title: Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts.
abstract: We have previously shown that convection-enhanced delivery (CED) of highly stable nanoparticle/liposome agents encapsulating chemotherapeutic drugs is effective against intracranial rodent brain tumor xenografts. In this study, we have evaluated the combination of a newly developed nanoparticle/liposome containing the topoisomerase I inhibitor CPT-11 (nanoliposomal CPT-11 [nLs-CPT-11]), and PEGylated liposomal doxorubicin (Doxil) containing the topoisomerase II inhibitor doxorubicin. Both drugs were detectable in the CNS for more than 36 days after a single CED application. Tissue half-life was 16.7 days for nLs-CPT-11 and 10.9 days for Doxil. The combination of the two agents produced synergistic cytotoxicity in vitro. In vivo in U251MG and U87MG intracranial rodent xenograft models, CED of the combination was also more efficacious than either agent used singly. Analysis of the parameters involved in this approach indicated that tissue pharmacokinetics, tumor microanatomy, and biochemical interactions of the drugs all contributed to the therapeutic efficacy observed. These findings have implications for further clinical applications of CED-based treatment of brain tumors.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA 94103-0555, USA.
authors.forename: Michal T
authors.initials: MT
authors.lastname: Krauze
authors.forename: Charles O
authors.initials: CO
authors.lastname: Noble
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Daryl
authors.initials: D
authors.lastname: Drummond
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kirpotin
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Erika
authors.initials: E
authors.lastname: Kullberg
authors.forename: John
authors.initials: J
authors.lastname: Forsayeth
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D018481:Convection; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004357:Drug Synergism; D006207:Half-Life; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes; D008297:Male; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D000077146:Irinotecan; D004317:Doxorubicin; D002166:Camptothecin