title: Development and testing of gold nanoparticles for drug delivery and treatment of heart failure: a theranostic potential for PPP cardiology.
abstract: BACKGROUND
  Nanoscale gold particles (AuNPs) have wide perspectives for biomedical applications because of their unique biological properties, as antioxidative activity and potentials for drug delivery.
  
  
  OBJECTIVE
  The aim was to test effects of AuNPs using suggested heart failure rat model to compare with proved medication Simdax, to test gold nanoparticle for drug delivery, and to test sonoporation effect to increase nanoparticles delivery into myocardial cells.
  
  
  METHODS
  We performed biosafety and biocompatibility tests for AuNPs and conjugate with Simdax. For in vivo tests, we included Wistar rats weighing 180-200 g (n = 54), received doxorubicin in cumulative dose of 12.0 mg/kg to model advance heart failure, registered by ultrasonography. We formed six groups: the first three groups of animals received, respectively, 0.06 ml Simdax, AuNPs, and conjugate (AuNPs-Simdax), intrapleurally, and the second three received them intravenously. The seventh group was control (saline). We performed dynamic assessment of heart failure regression in vivo measuring hydrothorax. Sonoporation of gold nanoparticles to cardiomyocytes was tested.
  
  
  RESULTS
  We designed and constructed colloidal, spherical gold nanoparticles, AuNPs-Simdax conjugate, both founded biosafety (in cytotoxicity, genotoxicity, and immunoreactivity). In all animals of the six groups after the third day post-medication injection, no ascites and liver enlargement were registered (P < 0.001 vs controls). Conjugate injection showed significantly higher hydrothorax reduction than Simdax injection only (P < 0.01); gold nanoparticle injection showed significantly higher results than Simdax injection (P < 0.05). AuNPs and conjugate showed no significant difference for rat recovery. Difference in rat life continuity was significant between Simdax vs AuNPs (P < 0.05) and Simdax vs conjugate (P < 0.05). Sonoporation enhances AuNP transfer into the cell and mitochondria that were highly localized, superior to controls (P < 0.01 for both).
  
  
  CONCLUSIONS
  Gold nanoparticles of 30 nm and its AuNPs-Simdax conjugate gave positive results in biosafety and biocompatibility in vitro and in vivo. AuNPs-Simdax and AuNPs have similar significant cardioprotective effects in rats with doxorubicin-induced heart failure, higher than that of Simdax. Intrapleural (local) delivery is preferred over intravenous (systemic) delivery according to all tested parameters. Sonoporation is able to enhance gold nanoparticle delivery to myocardial cells in vivo.
authors.affiliation: Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, Zabolotny str,, 154, Kyiv 03680, Ukraine. rostbubnov@gmail.com.
authors.forename: Mykola Ya
authors.initials: MY
authors.lastname: Spivak
authors.forename: Rostyslav V
authors.initials: RV
authors.lastname: Bubnov
authors.forename: Ilya M
authors.initials: IM
authors.lastname: Yemets
authors.forename: Liudmyla M
authors.initials: LM
authors.lastname: Lazarenko
authors.forename: Natalia O
authors.initials: NO
authors.lastname: Tymoshok
authors.forename: Zoia R
authors.initials: ZR
authors.lastname: Ulberg
references.citation: Pediatrics. 1992 May;89(5 Pt 1):942-9
references.pmid: 1579408
references.citation: J Control Release. 2010 Sep 1;146(2):219-27
references.pmid: 20403397
references.citation: Trends Plant Sci. 2002 Sep;7(9):405-10
references.pmid: 12234732
references.citation: Heart. 2002 Mar;87(3):235-41
references.pmid: 11847161
references.citation: Annu Rev Phys Chem. 2003;54:331-66
references.pmid: 12626731
references.citation: Part Fibre Toxicol. 2012 Jul 03;9:23
references.pmid: 22759355
references.citation: Cardiovasc Ultrasound. 2011 May 26;9:15
references.pmid: 21615917
references.citation: Ultrasound Med Biol. 2012 Aug;38(8):1476-82
references.pmid: 22698500
references.citation: Angew Chem Int Ed Engl. 2007;46(26):4999-5002
references.pmid: 17526044
references.citation: Med Ultrason. 2013 Mar;15(1):23-8
references.pmid: 23486620
references.citation: J Am Chem Soc. 2010 Apr 7;132(13):4678-84
references.pmid: 20225865
references.citation: J R Soc Interface. 2010 Feb 6;7 Suppl 1:S119-29
references.pmid: 19726441
references.citation: Trends Pharmacol Sci. 1993 May;14(5):164-8
references.pmid: 8105593
references.citation: Med Ultrason. 2013 Jun;15(2):101-5
references.pmid: 23702498
references.citation: Chem Soc Rev. 2009 Jun;38(6):1759-82
references.pmid: 19587967
references.citation: Nano Lett. 2006 Jan;6(1):110-5
references.pmid: 16402797
references.citation: J Interferon Cytokine Res. 2011 Dec;31(12):927-40
references.pmid: 22149412
references.citation: Eur J Echocardiogr. 2001 Jun;2(2):78-87
references.pmid: 11911099
references.citation: Eur J Heart Fail. 2006 Dec;8(8):804-9
references.pmid: 16713737
references.citation: Angew Chem Int Ed Engl. 2005 Oct 7;44(39):6358-62
references.pmid: 16138384
references.citation: EPMA J. 2012 Nov 01;3(1):14
references.pmid: 23116135
references.citation: Lik Sprava. 2011 Jan-Mar;(1-2):3-21
references.pmid: 21954631
references.citation: N Engl J Med. 2007 Mar 15;356(11):1140-51
references.pmid: 17360992
references.citation: Biomacromolecules. 2006 Feb;7(2):597-603
references.pmid: 16471936
references.citation: EPMA J. 2010 Mar;1(1):164-209
references.pmid: 23199049
references.citation: Oxid Med Cell Longev. 2012;2012:619185
references.pmid: 22619697
references.citation: Cardiovasc Res. 1998 Jul;39(1):89-105
references.pmid: 9764192
references.citation: Nat Mater. 2003 Oct;2(10):668-71
references.pmid: 12970757
references.citation: J Am Soc Echocardiogr. 1995 Sep-Oct;8(5 Pt 1):602-10
references.pmid: 9417202
references.citation: J Nanobiotechnology. 2010 Jul 14;8:16
references.pmid: 20630072
references.citation: EPMA J. 2012 Oct 22;3(1):13
references.pmid: 23088743
references.citation: Hypertens Res. 2005 Jul;28(7):601-9
references.pmid: 16335889
references.citation: J Appl Physiol (1985). 2011 Aug;111(2):543-51
references.pmid: 21617080
references.citation: Eur Heart J. 2002 Dec;23(23):1867-76
references.pmid: 12445536
references.citation: Angew Chem Int Ed Engl. 2010 Nov 2;49(45):8403-7
references.pmid: 20878820
references.citation: Proc Natl Acad Sci U S A. 2006 May 23;103(21):8155-60
references.pmid: 16698918
references.citation: Adv Drug Deliv Rev. 2008 Aug 17;60(11):1307-15
references.pmid: 18555555
references.citation: Braz J Med Biol Res. 2011 Sep;44(9):890-8
references.pmid: 21829898
references.citation: J Am Chem Soc. 2008 Jun 4;130(22):6896-7
references.pmid: 18473457
references.citation: J Cardiovasc Pharmacol. 1993;21 Suppl 2:S27-37
references.pmid: 7692148
references.citation: Hypertension. 2003 Feb;41(2):249-54
references.pmid: 12574090
references.citation: Nanotoxicology. 2011 Sep;5(3):284-95
references.pmid: 20849214
references.citation: Bioconjug Chem. 2010 Dec 15;21(12):2250-6
references.pmid: 21070003
references.citation: N Engl J Med. 1998 Sep 24;339(13):900-5
references.pmid: 9744975
references.citation: Am J Physiol. 1997 Oct;273(4):H2078-82
references.pmid: 9362279
references.citation: Exp Oncol. 2012;34(1):25-8
references.pmid: 22453144
references.citation: J Appl Physiol (1985). 2000 Oct;89(4):1445-54
references.pmid: 11007581
references.citation: Anat Rec. 1988 Feb;220(2):132-7
references.pmid: 3354856
references.citation: Curr Med Chem. 2004 Jan;11(2):199-219
references.pmid: 14754417
references.citation: Langmuir. 2005 Nov 8;21(23):10644-54
references.pmid: 16262332
references.citation: Biomacromolecules. 2004 Mar-Apr;5(2):524-9
references.pmid: 15003016
references.citation: EPMA J. 2013 Jun 24;4(1):18
references.pmid: 23800174
references.citation: Ukr Biokhim Zh (1999). 2009 Nov-Dec;81(6):70-6
references.pmid: 20387660
references.citation: Cell Tissue Res. 2012 Nov;350(2):361-72
references.pmid: 22864983
references.citation: Hypertension. 1987 Sep;10(3):328-38
references.pmid: 3623685
references.citation: J Am Chem Soc. 2009 Feb 18;131(6):2072-3
references.pmid: 19170493
references.citation: Annu Int Conf IEEE Eng Med Biol Soc. 2008;2008:367-70
references.pmid: 19162669
references.citation: Anal Bioanal Chem. 2008 Jun;391(3):943-50
references.pmid: 18157524
references.citation: Braz J Med Biol Res. 2007 Nov;40(11):1557-65
references.pmid: 17934652
references.citation: J Cardiovasc Transl Res. 2010 Oct;3(5):461-8
references.pmid: 20628908
references.citation: Clin Chem. 2006 Jul;52(7):1433-4
references.pmid: 16798971
references.citation: J Clin Invest. 2006 Jan;116(1):237-48
references.pmid: 16357943
references.citation: Ann N Y Acad Sci. 2007 Dec;1122:169-84
references.pmid: 18077572
references.citation: Physiol Genomics. 2003 Jun 24;14(1):3-15
references.pmid: 12824473
references.citation: Anat Rec. 1988 Sep;222(1):1-5
references.pmid: 3189880
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12426-31
references.pmid: 22802668
references.citation: Fundam Clin Pharmacol. 2013 Aug;27(4):364-72
references.pmid: 22429163
references.citation: J Am Assoc Lab Anim Sci. 2007 Jul;46(4):20-32
references.pmid: 17645292
references.citation: J Am Chem Soc. 2005 Feb 23;127(7):2264-71
references.pmid: 15713105
references.citation: Chem Soc Rev. 2008 Sep;37(9):1896-908
references.pmid: 18762838
references.citation: Am J Hypertens. 1990 Sep;3(9):688-96
references.pmid: 2222977