title: Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo.
abstract: Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat glioma cell lines, 9L and F98, to discover nanoparticle formulations more effective than the leading commercial reagent Lipofectamine 2000. The lead polymer structure, poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-modified with 1-(3-aminopropyl)-4-methylpiperazine, is a poly(β-amino ester) (PBAE) and formed nanoparticles with HSVtk DNA that were 138 ± 4 nm in size and 13 ± 1 mV in zeta potential. These nanoparticles containing HSVtk DNA showed 100% cancer cell killing in vitro in the two glioma cell lines when combined with GCV exposure, while control nanoparticles encoding GFP maintained robust cell viability. For in vivo evaluation, tumor-bearing rats were treated with PBAE/HSVtk infusion via convection-enhanced delivery (CED) in combination with systemic administration of GCV. These treated animals showed a significant benefit in survival (p = 0.0012 vs control). Moreover, following a single CED infusion, labeled PBAE nanoparticles spread completely throughout the tumor. This study highlights a nanomedicine approach that is highly promising for the treatment of malignant glioma.
authors: Department of Neurosurgery, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.
authors: Antonella
authors: A
authors: Mangraviti
authors: Stephany Yi
authors: SY
authors: Tzeng
authors: Kristen Lynn
authors: KL
authors: Kozielski
authors: Yuan
authors: Y
authors: Wang
authors: Yike
authors: Y
authors: Jin
authors: David
authors: D
authors: Gullotti
authors: Mariangela
authors: M
authors: Pedone
authors: Nitsa
authors: N
authors: Buaron
authors: Ann
authors: A
authors: Liu
authors: David R
authors: DR
authors: Wilson
authors: Sarah K
authors: SK
authors: Hansen
authors: Fausto J
authors: FJ
authors: Rodriguez
authors: Guo-Dong
authors: GD
authors: Gao
authors: Francesco
authors: F
authors: DiMeco
authors: Henry
authors: H
authors: Brem
authors: Alessandro
authors: A
authors: Olivi
authors: Betty
authors: B
authors: Tyler
authors: Jordan J
authors: JJ
authors: Green
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D015774:Ganciclovir / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D012449:Safety; D016019:Survival Analysis; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection
chemical_list: D011108:Polymers; D011355:Prodrugs; C507253:poly(beta-amino ester); D004247:DNA; D013937:Thymidine Kinase; D015774:Ganciclovir
keywords: DNA; brain tumor; gene therapy; nanomedicine; nonviral gene delivery; polymer
references: Biomaterials. 2011 Aug;32(23):5402-10
references: 21536325
references: PLoS One. 2012;7(5):e37543
references: 22629417
references: Nanomedicine (Lond). 2008 Dec;3(6):813-21
references: 19025455
references: J Neurosurg. 2009 Jan;110(1):156-62
references: 18847342
references: Am J Pathol. 2007 May;170(5):1445-53
references: 17456751
references: Cancer Res. 1993 Nov 1;53(21):5274-83
references: 8221662
references: Cancer Gene Ther. 2000 Mar;7(3):413-21
references: 10766347
references: J Biomed Mater Res A. 2013 Jul;101(7):1837-45
references: 23559534
references: Biomaterials. 2009 Apr;30(12):2302-18
references: 19168213
references: Cancer Res. 1994 Apr 15;54(8):2207-12
references: 7909720
references: Cancer Res. 1999 Feb 1;59(3):669-75
references: 9973216
references: Front Microbiol. 2014 Jun 20;5:303
references: 24999342
references: J Control Release. 2007 Aug 16;121(1-2):64-73
references: 17588702
references: Biomacromolecules. 2009 Jan 12;10(1):119-27
references: 19061333
references: Expert Opin Biol Ther. 2004 Oct;4(10):1609-20
references: 15461572
references: J Clin Oncol. 2003 Jul 1;21(13):2508-18
references: 12839017
references: Cancer Res. 1993 Jan 15;53(2):329-33
references: 8417826
references: J Genet Syndr Gene Ther. 2013 Aug 9;4:null
references: 24294541
references: Mol Ther. 2004 Nov;10(5):967-72
references: 15509514
references: Front Oncol. 2014 Jul 21;4:126
references: 25101239
references: Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):11751-6
references: 23818631
references: Ann Biomed Eng. 2012 Jul;40(7):1408-18
references: 22451256
references: Cancers (Basel). 2013 Oct 23;5(4):1271-305
references: 24202446
references: Nat Biotechnol. 2008 May;26(5):561-9
references: 18438401
references: Hum Gene Ther. 1998 Apr 10;9(6):801-14
references: 9581903
references: Biomaterials. 2010 Nov;31(31):8088-96
references: 20674001
references: Methods Enzymol. 2005;391:200-8
references: 15721383
references: Hum Gene Ther. 1997 Oct 10;8(15):1825-35
references: 9358032
references: Gene Ther. 2000 May;7(10):867-74
references: 10845725
references: Nano Lett. 2009 May;9(5):2059-64
references: 19331425
references: Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8850-4
references: 1681545
references: Bioconjug Chem. 1999 May-Jun;10(3):406-11
references: 10346871
references: J Biomed Opt. 2008 May-Jun;13(3):031209
references: 18601533
references: J Control Release. 2011 Mar 10;150(2):177-86
references: 21130817
references: Bioconjug Chem. 2014 Jan 15;25(1):43-51
references: 24320687
references: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12564-9
references: 20538976
references: Lancet. 2001 Sep 1;358(9283):727-9
references: 11551583
references: Hum Gene Ther. 2000 Nov 20;11(17):2389-401
references: 11096443
references: Adv Healthc Mater. 2013 Mar;2(3):468-80
references: 23184674
references: Nat Biotechnol. 2000 Jan;18(1):33-7
references: 10625387
references: J Control Release. 2012 Sep 10;162(2):438-45
references: 22771979
references: Adv Mater. 2009 Dec 28;21(48):4947-4951
references: 25165411
references: J Control Release. 2006 Apr 10;111(3):368-70
references: 16504335
references: Gene Ther. 2001 Aug;8(15):1157-66
references: 11509946
references: Cancer Gene Ther. 1994 Dec;1(4):279-87
references: 7543006
references: Cancer Genomics Proteomics. 2011 Sep-Oct;8(5):245-50
references: 21980039
references: J Neurosurg. 2000 Mar;92(3):419-27
references: 10701528
references: Science. 1991 May 10;252(5007):854-6
references: 1851332
references: Hum Gene Ther. 1999 Sep 20;10(14):2325-35
references: 10515452
references: Oncogene. 2002 Mar 28;21(14):2141-53
references: 11948397
references: Pharmacol Ther. 2013 Sep;139(3):341-58
references: 23694764
references: Nanomedicine. 2012 Oct;8(7):1200-7
references: 22306159
references: N Engl J Med. 2005 Mar 10;352(10):987-96
references: 15758009
references: Nat Med. 2011 Jan;17(1):130-4
references: 21170048
references: Neurosurgery. 2003 Apr;52(4):872-9; discussion 879-80
references: 12657184
references: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7297-301
references: 7638184
references: Cancer Invest. 2012 Jan;30(1):48-56
references: 22236189
references: Cancer Gene Ther. 2002 Feb;9(2):149-55
references: 11857032
references: Cancer Res. 2004 Apr 1;64(7):2572-9
references: 15059914
references: Biomaterials. 2012 May;33(13):3594-603
references: 22341939
references: Sci Transl Med. 2013 Oct 30;5(209):209ra152
references: 24174328
references: Cancer Res. 2000 Aug 1;60(15):3989-99
references: 10945596
references: J Neurosurg. 2013 Apr;118(4):812-20
references: 23082884
references: Bioconjug Chem. 2007 Sep-Oct;18(5):1391-6
references: 17630789
references: ACS Nano. 2014 Oct 28;8(10):10383-95
references: 25247850
references: J Control Release. 2008 Aug 25;130(1):57-63
references: 18599144
references: Nat Biotechnol. 2010 Feb;28(2):172-6
references: 20081866
references: Nanomedicine. 2014 Jan;10(1):149-57
references: 23891990
references: Mol Ther. 2000 Feb;1(2):195-203
references: 10933931
references: Neuro Oncol. 2011 Jul;13(7):700-9
references: 21727209
references: Biomacromolecules. 2011 Oct 10;12(10):3592-600
references: 21888340
references: J Neurosurg. 2000 May;92(5):804-11
references: 10794295
references: NMR Biomed. 2008 Jun;21(5):489-97
references: 17924591
references: Nat Rev Drug Discov. 2005 Jul;4(7):581-93
references: 16052241
references: Mol Ther. 2005 Oct;12(4):585-98
references: 16095972
references: J Neurosurg. 1995 Apr;82(4):635-40
references: 7897527
references: J Am Chem Soc. 2013 May 8;135(18):6951-7
references: 23570657
references: Acc Chem Res. 2008 Jun;41(6):749-59
references: 18507402
references: ACS Nano. 2014 Apr 22;8(4):3232-41
references: 24673565
references: Biochem Biophys Res Commun. 2001 Sep 14;287(1):173-80
references: 11549271
references: Surgery. 1994 Aug;116(2):205-13
references: 8047987
references: ACS Nano. 2014 May 27;8(5):5141-53
references: 24766032
references: PLoS One. 2014;9(5):e97151
references: 24824754
references: J Neurooncol. 2003 May;63(1):1-7
references: 12814248
references: Neurosurgery. 2010 Mar;66(3):530-7; discussion 537
references: 20173548
references: Mol Pharm. 2012 Nov 5;9(11):3375-83
references: 22970908
references: J Neurosurg. 1993 Nov;79(5):729-35
references: 8410252
references: Nat Rev Genet. 2003 May;4(5):346-58
references: 12728277
references: Mol Ther. 2007 Jul;15(7):1373-81
references: 17457322