title: Student award winner in the Ph.D. category for the 2013 society for biomaterials annual meeting and exposition, april 10-13, 2013, Boston, Massachusetts : biomaterial-mediated cancer-specific DNA delivery to liver cell cultures using synthetic poly(beta-amino ester)s.
abstract: Liver cancer is a leading cause of cancer death. Most patients are treated by arterial injection of chemoembolizing agents, providing a convenient avenue for local treatment by novel therapies, including gene therapy. Poly(beta-amino ester)s (PBAEs) were synthesized and used to form nanoparticles for non-viral transfection of buffalo rat hepatoma (MCA-RH7777) and hepatocyte (BRL-3A) lines with eGFP and luciferase DNA. Hepatoma cells were transfected with up to (98 ± 0.4)% efficacy with no measurable cytotoxicity. Hepatocytes were transfected with as high as (73 ± 0.4)% efficacy with (10 ± 4)% non-specific cytotoxicity. In contrast, positive controls (branched polyethylenimine, Lipofectamine™ 2000, and X-tremeGENE(®) DNA HP) caused 30-90% toxicity in BRL-3A cells at doses required for >50% transfection. Of the 21 optimized PBAE-DNA formulations tested, 12 showed significant specificity for hepatoma cells over hepatocytes in monoculture (p < 0.05 for both percentage transfected and eGFP expression intensity). Top polymers from eGFP studies also delivered luciferase DNA with 220 ± 30-fold and 470 ± 30-fold greater specificity for hepatoma cells than hepatocytes. Transfections of co-cultures of hepatoma and hepatocytes with eGFP DNA also showed high specificity (1.9 ± 0.1- to 5.8± 1.4-fold more transfected hepatoma cells than hepatocytes, measured by percentage transfected and flow cytometry). By eGFP intensity, up to 530 ±60-fold higher average expression per cell was measured in hepatoma cells. One top formulation caused (95 ± 0.2)% transfection in hepatoma cells and (27 ± 0.2)% in hepatocytes [(96 ± 9)% relative hepatocyte viability]. PBAE-based nanoparticles are a viable strategy for liver cancer treatment, delivering genes to nearly 100% of cancer cells while maintaining high biomaterial-mediated specificity to prevent toxic side-effects on healthy hepatocytes.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Stephany Y
authors.initials: SY
authors.lastname: Tzeng
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Higgins
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Green
mesh_terms: D000818:Animals; D001363:Awards and Prizes; D001672:Biocompatible Materials; D006528:Carcinoma, Hepatocellular / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D016503:Drug Delivery Systems; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D008099:Liver / Q000166:cytology*; D008113:Liver Neoplasms / Q000628:therapy; D008156:Luciferases / Q000235:genetics; D053758:Nanoparticles; D009369:Neoplasms / Q000628:therapy*; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D014162:Transfection
chemical_list: D001672:Biocompatible Materials; D011091:Polyesters; D049452:Green Fluorescent Proteins; D008156:Luciferases
references.citation: Cardiovasc Intervent Radiol. 2007 Jan-Feb;30(1):6-25
references.pmid: 17103105
references.citation: Abdom Imaging. 2011 Dec;36(6):677-83
references.pmid: 21674193
references.citation: Expert Opin Drug Deliv. 2010 Jun;7(6):721-35
references.pmid: 20367531
references.citation: J Vasc Interv Radiol. 2011 Oct;22(10):1457-1463.e2
references.pmid: 21856173
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1059-64
references.pmid: 15647352
references.citation: J Am Coll Surg. 2000 Oct;191(4):381-8
references.pmid: 11030243
references.citation: Acc Chem Res. 2008 Jun;41(6):749-59
references.pmid: 18507402
references.citation: PLoS One. 2012;7(5):e37543
references.pmid: 22629417
references.citation: J Natl Cancer Inst. 2008 May 21;100(10):698-711
references.pmid: 18477802
references.citation: Nat Mater. 2006 Jun;5(6):439-51
references.pmid: 16738681
references.citation: Hepatology. 2002 Nov;36(5):1106-14
references.pmid: 12395320
references.citation: Adv Mater. 2009 Dec 28;21(48):4947-4951
references.pmid: 25165411
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Ther Deliv. 2011 Apr;2(4):493-521
references.pmid: 22826857
references.citation: Nucl Med Biol. 1995 Apr;22(3):379-86
references.pmid: 7627154
references.citation: Adv Healthc Mater. 2013 Mar;2(3):468-80
references.pmid: 23184674
references.citation: Nanomedicine. 2012 Oct;8(7):1200-7
references.pmid: 22306159
references.citation: Nat Med. 2011 Jan;17(1):123-9
references.pmid: 21151140
references.citation: Biomaterials. 2010 Nov;31(31):8088-96
references.pmid: 20674001
references.citation: Gastroenterology. 2004 Nov;127(5 Suppl 1):S225-31
references.pmid: 15508088
references.citation: Nat Mater. 2011 May;10(5):389-97
references.pmid: 21499315
references.citation: Biomaterials. 2012 Nov;33(32):8142-51
references.pmid: 22871421
references.citation: Biomaterials. 2011 Aug;32(23):5402-10
references.pmid: 21536325
references.citation: Gastroenterology. 2004 Nov;127(5 Suppl 1):S27-34
references.pmid: 15508094
references.citation: Ann Biomed Eng. 2012 Jul;40(7):1408-18
references.pmid: 22451256
references.citation: J Vasc Interv Radiol. 2012 May;23(5):704-11
references.pmid: 22387029