title: In vivo antitumor activity of folate receptor-targeted liposomal daunorubicin in a murine leukemia model.
abstract: BACKGROUND
  Folate receptor (FR) is selectively amplified among human tumors, including in 70% of myeloid leukemias. FR-targeted liposomal delivery is an attractive strategy for enhancing the therapeutic efficacy of anticancer agents against FR(+) tumors. In this study, FR-targeted liposomal daunorubicin was evaluated in an FR+ L1210JF murine ascites tumor model for therapeutic efficacy in vivo.
  
  
  METHODS
  FR-targeted liposomal daunorubicin (F-L-DNR) and non-targeted liposomal daunorubicin (L-DNR) were prepared by polycarbonate membrane extrusion followed by remote loading of DNR. FR-targeted liposomal uptake by L1210JF cells was characterized in vitro using fluorescent liposomes entrapping calcein. For in vivo therapeutic study, B6D2F1 mice on a folate-free diet were intraperitoneally implanted with FR (+) L1210JF cells and treated with 4 intraperitoneal injections of 10 mg/kg liposomal DNR at 1, 5, 9 and 13 days following tumor cell inoculation. Animal survival was then monitored daily.
  
  
  RESULTS
  LI210JF cells showed approximately 10(3) times greater uptake for FR-targeted liposomal calcein compared to the non-targeted control. Uptake of the targeted liposomes could be blocked by 1 mM folic acid. In the therapeutic study, mice treated with F-L-DNR showed significantly greater tumor inhibition and 40.7% greater increase in life-span compared to those that received identical doses of L-DNR. Meanwhile, free DNR given at the same dose failed to prolong the survival of the treated mice.
  
  
  CONCLUSIONS
  F-L-DNR can effectively target FR(+) leukemia cells in vivo. Further preclinical evaluation is warranted to determine its potential application in leukemia therapy.
authors.affiliation: Sibyl Pharmaceutical Inc, Columbus, OH 43212, USA.
authors.forename: Xing Q
authors.initials: XQ
authors.lastname: Pan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D001201:Ascites / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003630:Daunorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics; D058973:Folate Receptors, GPI-Anchored; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D005456:Fluorescent Dyes; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D011956:Receptors, Cell Surface; C483858:phosphatidylethanolamine; D011092:Polyethylene Glycols; C010942:1,2-distearoyllecithin; D003630:Daunorubicin