Ultrasound-Assisted miR-122-Loaded Polymeric Nanodroplets for Hepatocellular Carcinoma Gene Therapy

• Published in: Molecular pharmaceutics 2020-02, Vol.17 (2), p.541-553, Article acs.molpharmaceut.9b00983
• Main Authors: Guo, Huanling, Xu, Ming, Cao, Zhong, Li, Wei, Chen, Lida, Xie, Xiaoyan, Wang, Wei, Liu, Jie
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Carcinoma, Hepatocellular - therapy; Drug Carriers - administration & dosage; Female; Fluorocarbons - administration & dosage; Genetic Therapy - methods; Hep G2 Cells; Humans; Liver Neoplasms - therapy; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - administration & dosage; MicroRNAs - genetics; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Phase Transition - radiation effects; Polyethylene Glycols - administration & dosage; Polyglutamic Acid - administration & dosage; Transfection; Tumor Burden - drug effects; Ultrasonic Waves; Xenograft Model Antitumor Assays
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.9b00983

Ultrasound-induced microbubble sonoporation has been shown to effectively improve drug/gene delivery efficiency by enhancing tissue and cell permeability. However, the microscale size and short duration of ultrasound contrast agents limit their accumulation in target areas. Here, a kind of ultrasound-triggered phase-transitioning and size-changing cationic nanodroplet, perfluoropentane/C9F17-PAsp­(DET)/miR-122/poly­(glutamic acid)-g-MeO-poly­(ethylene glycol) (PGA-g-mPEG) ternary nanodroplets (PFP-TNDs/miR-122), was developed to deliver microRNA-122 (miR-122) for hepatocellular carcinoma (HCC) treatment. PFP served as an ultrasound-sensitive core for ultrasound-triggered phase transition and size change from the nanoscale to the microscale. Positively charged C9F17-PAsp­(DET) ensured adequate miRNA loading. PGA-g-mPEG, which served as the shell of the nanodroplet, modified the nanodroplets, enhanced their stability in serum, and protected miR-122 from degradation in vivo. The results exhibited that PFP-TNDs/miR-122 has a nanosize diameter (362 ± 15 nm) and remained stable for 24 h. After treatment with PFP-TNDs/miR-122 combined with ultrasound irradiation, the miR-122 expression level was significantly increased by approximately 600-fold in HepG2 cells, 500-fold in SMMC-7721 cells, and 30-fold in human HCC xenografts. Moreover, PFP-TNDs/miR-122 combined with ultrasound radiation effectively suppressed the growth, migration, and invasion of HCC cells, and inhibited tumor proliferation in mice. This study revealed that the biodegradable PFP-TNDs is a promising therapeutic gene carrier with functions of gene protection and effective gene delivery for clinical applications. Furthermore, PFP-TNDs/miR-122 associated with ultrasound irradiation may pave a new way to improve the prognosis of patients with HCC.