title: Synergistic cytotoxicity of the poly (ADP-ribose) polymerase inhibitor ABT-888 and temozolomide in dual-drug targeted magnetic nanoparticles.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is associated with a poor prognosis because of a lack of effective treatment options. The objective of this study was to examine a new strategy for HCC treatment, namely the use of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor (ABT-888) together with Temozolomide (TMZ) incorporated onto magnetic nanoparticles.
  
  
  METHODS
  Magnetic Fe3 O4 /Fe cores were encapsulated within a silica shell to facilitate the simultaneous incorporation of ABT-888 and TMZ. In vitro tests were performed with HepG2, Hep3B and PLC-PRF-5 liver tumoural cell lines and with WRL-68 liver non-tumoural cells.
  
  
  RESULTS
  The magnetic nanocarriers were loaded simultaneously with ABT-888 and TMZ. High stability and extended release were achieved in culture medium. Confocal microscopy images showed that drug-loaded particles were uptaken and accumulated into the cytoplasm of liver tumoural cells, inducing the following effects: G2/M cell cycle arrest (P < 0.05), accumulation of DNA damage (P < 0.05), mitochondrial depolarization (P < 0.01), reduction in BCL-xL, FOS, JUND gene expression (P < 0.05), PARP-1 fragmentation, Caspase-3 activation and apoptotic cell death (P < 0.05). Interestingly, drugs loaded onto nanoparticles exhibited better efficiency than free drugs (cell death triggered by drug delivery nanosystem: 53.5% vs. 34.5% by free drugs, P = 0.01).
  
  
  CONCLUSIONS
  These magnetic nanocompounds are able to incorporate both drugs simultaneously, enter the tumour cells and release them. ABT-888/TMZ/NPs decrease the transcription of key genes involved in tumour survival and induce apoptotic cell death in a more effective manner than is achieved by free drugs.
authors.affiliation: Clinical Management Unit of Digestive Disease and UNAI, San Cecilio University Hospital, Granada, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Muñoz-Gámez
authors.forename: Julián
authors.initials: J
authors.lastname: López Viota
authors.forename: Andrés
authors.initials: A
authors.lastname: Barrientos
authors.forename: Ángel
authors.initials: Á
authors.lastname: Carazo
authors.forename: Laura
authors.initials: L
authors.lastname: Sanjuán-Nuñez
authors.forename: Rosa
authors.initials: R
authors.lastname: Quiles-Perez
authors.forename: Paloma
authors.initials: P
authors.lastname: Muñoz-de-Rueda
authors.forename: Ángel
authors.initials: Á
authors.lastname: Delgado
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Ruiz-Extremera
authors.forename: Javier
authors.initials: J
authors.lastname: Salmerón
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002626:Chemistry, Pharmaceutical; D004249:DNA Damage; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004338:Drug Combinations; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D058185:Magnetite Nanoparticles; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013678:Technology, Pharmaceutical / Q000379:methods; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D004337:Drug Carriers; D004338:Drug Combinations; D058185:Magnetite Nanoparticles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide
keywords: PARP-1 [Poly (ADP-ribose) polymerase-1] PARP-1 inhibitor: ABT-888; antineoplastic therapy; hepatocellular carcinoma (HCC); nanoparticles; temozolomide