Treatment efficacy of low-dose 5-fluorouracil with ultrasound in mediating 5-fluorouracil-loaded microbubble cavitation in head and neck cancer

Abstract

Over the past 50 years, 5-fluorouracil (5-FU) has played a critical role in the systemic chemotherapy of cancer patients. Bolus intravenous (IV) 5-FU infusion has been used due to the limitation of its extremely short half-life (10–15 min). This study used ultrasound (US) mediating 5-FU-loaded microbubbles (MBs) cavitation as a tool to increase local intratumoral 5-FU levels with a reduced dose of 5-FU (a single IV injection of 2.5 mg/kg instead of a single intraperitoneal injection of 25–200 mg/kg as used in previous studies in mice). The 5-FU-MBs were prepared with a 132 mg/mL albumin solution and a 0.30 mg/mL 5-FU solution. The diameters of the MBs and 5-FU-MBs were 1.24 ± 0.85 and 2.00 ± 0.53 µm (mean ± SEM), respectively, and the maximum loading efficiency of 5-FU on MBs was 19.04 ± 0.25%. In the in vitro study, the cell viabilities of 5-FU and 5-FU-MBs did not differ significantly, but compared with the 5-FU-MBs treatment-alone group, cell toxicity increased to 31% in the 5-FU-MBs + US group (p < 0.001). The biodistribution results indicated that the 5-FU levels of the tumors in small animals were significant higher for the 5-FU-MBs + US treatment than for either the 5-FU-MBs or 5-FU treatment with low 5-FU systemic treatment doses (2.5 mg/kg 5-FU IV). In small-animal treatment, 2.5 mg/kg 5-FU therapeutic IV doses injected into mice caused a more-significant reduction in tumor growth in the 5-FU-MBs + US group (65.9%) than in the control group after 34 days of treatment.

GRAPHICAL ABSTRACT

Keywords:

• Microbubbles
• ultrasound
• half-life
• 5-fluorouracil
• head nd neck cancer
• cavitation

Acknowledgments

The authors thank National Defense Medical Center, Taipei support for the experimental space and equipment, and making it possible to complete this study.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

This work was partially supported by grants from the National Science and Technology Council, Taiwan (NSTC 108-2221-E-011-161-MY4 to A.H.L. and NSTC 110-2314-B-016-046- to Y.H.C.), the Tri-Service General Hospital (TSGH-E-110220 and TSGH-E-111202 to Y.H.C.), and the National Taiwan University of Science and Technology/Tri-Service General Hospital Joint Research Program (NTUST-TSGH-110-01 and NTUST-TSGH-111-01 to A.H.L.).