title: Treatment of experimental brain metastasis with MTO-liposomes: impact of fluidity and LRP-targeting on the therapeutic result.
abstract: OBJECTIVE
  To test targeted liposomes in an effort to improve drug transport across cellular barriers into the brain.
  
  
  METHODS
  Therefore we prepared Mitoxantrone (MTO) entrapping, rigid and fluid liposomes, equipped with a 19-mer angiopeptide as ligand for LDL lipoprotein receptor related protein (LRP) targeting.
  
  
  RESULTS
  Fluid, ligand bearing liposomes showed in vitro the highest cellular uptake and transcytosis and were significantly better than the corresponding ligand-free liposomes and rigid, ligand-bearing vesicles. Treatment of mice, transplanted with human breast cancer cells subcutaneously and into the brain, with fluid membrane liposomes resulted in a significant reduction in the tumor volume by more than 80% and in a clear reduction in drug toxicity. The improvement was mainly depended on liposome fluidity while the targeting contributed only to a minor degree. Pharmacokinetic parameters were also improved for liposomal MTO formulations in comparison to the free drug. So the area under the curve was increased and t(1/2) was extended for liposomes.
  
  
  CONCLUSIONS
  Our data show that it is possible to significantly improve the therapy of brain metastases if MTO-encapsulating, fluid membrane liposomes are used instead of free MTO. This effect could be further enhanced by fluid, ligand bearing liposomes.
authors.affiliation: Experimental Pharmacology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin-Buch, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Orthmann
authors.forename: Reiner
authors.initials: R
authors.lastname: Zeisig
authors.forename: Regine
authors.initials: R
authors.lastname: Süss
authors.forename: Dorothea
authors.initials: D
authors.lastname: Lorenz
authors.forename: Margit
authors.initials: M
authors.lastname: Lemm
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008942:Mitoxantrone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D026502:LDL-Receptor Related Proteins; D008081:Liposomes; D010455:Peptides; D008942:Mitoxantrone