TY - JOUR T1 - Synergistic cytotoxicity of the poly (ADP-ribose) polymerase inhibitor ABT-888 and temozolomide in dual-drug targeted magnetic nanoparticles. AU - Muñoz-Gámez,José A, AU - López Viota,Julián, AU - Barrientos,Andrés, AU - Carazo,Ángel, AU - Sanjuán-Nuñez,Laura, AU - Quiles-Perez,Rosa, AU - Muñoz-de-Rueda,Paloma, AU - Delgado,Ángel, AU - Ruiz-Extremera,Ángeles, AU - Salmerón,Javier, Y1 - 2014/06/03/ PY - 2013/11/22/received PY - 2014/05/03/accepted PY - 2014/5/14/entrez PY - 2014/5/14/pubmed PY - 2015/12/17/medline KW - PARP-1 [Poly (ADP-ribose) polymerase-1] PARP-1 inhibitor: ABT-888 KW - antineoplastic therapy KW - hepatocellular carcinoma (HCC) KW - nanoparticles KW - temozolomide SP - 1430 EP - 41 JF - Liver international : official journal of the International Association for the Study of the Liver JO - Liver Int VL - 35 IS - 4 N2 - BACKGROUND & AIMS: 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. SN - 1478-3231 UR - https://www.unboundmedicine.com/medline/citation/24821649/Synergistic_cytotoxicity_of_the_poly__ADP_ribose__polymerase_inhibitor_ABT_888_and_temozolomide_in_dual_drug_targeted_magnetic_nanoparticles_ DB - PRIME DP - Unbound Medicine ER -