UTMD promoted local delivery of miR-34a-mimic for ovarian cancer therapy

Yue Li; Meng Du; Jinghui Fang; Jia Zhou; Zhiyi Chen

doi:10.1080/10717544.2021.1955041

UTMD promoted local delivery of miR-34a-mimic for ovarian cancer therapy

Drug Deliv. 2021 Dec;28(1):1616-1625. doi: 10.1080/10717544.2021.1955041.

Authors

Yue Li^{1

2

3}, Meng Du^{1

2}, Jinghui Fang³, Jia Zhou⁴, Zhiyi Chen^{1

2}

Affiliations

¹ The First Affiliated Hospital, Medical Imaging Centre, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
² Institute of Medical Imaging, University of South China, Hengyang, China.
³ Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁴ The First Affiliated Hospital, Department of Ultrasound Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China.

Abstract

MicroRNA-mediated gene therapy is emerging as a promising method for the treatment of ovarian cancer, but the development of miRNA mimic delivery vectors is still in its infancy, where the safety and efficacy of miR-34a-mimic remain unknown. Ultrasound-targeted microbubble destruction (UTMD) can be an effective and minimally invasive tool for the delivery of miR-34a-mimic in vitro and in vivo. Here, we describe a high-efficiency gene delivery strategy by using miR-34a-mimic loaded folate modified microbubbles (miR-34a-FM) with a portable ultrasonic irradiation system. Ultrasonic parameters, including acoustic intensity (AI), exposure time (ET) and duty cycle (DC), were optimized and the optimal acoustic condition (1.0 W/cm², 20 s, and 15% DC) was used to deliver miRNA-34a into cells in vitro. MiR-34a mimic was successfully introduced into the cytoplasm and was found to inhibit proliferation and induce apoptosis of SK-OV-3 cells. Next, miR-34a-mimic was delivered to tumor tissue via UTMD, inhibiting tumor growth and prolonging the survival time of mice. In summary, UTMD-mediated miR-34a-mimic delivery has potential application in the clinical treatment of ovarian cancer.

Keywords: MiR-34a mimic; Ultrasound; cancer therapy; microbubbles; multi-parameters.

MeSH terms

Animals
Apoptosis
Caspase 3 / metabolism
Cell Line, Tumor
Chemistry, Pharmaceutical
Fatty Acids, Monounsaturated / chemistry
Female
Folic Acid / chemistry
Gene Transfer Techniques
Humans
Lipids / chemistry
Mice
Mice, Inbred BALB C
MicroRNAs / administration & dosage*
MicroRNAs / pharmacology*
Microbubbles*
Ovarian Neoplasms / drug therapy*
Particle Size
Phosphatidylethanolamines / chemistry
Polyethylene Glycols / chemistry
Proto-Oncogene Proteins c-bcl-2 / metabolism
Quaternary Ammonium Compounds / chemistry
Random Allocation
Signal Transduction
Surface Properties
Ultrasonography, Interventional / methods*

Substances

Fatty Acids, Monounsaturated
Lipids
MIRN34 microRNA, human
MicroRNAs
Phosphatidylethanolamines
Proto-Oncogene Proteins c-bcl-2
Quaternary Ammonium Compounds
1,2-distearoylphosphatidylethanolamine
Polyethylene Glycols
Folic Acid
Caspase 3
polyethylene glycol 2000
1,2-dioleoyloxy-3-(trimethylammonium)propane

Grants and funding

This work was supported by the National Key R&D Program of China [2019YFE0110400], the National Natural Science Foundation of China [81971621], Natural Science Foundation of Guangdong Province. [2021A1515011177], the Natural Science Foundation of Guangdong Province. [2020A1515110628] and the Natural Science Foundation of Guangdong Province. [2019A1515012212].