Non-PEGylated liposomes for convection-enhanced delivery of topotecan and gadodiamide in malignant glioma: initial experience

J Neurooncol. 2009 Nov;95(2):185-197. doi: 10.1007/s11060-009-9917-1. Epub 2009 May 24.

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.

MeSH terms

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

Substances

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