Abstract 5537: GSH-conjugation improves efficacy of Doxil against intracranial xenografts
Authors: van Tellingen Olaf , Brandsma Dieta , Appeldoorn Chantal C.M. , Manca M Francesca , Rip Jaap , Dorland Rick , van Kregten Joan M.R , Boogerd Willem J. , Beijnen Jos H. , Gaillard Pieter J. 
Published: February 2011

High-grade glioma is a uniformly fatal disease with an unmet need for better therapy. A major reason for this poor outcome is the invasive nature of gliomas. Novel therapies that target invasive brain tumor cells should be invented, but a major impediment to the delivery of adequate amounts of therapeutics is the blood brain barrier (BBB), which is largely intact in regions where invasive cells reside.

Glutathione (GSH)-conjugated PEGylated liposomes (G-TechnologyTM) may be suitable vehicles for targeted delivery of small molecule cytotoxic drugs across the BBB. GSH is a natural anti-oxidant that is found at high levels in the brain and its active transporter is abundantly expressed at the BBB. Previous studies using microdialysis with an increasing % of GSH conjugated to liposomes carrying ribavirin have shown a %GSH-dependent increase of drug levels in brain interstitial fluid (up to 5-fold higher), and GSH-liposomes carrying endomorphin-1 were more effective in hot-plate tests when compared to unconjugated liposomes.

We have now tested GSH-conjugated PEGylated liposomes containing doxorubicin (GSH-Doxil) for treatment of mice carrying intracranial U87 xenografts. In a first series, we compared 5%GSH-Doxil to conventional Doxil, free doxorubicin (Dx) and untreated controls. Mice were injected with 10^5 U87-luc cells and bioluminescence (BL) imaging was used for follow up. After 11 days, mice were stratified into control or test groups (n=9 / group). Mice received 3 consecutive weekly dosings of 5 mg/kg Dx-equivalents. The cohorts receiving Doxil and Dx showed a marginal growth delay relative to controls. The response with 5%GSH-Doxil was more promising but variable: two animals receiving 5%GSH-Doxil showed complete regression, which was not observed in any of the other cohorts, whereas other tumors in this cohort responded more similar to the other treatment groups. Since the treatment was well tolerated, we performed another more dose-intense series, administering biweekly 5 mg/kg Dx equivalents. Moreover, 5%GSH-Doxil and 3%GSH-Doxil were tested relative to Doxil and untreated controls. Treatment started at day 14 after tumor cell injection, stratifying only animals whose tumor BL signals increased relative to day 11. After day 25 the animals experienced weight loss that precluded further dosing. In this series, the variation in tumor response was small. There was again one complete regression in the cohort of 5%GSH and not in any of the other cohorts. Moreover, the growth delay in the other tumors in this 5%GSH-Doxil cohort was significantly longer than in any of the other groups. This growth delay translated into a significantly increased median survival of 32.5 days relative to 27 days for untreated controls. The response in the 3%GSH and Doxil cohorts was marginally better relative to controls.

Overall these results warrant further preclinical and clinical investigation using 5%GSH-Doxil liposomes.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5537.