title: Preclinical studies of pegylated- and non-pegylated liposomal forms of doxorubicin as radiosensitizer on orthotopic high-grade glioma xenografts.
abstract: OBJECTIVE
  Free doxorubicin (DXR) is not currently used to treat brain tumors because (i) the blood-brain barrier limits the drug deposition into the brain (ii) lethal toxic effects occur when combined with radiation therapy. Since encapsulation of DXR within liposomal carriers could overcome these drawbacks, the present study aimed at evaluating the radiosensitizing properties of non-pegylated (NPL-DXR) and pegylated (PL-DXR) liposomal doxorubicin on orthotopic high-grade glioma xenografts (U87).
  
  
  METHODS
  DXR accumulation in brain tissues was assessed by a high-performance liquid chromatography method and antitumor efficacy was evaluated by mice survival determination.
  
  
  RESULTS
  We showed that encapsulation of DXR ensured a preferential deposition of DXR in tumoral tissue in comparison with normal brain tissue: the best AUC tumor tissue/AUC normal tissue ratio depended greatly on the schedule. Overall, thanks to the optimization of the delivery schedule, we demonstrated a radiosensitizing effect for both liposomal DXR without toxicity of this combination on the U87 human malignant glioma orthotopic xenografts.
  
  
  CONCLUSIONS
  This study shows that the use of nanocarriers, allowing targeting of intracerebral tumor, renders relevant the combination of anthracyclin with radiation therapy to treat brain tumors, opening a new field of therapeutic applications. However, our results point out that, for each new delivery system, the administration schedules need to be rigorously optimized.
authors.affiliation: Université de Lorraine, CRAN UMR 7039, Campus Sciences BP70239, Vandoeuvre-les-Nancy, 54500, France.
authors.forename: P
authors.initials: P
authors.lastname: Chastagner
authors.forename: H
authors.initials: H
authors.lastname: Sudour
authors.forename: J
authors.initials: J
authors.lastname: Mriouah
authors.forename: M
authors.initials: M
authors.lastname: Barberi-Heyob
authors.forename: V
authors.initials: V
authors.lastname: Bernier-Chastagner
authors.forename: S
authors.initials: S
authors.lastname: Pinel
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D008819:Mice, Nude; D060787:Neoplasm Grading; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D014018:Tissue Distribution; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D011838:Radiation-Sensitizing Agents; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin