Microbubble-mediated ultrasonic techniques for improved chemotherapeutic delivery in cancer

Abstract

Background Ultrasound (US) exposed microbubble (MB) contrast agents have the capability to transiently enhance cell membrane permeability. Using this technique in cancer treatment to increase the efficiency of chemotherapy through passive, localized delivery has been an emerging area of research. Purpose Investigation of the influence of US parameters on MB mediated drug delivery in cancer. Methods 2LMP breast cancer cells were used for in vitro experiments and 2LMP tumor-bearing mice were used during in vivo experiments. Changes in membrane permeability were investigated after the influence of MB-mediated US therapy parameters (i.e. frequency, mechanical index, pulse repetition period, US duration, and MB dosing and characteristics) on cancer cells. Calcein, a non-permeable fluorescent molecule, and Taxol, chemotherapeutic, were used to evaluate membrane permeability. Tumor response was also assessed histologically. Results Combination chemotherapy and MB-mediated US therapy with optimized parameters increased cancer cell death by 50% over chemotherapy alone. Discussion Increased cellular uptake of chemotherapeutic was dependent upon US system parameters. Conclusion Optimized MB-mediated US therapy has the potential to improve cancer patient response to therapy via increased localized drug uptake, which may lead to a lowering of chemotherapeutic drug dosages and systemic toxicity.

Low-frequency ultrasound-mediated microvessel disruption combined with docetaxel to treat prostate carcinoma xenografts in nude mice: A novel type of chemoembolization

“…The bioeffects range from increasing the vascular permeability for the chemotherapy drug and target gene delivery by opening the blood-brain barrier locally and transiently, to vessel rupture and occlusion (11,12,(18)(19)(20)(21)(22)(23). The antivascular effects of USMB can induce the interruption of blood flow in tumors and cause microvessels to dilate extensively.…”

Monitoring of microbubble-mediated ultrasound therapy using fluorescent imaging: A feasibility study

“…Monitoring of in vivo microbubble-mediated therapy in past studies has been limited to analyzing secondary effects, such as tumor size reduction post therapy and histology [5,9]. This optical imaging technique gives knowledge into the realtime processes of this therapy.…”

“…The ability to image at nearinfrared fluorescent levels decreases error by minimizing the fluorescent levels contributed from the tissue, allowing for more precise measurements [10]. The ultrasound parameters used in this study were previously optimized and used in a combination chemotherapy plus microbubble-mediated ultrasound study in vitro and in vivo [5]. The previous study used paclitaxel (0.85 kDa), which is similar in size to the Cy5.5 dye used in these experiments (1.1 kDa).…”

“…Microbubbles have shown increased therapeutic effects through two methods. The mechanical oscillation of microbubbles under certain ultrasound conditions and physical interaction with cell membranes presumably cause temporarily enhanced cell membrane permeability [2,3,4,5]. Microbubbles have also been shown to increase extravasation by breaking down gap junctions between endothelial cells [6].…”

Antibody-based imaging strategies for cancer

“…Furthermore, microbubbles have been utilized as mechanisms for an ultrasound induced drug or gene delivery approach through improving extravasation and gateways for current systemic therapies [68,69]. The high sensitivity and specificity when imaged in vivo , and ability of antibody-targeted microbubbles to function as drug delivery and imaging agents [70-72] permits them to be a dual-purpose vehicle.…”