title: Enhanced tumor delivery and antitumor activity in vivo of liposomal doxorubicin modified with MCF-7-specific phage fusion protein.
abstract: A novel strategy to improve the therapeutic index of chemotherapy has been developed by the integration of nanotechnology with phage technique. The objective of this study was to combine phage display, identifying tumor-targeting ligands, with a liposomal nanocarrier for targeted delivery of doxorubicin. Following the proof of concept in cell-based experiments, this study focused on in vivo assessment of antitumor activity and potential side-effects of phage fusion protein-modified liposomal doxorubicin. MCF-7-targeted phage-Doxil treatments led to greater tumor remission and faster onset of antitumor activity than the treatments with non-targeted formulations. The enhanced anticancer effect induced by the targeted phage-Doxil correlated with an improved tumor accumulation of doxorubicin. Tumor sections consistently revealed enhanced apoptosis, reduced proliferation activity and extensive necrosis. Phage-Doxil-treated mice did not show any sign of hepatotoxicity and maintained overall health. Therefore, MCF-7-targeted phage-Doxil seems to be an active and tolerable chemotherapy for breast cancer treatment.
  
  
  BACKGROUND
  The authors of this study successfully combined phage display with a liposomal nanocarrier for targeted delivery of doxorubicin using MCF-7-targeted phage-Doxil nanocarriers in a rodent model. The method demonstrated improved efficiency and reduced hepatotoxicity, paving the way to future clinical trials addressing breast cancer.
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hartner
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Gillespie
authors.affiliation: Center for Translational Imaging, Northeastern University, Boston, MA, USA.
authors.forename: Kulkarni P
authors.initials: KP
authors.lastname: Praveen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Biology, College of Science, Northeastern University, Boston, MA, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Mei
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL, USA.
authors.forename: Valery A
authors.initials: VA
authors.lastname: Petrenko
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA. Electronic address: v.torchilin@neu.edu.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001435:Bacteriophages / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004337:Drug Carriers; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D019394:Ki-67 Antigen; D008081:Liposomes; D011993:Recombinant Fusion Proteins; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: Breast cancer targeting; Cancer nanomedicines; Drug delivery; Liposomes; Phage display
references.citation: Expert Opin Ther Targets. 2004 Aug;8(4):335-53
references.pmid: 15268628
references.citation: Biochemistry. 1996 Jan 30;35(4):1232-41
references.pmid: 8573578
references.citation: Mol Pharm. 2010 Aug 2;7(4):1007-14
references.pmid: 20518562
references.citation: EMBO J. 1999 Nov 15;18(22):6299-306
references.pmid: 10562542
references.citation: BMC Cancer. 2010 Jan 05;10:2
references.pmid: 20047698
references.citation: Protein Eng Des Sel. 2009 Jan;22(1):9-18
references.pmid: 18988692
references.citation: Exp Mol Med. 2003 Dec 31;35(6):509-17
references.pmid: 14749528
references.citation: Protein Eng Des Sel. 2012 Jun;25(6):271-83
references.pmid: 22490956
references.citation: J Nanomed Nanotechnol. 2012;Suppl 4:008
references.pmid: 26451274
references.citation: Protein Eng. 1996 Sep;9(9):797-801
references.pmid: 8888146
references.citation: Br J Cancer. 2008 Aug 5;99(3):392-7
references.pmid: 18648371
references.citation: Nanomedicine (Lond). 2010 Jun;5(4):563-74
references.pmid: 20528452
references.citation: Anticancer Drugs. 2005 Jun;16(5):569-79
references.pmid: 15846123
references.citation: Clin Pharmacokinet. 2003;42(5):419-36
references.pmid: 12739982
references.citation: J Drug Target. 2011 Sep;19(8):597-605
references.pmid: 21275826
references.citation: Protein Eng. 1987 Aug-Sep;1(4):289-94
references.pmid: 3508279
references.citation: Mol Pharm. 2011 Oct 3;8(5):1720-8
references.pmid: 21675738
references.citation: Curr Protoc Protein Sci. 2008 Feb;Chapter 18:Unit 18.9
references.pmid: 18429059
references.citation: Curr Pharm Des. 2004;10(19):2335-43
references.pmid: 15279612
references.citation: Mol Pharm. 2010 Aug 2;7(4):1149-58
references.pmid: 20438086
references.citation: Ann Oncol. 2005 Nov;16(11):1723-39
references.pmid: 15980158
references.citation: Nat Rev Clin Oncol. 2010 Dec;7(12):669-70
references.pmid: 21116236
references.citation: Anticancer Drugs. 2005 Aug;16(7):691-707
references.pmid: 16027517
references.citation: Breast Cancer Res. 2002;4(3):95-9
references.pmid: 12052251
references.citation: Adv Drug Deliv Rev. 2004 Apr 29;56(8):1177-92
references.pmid: 15094214
references.citation: Cancer. 2002 Jan 1;94(1):25-36
references.pmid: 11815957
references.citation: Expert Opin Drug Deliv. 2008 Aug;5(8):825-36
references.pmid: 18712993
references.citation: Chem Phys Lipids. 2006 Jun;141(1-2):83-93
references.pmid: 16620800
references.citation: Pharmacol Rev. 1999 Dec;51(4):691-743
references.pmid: 10581328
references.citation: Cancer Res. 2006 Jul 1;66(13):6732-40
references.pmid: 16818648
references.citation: N Engl J Med. 1998 Sep 24;339(13):900-5
references.pmid: 9744975
references.citation: Endocr Rev. 2003 Aug;24(4):389-427
references.pmid: 12920149
references.citation: Ann Oncol. 2004 Mar;15(3):440-9
references.pmid: 14998846
references.citation: FEMS Microbiol Rev. 1995 Aug;17(1-2):185-90
references.pmid: 7669345
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: Int J Pept Res Ther. 2006 Mar;12(1):79-91
references.pmid: 19444323
references.citation: Curr Opin Biotechnol. 1996 Dec;7(6):616-21
references.pmid: 8939640
references.citation: Nanomedicine. 2010 Aug;6(4):538-46
references.pmid: 20138246
references.citation: Biochemistry. 1989 Nov 14;28(23):9158-65
references.pmid: 2690954
references.citation: Mol Pharm. 2007 Sep-Oct;4(5):631-51
references.pmid: 17880166