title: Synthesis of novel tetravalent galactosylated DTPA-DSPE and study on hepatocyte-targeting efficiency in vitro and in vivo.
abstract: For the purposes of obtaining a hepatocyte-selective drug delivery system, a novel tetravalent galactosylated diethylenetriaminepentaacetic acid-distearoyl phosphatidylethanolamine (4Gal-DTPA-DSPE) was synthesized. The chemical structure of 4Gal-DTPA-DSPE was confirmed by proton nuclear magnetic resonance and mass spectrometry. The four galactose-modified liposomes (4Gal-liposomes) were prepared by thin-film hydration method, then doxorubicin (DOX) was encapsulated into liposomes using an ammonium sulfate gradient loading method. The liposomal formulations with 4Gal-DTPA-DSPE were characterized by laser confocal scanning microscopy and flow cytometry analysis, and the results demonstrated that the 4Gal-liposomes facilitated the intracellular uptake of DOX into HepG2 cells via asialoglycoprotein receptor-mediated endocytosis. Cytotoxicity assay showed that the cell proliferation inhibition effect of 4Gal-liposomes was higher than that of the conventional liposomes without the galactose. Additionally, pharmacokinetic experiments in rats revealed that the 4Gal-liposomes displayed slower clearance from the systemic circulation compared with conventional liposomes. The organ distributions in mice and the study on frozen sections of liver implied that the 4Gal-liposomes enhanced the intracellular uptake of DOX into hepatocytes and prolonged the circulation. Taken together, these results indicate that liposomes containing 4Gal-DTPA-DSPE have great potential as drug delivery carriers for hepatocyte-selective targeting.
authors: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors: Yan
authors: Y
authors: Xiao
authors: Huafang
authors: H
authors: Zhang
authors: Zhaoguo
authors: Z
authors: Zhang
authors: Mina
authors: M
authors: Yan
authors: Ming
authors: M
authors: Lei
authors: Ke
authors: K
authors: Zeng
authors: Chunshun
authors: C
authors: Zhao
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005690:Galactose / Q000737:chemistry / Q000493:pharmacokinetics*; D056945:Hep G2 Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D004369:Pentetic Acid / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008081:Liposomes; D010714:Phosphatidylethanolamines; C038089:1,2-distearoylphosphatidylethanolamine; D004369:Pentetic Acid; D004317:Doxorubicin; D005690:Galactose
keywords: ASGP-R; doxorubicin; galactose; liposomes; pharmacokinetics; targeted drug delivery
references: J Pharm Sci. 2005 Oct;94(10):2266-75
references: 16136555
references: Circ Res. 1991 Jul;69(1):216-27
references: 2054935
references: Expert Opin Drug Deliv. 2009 Aug;6(8):827-34
references: 19558333
references: J Natl Cancer Inst. 1986 Aug;77(2):459-69
references: 3461207
references: J Biol Chem. 1980 May 25;255(10):4607-13
references: 7372599
references: Cancer Res. 1992 Feb 15;52(4):891-6
references: 1737351
references: J Org Chem. 2008 Jul 4;73(13):4978-85
references: 18529027
references: Hematol Oncol Clin North Am. 1994 Apr;8(2):431-50
references: 8040147
references: Chem Pharm Bull (Tokyo). 1995 Jun;43(6):1005-11
references: 7641302
references: Trends Mol Med. 2010 Dec;16(12):594-602
references: 20846905
references: J Pharm Sci. 2001 Jun;90(6):667-80
references: 11357170
references: Histochem Cell Biol. 2009 Jun;131(6):713-26
references: 19255771
references: Biochemistry. 1976 May 18;15(10):2062-70
references: 776212
references: Cancer Res. 1992 Jun 1;52(11):3157-63
references: 1591727
references: Cell. 1980 Nov;22(2 Pt 2):611-20
references: 7448875
references: Adv Drug Deliv Rev. 1999 Nov 10;40(1-2):3-18
references: 10837777
references: Int J Pharm. 2009 Dec 1;382(1-2):222-33
references: 19664697
references: Br J Cancer. 1993 Jun;67(6):1316-23
references: 8099807
references: J Control Release. 2011 Jun 30;152(3):402-10
references: 21435361
references: J Control Release. 2008 Oct 21;131(2):150-7
references: 18706946
references: Int J Pharm. 2003 May 12;257(1-2):103-10
references: 12711166
references: Pharm Res. 2002 Dec;19(12):1808-14
references: 12523658
references: Cell Mol Biol Lett. 2009;14(2):347-62
references: 19194666
references: Biomaterials. 2007 Mar;28(7):1434-42
references: 17141864
references: J Control Release. 2012 Jul 20;161(2):188-97
references: 22370583
references: Magn Reson Med. 1989 Aug;11(2):236-43
references: 2779414
references: Eur J Cancer Clin Oncol. 1982 Feb;18(2):167-76
references: 7201392
references: J Control Release. 2005 Feb 16;102(3):749-63
references: 15681095
references: J Drug Target. 2000;8(3):137-42
references: 10938523
references: Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H933-9
references: 14766674
references: Breast Cancer Res. 2002;4(3):95-9
references: 12052251
references: Physiol Rev. 1995 Jul;75(3):591-609
references: 7624395
references: Arch Pharm Res. 2004 Dec;27(12):1284-9
references: 15648108
references: J Biol Chem. 1983 Jan 10;258(1):199-202
references: 6848494
references: J Pharmacol Exp Ther. 2007 Mar;320(3):994-1001
references: 17138861
references: Biochem J. 1980 Feb 15;186(2):591-8
references: 7378067
references: Acta Oncol. 1994;33(7):779-86
references: 7993646
references: J Virol Methods. 2008 Jan;147(1):54-60
references: 17850893
references: Biochim Biophys Acta. 2002 Feb 10;1559(1):32-42
references: 11825586
references: Biochim Biophys Acta. 1985 Dec 9;822(3-4):267-87
references: 3904832
references: Int Rev Cytol. 1992;137B:181-219
references: 1478820
references: AAPS PharmSciTech. 2010 Jun;11(2):870-7
references: 20490957
references: Biochemistry. 1990 Oct 30;29(43):10009-18
references: 2125488
references: Bioorg Med Chem. 2008 May 1;16(9):5216-31
references: 18358727