title: In vitro and in vivo evaluation of lipofufol, a new triple stealth liposomal formulation of modulated 5-fu: impact on efficacy and toxicity.
abstract: OBJECTIVE
  Drug resistance and severe toxicities are limitations when handling 5-FU. We have developed a triple liposomal formulation of 5-FU combined to 2'-deoxyinosine and folinic acid to improve its efficacy-toxicity balance.
  
  
  METHODS
  Stealth liposomes were obtained using the thin-film method. Antiproliferative activity was tested on human colorectal and breast cancer models using sensitive (HT29) and resistant (SW620, LS174t, MDA231) cell lines. In vivo, pharmacokinetics, biodistribution and safety studies were performed in rodents. Finally, efficacy was evaluated using two tumor-bearing mice models (LS174 and MDA231) with response and survival as main endpoints.
  
  
  RESULTS
  LipoFufol is a 120-nm pegylated liposome, displaying 20-30% encapsulation rates. In vitro, antiproliferative activities were higher than 5-FU, and matched that of FolFox combination in colorectal models, but not in breast. Drug monitoring showed an optimized pharmacokinetics profile with reduced clearance and prolonged half-life. Liposome accumulation in tumors was shown by fluorescence-based biodistribution studies. Beside, milder neutropenia was observed when giving LipoFufol to animals with transient partial DPD-deficiency, as compared with standard 5-FU. In LS174t-bearing mice, higher response and 55% longer survival were achieved with Lipofufol, as compared with 5-FU.
  
  
  CONCLUSIONS
  The issues of drug-resistance and drug-related toxicity can be both addressed using a stealth liposomal formulation of modulated 5-FU.
authors: Pharmacokinetics Unit, School of Pharmacy, Aix Marseille University, Inserm U911 Cro-2, 27 Bd Jean Moulin, 13385, Marseille, France.
authors: Raphaelle
authors: R
authors: Fanciullino
authors: Séverine
authors: S
authors: Mollard
authors: Sarah
authors: S
authors: Giacometti
authors: Yael
authors: Y
authors: Berda-Haddad
authors: Mohamed
authors: M
authors: Chefrour
authors: Claude
authors: C
authors: Aubert
authors: Athanassios
authors: A
authors: Iliadis
authors: Joseph
authors: J
authors: Ciccolini
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019073:HT29 Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D011092:Polyethylene Glycols; D005472:Fluorouracil
references: Ther Drug Monit. 2006 Oct;28(5):678-85
references: 17038885
references: Curr Drug Metab. 2012 Jan;13(1):105-19
references: 21892917
references: Molecules. 2008 Aug 05;13(8):1551-69
references: 18794772
references: Clin Transl Oncol. 2012 Feb;14(2):83-93
references: 22301396
references: Prog Lipid Res. 2003 Nov;42(6):463-78
references: 14559067
references: Cancer Res. 1998 Feb 15;58(4):685-90
references: 9485021
references: Methods Enzymol. 2005;391:40-57
references: 15721373
references: Br J Clin Pharmacol. 2009 Jan;67(1):132-4
references: 19006547
references: Mol Oncol. 2011 Dec;5(6):492-503
references: 22071376
references: Clin Cancer Res. 2000 Apr;6(4):1529-35
references: 10778986
references: Clin Colorectal Cancer. 2010 Oct;9(4):224-8
references: 20920994
references: Curr Drug Targets. 2011 Jul 1;12(8):1151-65
references: 21443475
references: Oncologist. 2008 Mar;13(3):248-60
references: 18378535
references: J Clin Oncol. 1998 Jan;16(1):301-8
references: 9440757
references: Mol Cancer Ther. 2001 Dec;1(2):133-9
references: 12467230
references: Anticancer Drugs. 2003 Oct;14(9):695-702
references: 14551502
references: Pharm Res. 2005 Dec;22(12):2051-7
references: 16222443
references: Br J Cancer. 1999 Aug;80(11):1726-33
references: 10468288
references: Cancer Res. 1988 Feb 1;48(3):589-601
references: 3335022
references: Pharmacol Res. 2010 Aug;62(2):90-9
references: 20380880
references: Cancer Res. 1988 Mar 15;48(6):1676-9
references: 3345535
references: Rev Med Interne. 1997;18 Suppl 4:372s-378s
references: 9365715
references: Nat Rev Cancer. 2003 May;3(5):330-8
references: 12724731
references: Clin Colorectal Cancer. 2009 Oct;8(4):200-6
references: 19822510
references: J Control Release. 2011 Mar 10;150(2):212-9
references: 21094191
references: J Control Release. 2001 Jul 10;75(1-2):83-91
references: 11451499
references: J Chemother. 2004 Nov;16 Suppl 4:90-3
references: 15688620
references: Clin Pharmacol Ther. 2008 Mar;83(3):413-5
references: 17637782
references: Cancer Chemother Pharmacol. 2011 Jan;67(1):49-56
references: 20204365
references: Curr Med Chem. 2009;16(33):4361-71
references: 19835568
references: Br J Cancer. 2007 Oct 8;97(7):919-26
references: 17848948
references: Clin Cancer Res. 2005 Dec 1;11(23):8230-4
references: 16322279
references: Clin Pharmacokinet. 1989 Apr;16(4):215-37
references: 2656050