title: Delivery system for DNAzymes using arginine-modified hydroxyapatite nanoparticles for therapeutic application in a nasopharyngeal carcinoma model.
abstract: DNAzymes are synthetic, single-stranded, catalytic nucleic acids that bind and cleave target mRNA in a sequence-specific manner, and have been explored for genotherapeutics. One bottleneck restricting their application is the lack of an efficient delivery system. As an inorganic nanomaterial with potentially wide application, nano-hydroxyapatite particles (nHAP) have attracted increasing attention as new candidates for nonviral vectors. In this study, we developed an nHAP-based delivery system and explored its cellular uptake mechanisms, intracellular localization, and biological effects. Absorption of arginine-modified nanohydroxyapatite particles (Arg-nHAP) and DZ1 (latent membrane protein 1 [LMP1]-targeted) reached nearly 100% efficiency under in vitro conditions. Using specific inhibitors, cellular uptake of the Arg-nHAP/DZ1 complex was shown to be mediated by the energy-dependent endocytosis pathway. Further, effective intracellular delivery and nuclear localization of the complex was confirmed by confocal microscopy. Biologically, the complex successfully downregulated the expression of LMP1 in nasopharyngeal carcinoma cells. In a mouse tumor xenograft model, the complex was shown to be delivered efficiently to tumor tissue, downregulating expression of LMP1 and suppressing tumor growth. These results suggest that Arg-nHAP may be an efficient vector for nucleic acid-based drugs with potential clinical application.
authors: Center for Molecular Medicine, Xiangya Hospital, Changsha, People's Republic of China.
authors: Yan
authors: Y
authors: Chen
authors: Lifang
authors: L
authors: Yang
authors: Suping
authors: S
authors: Huang
authors: Zhi
authors: Z
authors: Li
authors: Lu
authors: L
authors: Zhang
authors: Jiang
authors: J
authors: He
authors: Zhijie
authors: Z
authors: Xu
authors: Liyu
authors: L
authors: Liu
authors: Ya
authors: Y
authors: Cao
authors: Lunquan
authors: L
authors: Sun
mesh_terms: D000042:Absorption; D000818:Animals; D001120:Arginine / Q000737:chemistry*; D002277:Carcinoma; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D021881:DNA, Catalytic; D004195:Disease Models, Animal; D017886:Durapatite / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D042541:Intracellular Space / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D021881:DNA, Catalytic; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D017886:Durapatite; D001120:Arginine
keywords: DNAzymes; cellular uptake; hydroxyapatite nanoparticles; latent membrane protein 1; transfection efficiency
references: J Drug Deliv. 2012;2012:767839
references: 22506124
references: J Cell Biol. 1994 Dec;127(5):1217-32
references: 7525606
references: FASEB J. 2002 Aug;16(10):1217-26
references: 12153989
references: Biomaterials. 2006 May;27(14):2798-805
references: 16430957
references: Cancer Gene Ther. 2005 Jul;12(7):647-54
references: 15803142
references: Clin Cancer Res. 2003 May;9(5):1579-89
references: 12738709
references: Pharm Res. 1996 Sep;13(9):1367-72
references: 8893276
references: Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2005 Oct;22(5):980-4
references: 16294735
references: Ther Deliv. 2012 May;3(5):623-32
references: 22834406
references: Expert Opin Drug Deliv. 2009 Feb;6(2):127-38
references: 19239385
references: Nanoscale Res Lett. 2011 Nov 23;6:600
references: 22108000
references: Cancer Biol Ther. 2009 Feb;8(4):366-71
references: 19276680
references: Cancer Lett. 2008 Jul 8;265(2):226-38
references: 18353539
references: Curr Pharm Biotechnol. 2010 Jun;11(4):333-42
references: 20199383
references: Trends Biotechnol. 2010 Jan;28(1):28-36
references: 19896228
references: Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2008 Jan;43(1):51-7
references: 18357714
references: Curr Drug Targets. 2002 Jun;3(3):269-79
references: 12041740
references: Antisense Nucleic Acid Drug Dev. 2002 Oct;12(5):289-99
references: 12477279
references: Int J Pharm. 2003 Jan 2;250(1):25-33
references: 12480270
references: Colloids Surf B Biointerfaces. 2009 Feb 1;68(2):136-44
references: 18993036
references: Cancer Res. 2002 Oct 1;62(19):5463-9
references: 12359754
references: Pharmacol Rev. 2000 Sep;52(3):325-47
references: 10977866
references: J Biol Chem. 1999 Jun 11;274(24):17236-41
references: 10358082
references: Biomaterials. 2007 Feb;28(6):1267-79
references: 17123600
references: Pharmazie. 2011 May;66(5):313-8
references: 21699063
references: Nucleic Acids Res. 2004 Jun 04;32(10):3065-9
references: 15181171
references: Cell Mol Life Sci. 2008 Jul;65(14):2156-74
references: 18373062
references: Nat Biotechnol. 2000 Jan;18(1):33-7
references: 10625387
references: Int J Pharm. 2005 Jan 6;288(1):157-68
references: 15607268
references: Hum Gene Ther. 1999 Nov 20;10(17):2847-57
references: 10584930
references: Pharmacol Rev. 2006 Mar;58(1):32-45
references: 16507881
references: Nanotechnology. 2011 Mar 11;22(10):105708
references: 21289408
references: Mol Ther. 2005 Sep;12(3):468-74
references: 15963763
references: Head Neck. 2008 Jul;30(7):946-63
references: 18446839
references: J Natl Cancer Inst. 2004 May 5;96(9):683-96
references: 15126605
references: Future Oncol. 2009 Aug;5(6):811-25
references: 19663731
references: Gene Ther. 2007 May;14(10):828-35
references: 17344903
references: J Control Release. 2006 Feb 21;110(3):490-504
references: 16387383
references: Biomaterials. 2008 Aug-Sep;29(24-25):3469-76
references: 18501424
references: Pharm Res. 2002 Oct;19(10):1488-94
references: 12425466
references: J Control Release. 2004 Jun 18;97(2):345-56
references: 15196761
references: Expert Opin Drug Deliv. 2009 Nov;6(11):1149-60
references: 19780712
references: Biomaterials. 2011 Oct;32(30):7662-70
references: 21774979
references: Thromb Haemost. 2002 Jan;87(1):134-40
references: 11848443
references: Molecules. 2010 Sep 01;15(9):6127-39
references: 20877211
references: J Control Release. 2007 Jul 16;120(1-2):111-21
references: 17512077
references: Int J Mol Med. 2008 Feb;21(2):153-62
references: 18204781