title: Star-shaped tetraspermine enhances cellular uptake and cytotoxicity of T-oligo in prostate cancer cells.
abstract: OBJECTIVE
  An oligonucleotide termed 'T-oligo' having sequence homology with telomere overhang has shown cytotoxicity in multiple cancers. We have demonstrated that T-oligo can induce apoptosis in androgen independent prostate cancer cell line DU-145. In this report, we evaluate the use of star-shaped tetraspermine (SSTS) for delivery of T-oligo.
  
  
  METHODS
  SSTS was synthesized from spermine and its intrinsic cytotoxicity towards DU-145 cells was compared with spermine and branched polyethyleneimine (bPEI). Atomistic molecular dynamic (MD) simulations were conducted to understand binding and complexation of spermine and SSTS with T-oligo. Complexation was also determined using gel electrophoresis and SYBR gold assay. Complexes were characterized for size, cellular uptake and antiproliferative effect.
  
  
  RESULTS
  SSTS exhibited significantly lower toxicity than spermine and bPEI. Its affinity towards T-oligo was significantly higher than spermine as determined by experimental studies and confirmed by MD simulations and it formed stable complexes (TONPs) with T-oligo. TONPs facilitated cellular uptake and nuclear accumulation of T-oligo and their cytotoxic potential was observed at concentration several folds lower than that required for T-oligo alone.
  
  
  CONCLUSIONS
  SSTS significantly enhanced therapeutic benefits associated with the use of T-oligo and can be developed as a delivery vehicle for its in-vivo therapeutic applications.
authors.affiliation: Department of Biopharmaceutical Sciences, University of Illinois Chicago, 1601 Parkview Ave, Rm N302, Rockford, Illinois, 61107, USA.
authors.forename: Vidula
authors.initials: V
authors.lastname: Kolhatkar
authors.forename: Hiren
authors.initials: H
authors.lastname: Khambati
authors.forename: Asawari
authors.initials: A
authors.lastname: Lote
authors.forename: Peter
authors.initials: P
authors.lastname: Shanine
authors.forename: Thomas
authors.initials: T
authors.lastname: Insley
authors.forename: Soumyo
authors.initials: S
authors.lastname: Sen
authors.forename: Gnanasekar
authors.initials: G
authors.lastname: Munirathinam
authors.forename: Petr
authors.initials: P
authors.lastname: Král
authors.forename: Rohit
authors.initials: R
authors.lastname: Kolhatkar
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D053758:Nanoparticles / Q000737:chemistry*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D009841:Oligonucleotides; D013096:Spermine; D004492:Edetic Acid
references.citation: Proc Natl Acad Sci U S A. 1986 Aug;83(16):5948-52
references.pmid: 3461466
references.citation: Acc Chem Res. 2012 Jul 17;45(7):961-70
references.pmid: 21905687
references.citation: Angew Chem Int Ed Engl. 2012 Aug 6;51(32):7938-41
references.pmid: 22807030
references.citation: Nat Rev Drug Discov. 2005 Jul;4(7):581-93
references.pmid: 16052241
references.citation: Int J Cancer. 2009 Jan 15;124(2):473-82
references.pmid: 19003960
references.citation: Mol Pharm. 2013 Oct 7;10(10):3776-88
references.pmid: 23971990
references.citation: Appl Biochem Biotechnol. 2013 Jun;170(4):841-53
references.pmid: 23615733
references.citation: Biomacromolecules. 2014 Apr 14;15(4):1299-310
references.pmid: 24552396
references.citation: ACS Nano. 2012 Nov 27;6(11):9447-54
references.pmid: 23036046
references.citation: J Urol. 2013 Aug;190(2):429-38
references.pmid: 23665272
references.citation: Bioconjug Chem. 2014 Feb 19;25(2):251-61
references.pmid: 24359105
references.citation: J Control Release. 2012 Dec 28;164(3):256-64
references.pmid: 22771981
references.citation: Bioconjug Chem. 2006 Jan-Feb;17(1):172-8
references.pmid: 16417266
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: Mol Pharm. 2009 May-Jun;6(3):696-705
references.pmid: 19267451
references.citation: Biomacromolecules. 2013 Jun 10;14(6):1961-70
references.pmid: 23641942
references.citation: Ann N Y Acad Sci. 1986;482:251-4
references.pmid: 3471109
references.citation: J Comput Chem. 2010 Mar;31(4):671-90
references.pmid: 19575467
references.citation: Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):3955-60
references.pmid: 24516150
references.citation: Mol Ther. 2010 Mar;18(3):561-9
references.pmid: 20010917
references.citation: Nat Rev Cancer. 2011 Mar;11(3):161-76
references.pmid: 21346783
references.citation: Mol Pharm. 2009 May-Jun;6(3):686-95
references.pmid: 19397332
references.citation: J Control Release. 2003 Apr 14;89(1):113-25
references.pmid: 12695067
references.citation: J Med Chem. 2010 Aug 12;53(15):5738-48
references.pmid: 20684609
references.citation: Nucleic Acid Ther. 2013 Oct;23(5):311-21
references.pmid: 23971906
references.citation: Biomacromolecules. 2010 Mar 8;11(3):721-30
references.pmid: 20131771
references.citation: Curr Opin Pharmacol. 2012 Aug;12(4):427-33
references.pmid: 22726555
references.citation: Biomacromolecules. 2011 Nov 14;12(11):3870-9
references.pmid: 21961938
references.citation: Oligonucleotides. 2009 Sep;19(3):287-92
references.pmid: 19642913
references.citation: Bioconjug Chem. 2007 Nov-Dec;18(6):2054-60
references.pmid: 17960872
references.citation: J Chem Inf Model. 2012 Dec 21;52(12):3144-54
references.pmid: 23146088
references.citation: Biomaterials. 2014 Aug;35(25):7068-76
references.pmid: 24856107
references.citation: Bioconjug Chem. 2008 Jan;19(1):370-6
references.pmid: 18095640
references.citation: Nucleic Acid Ther. 2014 Apr;24(2):101-13
references.pmid: 24383421
references.citation: J Phys Chem B. 2012 Mar 1;116(8):2405-13
references.pmid: 22292702
references.citation: Mol Pharm. 2010 Aug 2;7(4):969-83
references.pmid: 20524664
references.citation: Mol Ther. 2005 Sep;12(3):468-74
references.pmid: 15963763
references.citation: Gene Ther. 2005 Mar;12(6):494-503
references.pmid: 15565162
references.citation: Mol Cancer Ther. 2006 Jul;5(7):1669-75
references.pmid: 16891452
references.citation: Nat Nanotechnol. 2012 Jun 03;7(6):389-93
references.pmid: 22659608
references.citation: J Am Chem Soc. 2011 Dec 21;133(50):20288-300
references.pmid: 22040056
references.citation: FASEB J. 2007 Sep;21(11):2918-30
references.pmid: 17449721
references.citation: Angew Chem Int Ed Engl. 2012 Aug 27;51(35):8740-3
references.pmid: 22855422
references.citation: Breast Cancer Res. 2007;9(1):R13
references.pmid: 17257427
references.citation: J Biomed Biotechnol. 2010;2010:284840
references.pmid: 20617146
references.citation: FASEB J. 2004 Sep;18(12):1373-81
references.pmid: 15333580
references.citation: Chem Rev. 2009 Feb;109(2):259-302
references.pmid: 19053809
references.citation: J Phys Chem B. 2010 Mar 4;114(8):2667-75
references.pmid: 20146540
references.citation: J Control Release. 2010 Aug 3;145(3):182-95
references.pmid: 20226220
references.citation: Mol Pharm. 2011 Apr 4;8(2):416-29
references.pmid: 21291280
references.citation: J Control Release. 2012 Jul 20;161(2):554-65
references.pmid: 22123560
references.citation: J Liposome Res. 2006;16(3):237-47
references.pmid: 16952878
references.citation: Biomaterials. 2003 Mar;24(7):1121-31
references.pmid: 12527253
references.citation: Acc Chem Res. 2012 Jul 17;45(7):980-4
references.pmid: 22311735
references.citation: Pharm Res. 2009 Jun;26(6):1407-18
references.pmid: 19225872
references.citation: Chemistry. 2010 Apr 19;16(15):4519-32
references.pmid: 20235240
references.citation: Bioconjug Chem. 1996 Nov-Dec;7(6):703-14
references.pmid: 8950489
references.citation: Pharm Res. 2010 Sep;27(9):1927-38
references.pmid: 20577786
references.citation: CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29
references.pmid: 24399786
references.citation: J Chem Inf Model. 2012 Dec 21;52(12):3155-68
references.pmid: 23145473
references.citation: Biomaterials. 2009 Mar;30(8):1635-47
references.pmid: 19097641
references.citation: Eur J Pharm Biopharm. 2011 Jan;77(1):36-42
references.pmid: 20932903
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):527-31
references.pmid: 12515865
references.citation: Oligonucleotides. 2011 Feb;21(1):47-53
references.pmid: 21281128
references.citation: J Am Chem Soc. 2009 Jul 22;131(28):9686-94
references.pmid: 19555062
references.citation: Int J Nanomedicine. 2012;7:3813-22
references.pmid: 22888236