title: MiRNA-21 silencing mediated by tumor-targeted nanoparticles combined with sunitinib: A new multimodal gene therapy approach for glioblastoma.
abstract: Malignant brain tumors, including glioblastoma (GBM), are among the most lethal human cancers, due to their tremendous invasive capacity and limited therapeutic options. Despite remarkable advances in cancer theranostics, which resulted in significant improvement of clinical outcomes, GBM relapse is very frequent and patient survival remains under one year. The elucidation of the role of abnormally-expressed miRNAs in different steps of GBM pathogenesis and in tumor resistance to therapy paved the way for the development of new miRNA-based therapeutic approaches targeting this disease, aiming at increasing specific tumor cell killing and, ultimately, cancer eradication. Here, we demonstrate that intravenously-administered chlorotoxin (CTX)-coupled (targeted) stable nucleic acid lipid particle (SNALP)-formulated anti-miR-21 oligonucleotides accumulate preferentially within brain tumors and promote efficient miR-21 silencing, which results in increased mRNA and protein levels of its target RhoB, while showing no signs of systemic immunogenicity. Decreased tumor cell proliferation and tumor size, as well as enhanced apoptosis activation and, to a lesser extent, improvement of animal survival, were also observed in GBM-bearing mice upon systemic delivery of targeted nanoparticle-formulated anti-miR-21 oligonucleotides and exposure to the tyrosine kinase inhibitor sunitinib. Overall, our results provide evidence that CTX-coupled SNALPs are a reliable and efficient system for systemic delivery of anti-miRNA oligonucleotides. Moreover, although further studies are still necessary to demonstrate a therapeutic benefit in a clinical context, our findings suggest that miRNA modulation by the targeted nanoparticles combined with anti-angiogenic chemotherapy may hold promise as an attractive approach towards GBM treatment.
authors: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors: Pedro M
authors: PM
authors: Costa
authors: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors: Ana L
authors: AL
authors: Cardoso
authors: Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors: Carlos
authors: C
authors: Custódia
authors: Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3001-401 Coimbra, Portugal.
authors: Pedro
authors: P
authors: Cunha
authors: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors: Luís
authors: L
authors: Pereira de Almeida
authors: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3001-401 Coimbra, Portugal. Electronic address: mdelima@ci.uc.pt.
authors: Maria C
authors: MC
authors: Pedroso de Lima
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D017024:Chemotherapy, Adjuvant; D004337:Drug Carriers; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D050997:Nanomedicine; D053758:Nanoparticles; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000067492:RNAi Therapeutics / Q000379:methods*; D012604:Scorpion Venoms / Q000378:metabolism; D000077210:Sunitinib; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D004337:Drug Carriers; D007211:Indoles; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D012604:Scorpion Venoms; C091539:Chlorotoxin; D020743:rhoB GTP-Binding Protein; D000077210:Sunitinib
keywords: Anti-angiogenesis; Chlorotoxin; Glioma; Liposomes; MiRNAs; MicroRNA-21