title: Design of folate-linked liposomal doxorubicin to its antitumor effect in mice.
abstract: OBJECTIVE
  Tumor cell targeting is a promising strategy for enhancing the therapeutic potential of chemotherapy agents. Polyethylene glycol (PEG)-coated (sterically stabilized) liposomes show enhanced accumulation on the surface of tumors, but steric hindrance by PEGylation reduces the association of the liposome-bound ligand with its receptor. To increase folate receptor (FR) targeting, we optimized the concentration and PEG spacer length of folate-PEG-lipid in liposomes.
  
  
  METHODS
  Three types of folate-linked liposomal doxorubicin were designed and prepared by optimizing the concentration and PEG spacer length of folate-PEG-lipid in PEGylated or non-PEGylated liposomes and by masking folate-linked liposomes where the folate ligand is "masked" by adjacent PEG spacers. The liposome targeting efficacy was evaluated in vitro and in vivo.
  
  
  RESULTS
  In human oral carcinoma KB cells, which overexpress FR, modification with sufficiently long PEG spacer and a high concentration of folate ligand to non-PEGylated liposomes increased the FR-mediated association and cytotoxicity more than with PEGylated and masked folate-linked liposomes. On the contrary, in mice bearing murine lung carcinoma M109, modification with the folate ligand in PEGylated and masked folate-linked liposomes showed significantly higher antitumor effect than with non-PEGylated liposomes irrespective of the length of time in the circulation after intravenous injection.
  
  
  CONCLUSIONS
  The results of this study will be beneficial for the design and preparation of ligand-targeting carriers for cancer treatment.
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamada
authors.forename: Yukimi
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Kumi
authors.initials: K
authors.lastname: Kawano
authors.forename: Takashi
authors.initials: T
authors.lastname: Honda
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Maitani
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism*; D008081:Liposomes; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D011956:Receptors, Cell Surface; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid