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Lipid nanobubbles as an ultrasound-triggered artesunate delivery system for imaging-guided, tumor-targeted chemotherapy

Authors Gao S, Cheng X, Li J

Received 10 October 2018

Accepted for publication 4 December 2018

Published 6 March 2019 Volume 2019:12 Pages 1841—1850


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 3

Editor who approved publication: Dr Takuya Aoki

Shuang Gao,1,* Xiaohui Cheng,2,* Jinhua Li3

1Ultrasound Department, Guilin People’s Hospital, Guilin, Guangxi 541002, China; 2Department of Clinical Pharmacy, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163000, China; 3Traditional Chinese Medicine Department, Gansu Provincial Hospital, Lanzhou, Gansu 730000, China

*These authors contributed equally to this work

Purpose: Herein, this study is to prepare folic acid (FA)-conjugated lipid nanobubbles (NBs) that highly load artesunate (Arte; FA-ALNBs), as an ultrasound (US)-triggered Arte delivery system for imaging-guided, tumor-targeted chemotherapy.
Materials and methods: The morphology, size, zeta potential, and stability of the FA-ALNBs were detected by optical microscopy and dynamic light scattering analysis. The cellular uptake of the FA-ALNBs was evaluated by confocal laser scanning microscopy and flow cytometry.
Results: The FA-ALNBs showed uniform spheroidal structure, with 781.2±5.3 nm in average diameter, great physiological stability, and ~91.9%±1.1% encapsulation efficiency of Arte. Using focused US, about 36.1%±2.5% of the entrapped Arte was trigger-released from the FA-ALNBs. Owing to the US contrast property, FA-ALNBs showed an enhanced US signal in vitro when using an ultrasonic diagnostic apparatus with a 1-MHz linear transducer. Due to the FA receptor-mediated endocytosis effect, FA-ALNBs can be efficiently internalized by cells, showing an uptake ratio of about 56.4%±3.1%. FA-ALNBs showed an enhanced, dose-dependent cell-killing ability, while FA-ALNBs plus US irradiation exhibited a stronger anticancer effect in vitro. Post intravenous injection into tumor-bearing mice, FA-ALNBs showed an enhanced US contrast effect with increase in time, indicating the increasing accumulation of FA-ALNBs in tumor tissue, which peaked at 4 hours post injection. Focused US irradiation was conducted on the tumor region at 4 hours post injection of FA-ALNBs, which showed a greater tumor suppression effect after 30 days of treatment compared with all other treatment groups. Moreover, FA-ALNBs showed negligible systemic toxicity in vivo.
Conclusion: This versatile US-triggered drug delivery system with great anticancer efficacy was assessed both in vitro and in vivo, revealing great potential as a cancer theranostic agent for future application.

Keywords: nanobubbles, artesunate, ultrasound imaging, ultrasound-triggered drug release, cancer theranostics

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