title: Folate-receptor-targeted delivery of doxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugate.
abstract: For folate-receptor-targeted anti-cancer therapy, doxorubicin aggregates in a nano-scale size were produced employing doxorubicin-polyethylene glycol-folate (DOX-PEG-FOL) conjugate. Doxorubicin and folate were respectively conjugated to alpha- and omega-terminal end group of a PEG chain. The conjugates assisted to form doxorubicin nano-aggregates with an average size of 200 nm in diameter when combined with an excess amount of deprotonated doxorubicin in an aqueous phase. Hydrophobically deprotonated doxorubicin molecules were aggregated within the core, while the DOX-PEG-FOL conjugates stabilized the aggregates with exposing folate moieties on the surface. The doxorubicin nano-aggregates showed a greater extent of intracellular uptake against folate-receptor-positive cancer cells than folate-receptor-negative cells, indicating that the cellular uptake occurred via a folate-receptor-mediated endocytosis mechanism. They also exhibited more potent cytotoxic effect on KB cells than free doxorubicin. In a human tumor xenograft nude mouse model, folate-targeted doxorubicin nano-aggregates significantly reduced the tumor volume compared to non-targeted doxorubicin aggregates or free doxorubicin. These results suggested that folate-targeted doxorubicin nano-aggregates could be a potentially useful delivery system for folate-receptor-positive cancer cells.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Hyuk Sang
authors.initials: HS
authors.lastname: Yoo
authors.forename: Tae Gwan
authors.initials: TG
authors.lastname: Park
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004355:Drug Stability; D005079:Excipients; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008863:Microspheres; D011092:Polyethylene Glycols / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D005079:Excipients; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D013778:Tetrazolium Salts; D013844:Thiazoles; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid; C022616:thiazolyl blue