title: Ultrasound-guided therapeutic modulation of hepatocellular carcinoma using complementary microRNAs.
abstract: Treatment options for patients with hepatocellular carcinoma (HCC) are limited, in particular in advanced and drug resistant HCC. MicroRNAs (miRNA) are non-coding small RNAs that are emerging as novel drugs for the treatment of cancer. The aim of this study was to assess treatment effects of two complementary miRNAs (sense miRNA-122, and antisense antimiR-21) encapsulated in biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP), administered by an ultrasound-guided and microbubble-enhanced delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Proliferation and invasiveness of human HCC cells after miRNA-122/antimiR-21 and doxorubicin treatment were assessed in vitro. Confocal microscopy and qRT-PCR were used to visualize and quantitate successful intracellular miRNA-loaded PLGA-NP delivery. Up and down-regulation of miRNA downstream targets and multidrug resistance proteins and extent of apoptosis were assessed in vivo in treated human HCC xenografts in mice. Compared to single miRNA therapy, combination therapy with the two complementary miRNAs resulted in significantly (P<0.05) stronger decrease in cell proliferation, invasion, and migration of HCC cells as well as higher resensitization to doxorubicin. Ultrasound-guided delivery significantly increased in vivo miRNA-loaded PLGA-NP delivery in human HCC xenografts compared to control conditions by 5-9 fold (P<0.001). miRNA-loaded PLGA-NP were internalized in HCC cells and anti-apoptotic proteins were down regulated with apoptosis in ~27% of the tumor volume of doxorubicin-resistant human HCC after a single treatment with complementary miRNAs and doxorubicin. Thus, ultrasound-guided delivery of complementary miRNAs is highly efficient in the treatment of doxorubicin- resistant and non-resistant HCC. Further development of this new treatment approach could aid in better treatment of patients with HCC.
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA.
authors: Sayan
authors: S
authors: Mullick Chowdhury
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA.
authors: Tzu-Yin
authors: TY
authors: Wang
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA.
authors: Sunitha
authors: S
authors: Bachawal
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA.
authors: Rammohan
authors: R
authors: Devulapally
authors: Department of Electrical Engineering, Stanford University Stanford, CA, USA.
authors: Jung Woo
authors: JW
authors: Choe
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA.
authors: Lotfi
authors: L
authors: Abou Elkacem
authors: Department of Electrical Engineering, Stanford University Stanford, CA, USA.
authors: Butrus Khuri
authors: BK
authors: Yakub
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA.
authors: David S
authors: DS
authors: Wang
authors: Department of Health, Research & Policy, Stanford University, Stanford, CA, USA.
authors: Lu
authors: L
authors: Tian
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: paulmur8@stanford.edu.
authors: Ramasamy
authors: R
authors: Paulmurugan
authors: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: willmann@stanford.edu.
authors: Jürgen K
authors: JK
authors: Willmann
mesh_terms: D000818:Animals; D000070416:Antagomirs / Q000008:administration & dosage / Q000627:therapeutic use*; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy*; D004317:Doxorubicin / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D056945:Hep G2 Cells; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D045423:Microbubbles; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014465:Ultrasonics / Q000379:methods
chemical_list: D000070416:Antagomirs; D000903:Antibiotics, Antineoplastic; C531907:MIRN122 microRNA, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004317:Doxorubicin
keywords: Cancer therapy; Complementary miRNA; Drug resistance; Hepatocellular carcinoma; Ultrasound