title: Cationic microRNA-delivering nanocarriers for efficient treatment of colon carcinoma in xenograft model.
abstract: Manipulation of tumor microRNAs (miRNAs) may offer novel avenues for treatment of cancer. However, development of safe, robust, non-viral delivery methods remains a main challenge to obtain the promise of gene therapy. The miR-145 is dysregulated in many cancers, including colon carcer, and further in vitro investigation established antiproliferative and proapoptotic roles of miR-145. Herein, we study a PLGA/PEI (poly (d, l-lactide-co-glycolide)/polyethylenimine)-mediated miRNA vector delivery system; the validation of the method was carried out using a colon cancer xenograft model with miR-145 vector encoding for the expression of miR-145 (pDNA). First, high-molecular-weight PEI (25000 Da) was conjugated with cetyl to formulate reducible cetylated PEI (PEI-cet), and then PEI-cet was introduced to PLGA suspension. Next, PLGA/PEI-cet was crosslinked with hyaluronic acid (HA) to facilitate cellular uptake of miRNA plasmid vector via HA receptor-mediated endocytosis. After local administration of PLGA/PEI/HA complexes, intact miRNA plasmid vectors were delivered into HCT-116 colon cancer cells and xenograft tumor-bearing mice, and significant antitumor effects were achieved. The results show that the HA-based miR-145 nanocarrier could efficiently facilitate cellular uptake and significantly enhance miR-145 expression in HCT-116 cells. Consequently, the increased miR-145 induced G1 cell cycle arrest, reduced tumor proliferation and increased apoptosis, inhibited HCT-116 cell migration and suppressed c-MYC expressions, a regulatory target of miR-145. Of particular importance is the significant decrease in tumor growth in the mice model of colon cancer with the targeting miR-145 delivery system. The results in this work show that miR-145 has been effectively delivered to colon carcinomas through a PLGA/PEI/HA vehicle, indicating a promising miRNA replacement therapy strategy.
authors.affiliation: School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China.|Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.|State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
authors.forename: G
authors.initials: G
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China.
authors.forename: A
authors.initials: A
authors.lastname: Jing
authors.affiliation: State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
authors.forename: F
authors.initials: F
authors.lastname: Hu
authors.affiliation: School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China.
authors.forename: W
authors.initials: W
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
authors.forename: B
authors.initials: B
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000628:therapy*; D003110:Colonic Neoplasms / Q000628:therapy*; D059585:G1 Phase Cell Cycle Checkpoints; D005822:Genetic Vectors / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics; D053758:Nanoparticles / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D000067492:RNAi Therapeutics / Q000379:methods*
chemical_list: C542511:MIRN145 microRNA, rat; D035683:MicroRNAs; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011094:Polyethyleneimine; D006820:Hyaluronic Acid