title: Investigation of intravenous delivery of nanoliposomal topotecan for activity against orthotopic glioblastoma xenografts.
abstract: Achieving effective treatment outcomes for patients with glioblastoma (GBM) has been impeded by many obstacles, including the pharmacokinetic limitations of antitumor agents, such as topotecan (TPT). Here, we demonstrate that intravenous administration of a novel nanoliposomal formulation of TPT (nLS-TPT) extends the survival of mice with intracranial GBM xenografts, relative to administration of free TPT, because of improved biodistribution and pharmacokinetics of the liposome-formulated drug. In 3 distinct orthotopic GBM models, 3 weeks of biweekly intravenous therapy with nLS-TPT was sufficient to delay tumor growth and significantly extend animal survival, compared with treatment with free TPT (P ≤ .03 for each tumor tested). Analysis of intracranial tumors showed increased activation of cleaved caspase-3 and increased DNA fragmentation, both indicators of apoptotic response to treatment with nLS-TPT. These results demonstrate that intravenous delivery of nLS-TPT is a promising strategy in the treatment of GBM and support clinical investigation of this therapeutic approach.
authors.affiliation: Department of Neurological Surgery, University of California-San Francisco, 1450 Third St, San Francisco, CA 94158, USA.
authors.forename: Laura P
authors.initials: LP
authors.lastname: Serwer
authors.forename: Charles O
authors.initials: CO
authors.lastname: Noble
authors.forename: Karine
authors.initials: K
authors.lastname: Michaud
authors.forename: Daryl C
authors.initials: DC
authors.lastname: Drummond
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kirpotin
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozawa
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.forename: C David
authors.initials: CD
authors.lastname: James
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016503:Drug Delivery Systems; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008081:Liposomes; D008163:Luminescent Measurements; D051379:Mice; D008819:Mice, Nude; D036103:Nanotechnology; D015996:Survival Rate; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019772:Topotecan / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D059004:Topoisomerase I Inhibitors; D019772:Topotecan