title: Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes.
abstract: Folate receptors (FRs) have been identified as cellular surface markers for cancer and leukemia. Liposomes containing lipophilic derivatives of folate have been shown to effectively target FR-expressing cells. Here, we report the synthesis of a novel lipophilic folate derivative, folate-polyethylene glycol-cholesterol hemisuccinate (F-PEG-CHEMS), and its evaluation as a targeting ligand for liposomal doxorubicin (L-DOX) in FR-expressing cells. Liposomes containing F-PEG-CHEMS, with a mean diameter of 120+/-20 nm, were synthesized by polycarbonate membrane extrusion and were shown to have excellent colloidal stability. The liposomes were taken up selectively by KB cells, which overexpress FR-alpha. Compared to folate-PEG-cholesterol (F-PEG-Chol), which contains a carbamate linkage, F-PEG-CHEMS better retained its FR-targeting activity during prolonged storage. In addition, F-PEG-CHEMS containing liposomes loaded with DOX (F-L-DOX) showed greater cytotoxicity (IC(50)=10.0muM) than non-targeted control L-DOX (IC(50)=57.5 microM) in KB cells. In ICR mice, both targeted and non-targeted liposomes exhibited long circulation properties, although F-L-DOX (t(1/2)=12.34 h) showed more rapid plasma clearance than L-DOX (t(1/2)=17.10h). These results suggest that F-PEG-CHEMS is effective as a novel ligand for the synthesis of FR-targeted liposomes.
authors.affiliation: Pharmacy School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. gyxiang1968@hotmail.com
authors.forename: Guangya
authors.initials: G
authors.lastname: Xiang
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Lu
authors.forename: Zhilan
authors.initials: Z
authors.lastname: Liu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry; D002788:Cholesterol Esters / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D016503:Drug Delivery Systems; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D007624:KB Cells; D008024:Ligands; D008081:Liposomes; D051379:Mice; D008813:Mice, Inbred ICR; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D002788:Cholesterol Esters; D058973:Folate Receptors, GPI-Anchored; D008024:Ligands; D008081:Liposomes; D011956:Receptors, Cell Surface; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid; D002784:Cholesterol; C013440:cholesteryl succinate