title: A nanoparticle formulation that selectively transfects metastatic tumors in mice.
abstract: Nanoparticle gene therapy holds great promise for the treatment of malignant disease in light of the large number of potent, tumor-specific therapeutic payloads potentially available for delivery. To be effective, gene therapy vehicles must be able to deliver their therapeutic payloads to metastatic lesions after systemic administration. Here we describe nanoparticles comprised of a core of high molecular weight linear polyethylenimine (LPEI) complexed with DNA and surrounded by a shell of polyethyleneglycol-modified (PEGylated) low molecular weight LPEI. Compared with a state-of-the-art commercially available in vivo gene delivery formulation, i.v. delivery of the core/PEGylated shell (CPS) nanoparticles provided more than a 16,000-fold increase in the ratio of tumor to nontumor transfection. The vast majority of examined liver and lung metastases derived from a colorectal cancer cell line showed transgene expression after i.v. CPS injection in an animal model of metastasis. Histological examination of tissues from transfected mice revealed that the CPS nanoparticles selectively transfected neoplastic cells rather than stromal cells within primary and metastatic tumors. However, only a small fraction of neoplastic cells (<1%) expressed the transgene, and the extent of delivery varied with the tumor cell line, tumor site, and host mouse strain used. Our results demonstrate that these CPS nanoparticles offer substantial advantages over previously described formulations for in vivo nanoparticle gene therapeutics. At the same time, they illustrate that major increases in the effectiveness of such approaches are needed for utility in patients with metastatic cancer.
authors: Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins, Baltimore, MD 21231, USA.
authors: Jian
authors: J
authors: Yang
authors: William
authors: W
authors: Hendricks
authors: Guosheng
authors: G
authors: Liu
authors: J Michael
authors: JM
authors: McCaffery
authors: Kenneth W
authors: KW
authors: Kinzler
authors: David L
authors: DL
authors: Huso
authors: Bert
authors: B
authors: Vogelstein
authors: Shibin
authors: S
authors: Zhou
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D045325:HCT116 Cells; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D008164:Luminescent Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D014162:Transfection / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
chemical_list: D008164:Luminescent Proteins; D011092:Polyethylene Glycols; D011094:Polyethyleneimine
references: Nat Biotechnol. 2006 Aug;24(8):985-95
references: 16900147
references: Nature. 2012 Jun 28;486(7404):537-40
references: 22722843
references: Cancer Gene Ther. 2008 Nov;15(11):742-9
references: 18617917
references: Expert Rev Anticancer Ther. 2011 Aug;11(8):1243-51
references: 21916578
references: Small. 2012 Feb 6;8(3):367-73
references: 22139973
references: Br J Cancer. 2000 May;82(9):1513-8
references: 10789717
references: Cancer Res. 2003 Nov 1;63(21):7468-74
references: 14612547
references: J Control Release. 2012 Jun 10;160(2):117-34
references: 22484195
references: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2598-603
references: 20133737
references: Sci Transl Med. 2011 Mar 23;3(75):75ra26
references: 21430269
references: Drug Discov Today. 2002 Apr 15;7(8):479-85
references: 11965397
references: BMC Cancer. 2009 Apr 27;9:126
references: 19397814
references: Mol Ther. 2012 Feb;20(2):347-55
references: 22008909
references: Mol Cancer Ther. 2006 Mar;5(3):693-703
references: 16546984
references: Ann Oncol. 2006 Aug;17(8):1263-8
references: 16740598
references: J Urol. 2008 Dec;180(6):2379-83
references: 18950807
references: Cancer Lett. 2008 Mar 18;261(2):215-25
references: 18164806
references: Nat Mater. 2011 Dec 04;11(1):82-90
references: 22138789
references: Cancer Res. 1995 Sep 1;55(17):3752-6
references: 7641188
references: Pharm Res. 2010 May;27(5):796-810
references: 20204471
references: Nat Rev Drug Discov. 2005 Jul;4(7):581-93
references: 16052241
references: Science. 2013 Mar 29;339(6127):1546-58
references: 23539594
references: Int Immunopharmacol. 2003 Mar;3(3):319-28
references: 12639809
references: J Immunol. 2004 Sep 15;173(6):3755-62
references: 15356122
references: J Transl Med. 2010 Dec 16;8:134
references: 21162716
references: N Engl J Med. 2011 Jun 30;364(26):2507-16
references: 21639808
references: Cancer Gene Ther. 2007 Sep;14(9):815-8
references: 17589433
references: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7297-301
references: 7638184
references: Gene Ther. 1998 Sep;5(9):1291-5
references: 9930332
references: Nat Med. 2011 Jan;17(1):123-9
references: 21151140
references: J Gene Med. 2004 Oct;6(10):1102-11
references: 15386739
references: Nat Mater. 2011 May;10(5):389-97
references: 21499315
references: Adv Drug Deliv Rev. 2006 Jul 7;58(4):467-86
references: 16781003
references: Gene Ther. 2001 Oct;8(20):1587-92
references: 11704820
references: Nano Lett. 2009 May;9(5):1909-15
references: 19344179
references: Curr Opin Biotechnol. 2002 Apr;13(2):128-31
references: 11950563
references: Nat Rev Drug Discov. 2003 Mar;2(3):214-21
references: 12612647
references: Nature. 2012 Jul 26;487(7408):505-9
references: 22763448
references: Am Heart J. 2010 Mar;159(3):354-60
references: 20211295
references: PLoS One. 2012;7(5):e35416
references: 22590502