Longitudinal assessment of ultrasound-guided complementary microRNA therapy of hepatocellular carcinoma

• Published in: Journal of controlled release 2018-07, Vol.281, p.19-28
• Main Authors: Chowdhury, Sayan Mullick, Lee, Taehwa, Bachawal, Sunitha V., Devulapally, Rammohan, Abou-Elkacem, Lotfi, Yeung, Tristan Alan, Wischhusen, Jennifer, Tian, Lu, Dahl, Jeremy, Paulmurugan, Ramasamy, Willmann, Juergen Karl
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carcinoma, Hepatocellular - diagnostic imaging; Carcinoma, Hepatocellular - therapy; Cell Line, Tumor; Cell Survival - drug effects; Combined Modality Therapy; Doxorubicin - pharmacology; Drug Carriers; Drug Liberation; Drug Resistance, Neoplasm; Genetic Therapy; Hepatocellular carcinoma; Humans; Image guided therapy; Lactates - chemistry; Liver Neoplasms - diagnostic imaging; Liver Neoplasms - therapy; Mice, Nude; Microbubbles; microRNAs; MicroRNAs - administration & dosage; MicroRNAs - pharmacology; Polyethylene Glycols - chemistry; Treatment Outcome; Ultrasonic Waves; Ultrasound
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2018.05.009

Hepatocellular carcinoma (HCC) is the second-leading cause of cancer related deaths worldwide and new strategies to efficiently treat HCC are critically needed. The aim of this study was to assess the longitudinal treatment effects of two complementary miRNAs (miRNA-122 and antimiR-21) encapsulated in biodegradable poly lactic-co-glycolic acid (PLGA) - poly ethylene glycol (PEG) nanoparticles (PLGA-PEG-NPs), administered by an ultrasound-guided and microbubble-mediated delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Using in vitro assays, we show that repeated miRNA treatments resulted in gradual reduction of HCC cell proliferation and reversal of doxorubicin resistance. Optimized US parameters resulted in a 9–16 fold increase (p = 0.03) in miRNA delivery in vivo in HCC tumors after two US treatments compared to tumors without US treatment. Furthermore, when combined with doxorubicin (10 mg/kg), longitudinal miRNA delivery showed a significant inhibition of tumor growth in both resistant and non-resistant tumors compared to non-treated, and doxorubicin treated controls. We also found that ultrasound-guided miRNA therapy was not only effective in inhibiting HCC tumor growth but also allowed lowering the dose of doxorubicin needed to induce apoptosis. In conclusion, the results of this study suggest that ultrasound-guided and MB-mediated delivery of miRNA-122 and antimiR-21, when combined with doxorubicin, is a highly effective approach to treat resistant HCC while reducing doxorubicin doses needed for treating non-resistant HCC in longitudinal treatment experiments. Further refinement of this strategy could potentially lead to better treatment outcomes for patients with HCC. [Display omitted]