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: Amy Y Grahn, Krystof S Bankiewicz, Millicent Dugich-Djordjevic, John R Bringas, Piotr Hadaczek, Greg A Johnson, Simon Eastman, Matthias Luz
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 95 Issue 2 Pg. 185-197 (Nov 2009) ISSN: 1573-7373 [Electronic] United States
• PMID: 19466380 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Contrast Media
• Liposomes
• Polyethylene Glycols
• Topotecan
• gadodiamide
• Gadolinium DTPA

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Brain Neoplasms (drug therapy, pathology)
• Cell Survival (drug effects)
• Contrast Media (administration & dosage, pharmacokinetics)
• Convection
• Drug Delivery Systems
• Gadolinium DTPA (administration & dosage, pharmacokinetics)
• Glioblastoma (drug therapy, pathology)
• Humans
• Liposomes
• Male
• Polyethylene Glycols (chemistry)
• Rats
• Rats, Sprague-Dawley
• Survival Rate
• Tissue Distribution
• Topotecan (administration & dosage, pharmacokinetics)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays