title: Non-PEGylated liposomes for convection-enhanced delivery of topotecan and gadodiamide in malignant glioma: initial experience.
abstract: Convection-enhanced delivery (CED) of highly stable PEGylated liposomes encapsulating chemotherapeutic drugs has previously been effective against malignant glioma xenografts. We have developed a novel, convectable non-PEGylated liposomal formulation that can be used to encapsulate both the topoisomerase I inhibitor topotecan (topoCED) and paramagnetic gadodiamide (gadoCED), providing an ideal basis for real-time monitoring of drug distribution. Tissue retention of topoCED following single CED administration was significantly improved relative to free topotecan. At a dose of 10 microg (0.5 mg/ml), topoCED had a half-life in brain of approximately 1 day and increased the area under the concentration-time curve (AUC) by 28-fold over free topotecan (153.8 vs. 5.5 microg day/g). The combination of topoCED and gadoCED was found to co-convect well in both naïve rat brain and malignant glioma xenografts (correlation coefficients 0.97-0.99). In a U87MG cell assay, the 50% inhibitory concentration (IC(50)) of topoCED was approximately 0.8 microM at 48 and 72 h; its concentration-time curves were similar to free topotecan and unaffected by gadoCED. In a U87MG intracranial rat xenograft model, a two-dose CED regimen of topoCED co-infused with gadoCED greatly increased median overall survival at dose levels of 0.5 mg/ml (29.5 days) and 1.0 mg/ml (33.0 days) vs. control (20.0 days; P < 0.0001 for both comparisons). TopoCED at higher concentrations (1.6 mg/ml) co-infused with gadoCED showed no evidence of histopathological changes attributable to either agent. The positive results of tissue pharmacokinetics, co-convection, cytotoxicity, efficacy, and lack of toxicity of topoCED in a clinically meaningful dose range, combined with an ideal matched-liposome paramagnetic agent, gadoCED, implicates further clinical applications of this therapy in the treatment of malignant glioma.
authors.affiliation: MedGenesis Therapeutix Inc, Victoria, 730-730 View St, Victoria, BC, V8W 3Y7, Canada. amygrahn@medgenesis.com.
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Grahn
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, University of California San Francisco, 1855 Folsom Street, Suite 535, Box 1631, San Francisco, CA, 94143-1631, USA.
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
authors.affiliation: Neurocore, 12966 Caminito Bautizo, San Diego, CA, 92130, USA.
authors.forename: Millicent
authors.initials: M
authors.lastname: Dugich-Djordjevic
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, University of California San Francisco, 1855 Folsom Street, Suite 535, Box 1631, San Francisco, CA, 94143-1631, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Bringas
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, University of California San Francisco, 1855 Folsom Street, Suite 535, Box 1631, San Francisco, CA, 94143-1631, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Hadaczek
authors.affiliation: MedGenesis Therapeutix Inc, Victoria, 730-730 View St, Victoria, BC, V8W 3Y7, Canada.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Johnson
authors.affiliation: Northern Lipids Inc, 8855 Northbrook Court, Burnaby, BC, V5J 5J1, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Eastman
authors.affiliation: MedGenesis Therapeutix Inc, Victoria, 730-730 View St, Victoria, BC, V8W 3Y7, Canada.
authors.forename: Matthias
authors.initials: M
authors.lastname: Luz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics; D018481:Convection; D016503:Drug Delivery Systems; D019786:Gadolinium DTPA / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008081:Liposomes; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D014018:Tissue Distribution; D019772:Topotecan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D008081:Liposomes; D011092:Polyethylene Glycols; D019772:Topotecan; C064925:gadodiamide; D019786:Gadolinium DTPA