rather than a drug delivery approach. Experiments were conducted on MDA-MB-231 breast cancer tumors implanted in athymic mice. Metronomic cyclophosphamide (MCTX) was employed as an antiangiogenic therapy and was administered through the drinking water. Ultrasound stimulated microbubble treatments (USMB) were conducted at 1 MHz employing short bursts (0.00024 duty cycle) at 1.6 MPa in combination with the commercial microbubble agent Definity. USMB treatments were performed on a weekly basis for 4 weeks and MCTX was administered for 10 weeks. The USMB induced an acute reduction of blood flow as confirmed with US contrast imaging and DiOC 7 perfusion staining. Longitudinal experiments demonstrated that significant growth inhibition occurred in MCTX-only and USMB-only treatment groups relative to control tumors. The combined USMB and MCTX treatment group showed significant growth inhibition and survival prolongation relative to the USMB-only (p < 0.01) and MCTX-only treatment groups (p < 0.01). These results indicate the feasibility of a new approach to combining therapeutic ultrasound with an anticancer agent.Therapeutic ultrasound (US) is emerging as a nonsurgical approach for the treatment of a range of solid tumor types. 1The method employed in clinical work at present is to ablate tumor tissue with high intensity focused ultrasound (HIFU), which exploits the absorption of US energy by tissue. It is also under investigation as a means by which to promote the delivery of anticancer agents to tumor tissue.2 Hyperthermia is one method for accomplishing this, whereby mild temperature elevations induced by US promote the local release and uptake of therapeutic agents. Another approach for US-mediated drug delivery is to use US to induce oscillations of microbubbles (MBs), which are systemically injected encapsulated bubbles currently in clinical use as diagnostic contrast agents.3 This is based on substantial research demonstrating that microvascular permeability can be increased by oscillating MBs. 4,5 These effects have been shown in a range of tissue types, 2,6 though relevant work in tumors has been limited and, outside the brain, clear evidence of enhanced therapeutic effects of anticancer agents with US stimulated MBs remains to be established. [7][8][9] In addition to microvessel permeabilization effects, which generally occur at relatively low US amplitudes, the stimulation of circulating MBs with sufficiently high US amplitudes can cause microvascular damage. [10][11][12] While the precise mechanisms of damage are not well understood at present, there ...

Biomechanical Effects of Microbubbles: From Radiosensitization to Cell Death

“…More recently, work by Goertz et al [44,45] suggests that there may be other therapeutic strategies that directly target tumor vasculature to maximize the effects of chemotherapy. There, microbubbles were used in a manner resembling vascular disruptive agents (VDAs) [46] to target the more fragile blood vessels at the core of the tumor while permitting chemotherapeutic agents to act on rapidly proliferating cells at the periphery of the tumor.…”

Theranostic Performance of Acoustic Nanodroplet Vaporization-Generated Bubbles in Tumor Intertissue

“…The combination therapy of drug release and physical treatment for vascular disruption induced by bubble cavitation or acoustic droplet vaporization (ADV) improves the efficacy of tumor growth inhibition 11-14. Since bubbles oscillate, cavitate, and be destroyed during US stimulation, the adjacent cells might get damaged, resulting in changes to the membrane permeability or death from irreversible damage 15-18.…”

Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model

“…In fact, for example, in tumor ablation it might be useful, as the method could be accompanied by the administration of chemotherapy or other agent for local treatment in the surrounding margins. 29 Such a vascular strategy will restrict the supply of nutrients and oxygen in tumor, and, thus suppress its growth. Therefore, we envision that this work may lead to the development of new therapeutic strategies to treat solid tumors using acoustic cavitation to interrupt the blood supply to the tumor core, while delivering therapeutic agents to surrounding margins.…”