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: The 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.

Keywords::

• Ultrasound
• microbubble contrast agents
• cancer
• drug delivery
• chemotherapy

Acknowledgments

The authors are grateful for all the helpful suggestions and feedback from Drs. Eben Rosenthal and Kurt R. Zinn.

Declarations of interest

This research was supported in part by NIH grant UL1RR025777, EP50CA089019-09 and NCI grant CA13148-38.