Open Access Research article

Vascular normalization in orthotopic glioblastoma following intravenous treatment with lipid-based nanoparticulate formulations of irinotecan (Irinophore C™), doxorubicin (Caelyx®) or vincristine

Maite Verreault1*, Dita Strutt1, Dana Masin1, Malathi Anantha1, Andrew Yung5, Piotr Kozlowski5, Dawn Waterhouse1, Marcel B Bally1234 and Donald T Yapp12

Author Affiliations

1 Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10thAvenue, Vancouver, BC V5Z 1L3, Canada

2 Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC V6T 1Z3, Canada

3 Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada

4 Center for Drug Research and Development, Vancouver, BC V6T 1Z4, Canada

5 UBC MRI Research Center, 2221 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada

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BMC Cancer 2011, 11:124  doi:10.1186/1471-2407-11-124

Published: 8 April 2011

Abstract

Background

Chemotherapy for glioblastoma (GBM) patients is compromised in part by poor perfusion in the tumor. The present study evaluates how treatment with liposomal formulation of irinotecan (Irinophore C™), and other liposomal anticancer drugs, influence the tumor vasculature of GBM models grown either orthotopically or subcutaneously.

Methods

Liposomal vincristine (2 mg/kg), doxorubicin (Caelyx®; 15 mg/kg) and irinotecan (Irinophore C™; 25 mg/kg) were injected intravenously (i.v.; once weekly for 3 weeks) in Rag2M mice bearing U251MG tumors. Tumor blood vessel function was assessed using the marker Hoechst 33342 and by magnetic resonance imaging-measured changes in vascular permeability/flow (Ktrans). Changes in CD31 staining density, basement membrane integrity, pericyte coverage, blood vessel diameter were also assessed.

Results

The three liposomal drugs inhibited tumor growth significantly compared to untreated control (p < 0.05-0.001). The effects on the tumor vasculature were determined 7 days following the last drug dose. There was a 2-3 fold increase in the delivery of Hoechst 33342 observed in subcutaneous tumors (p < 0.001). In contrast there was a 5-10 fold lower level of Hoechst 33342 delivery in the orthotopic model (p < 0.01), with the greatest effect observed following treatment with Irinophore C. Following treatment with Irinophore C, there was a significant reduction in Ktrans in the orthotopic tumors (p < 0.05).

Conclusion

The results are consistent with a partial restoration of the blood-brain barrier following treatment. Further, treatment with the selected liposomal drugs gave rise to blood vessels that were morphologically more mature and a vascular network that was more evenly distributed. Taken together the results suggest that treatment can lead to normalization of GBM blood vessel the structure and function. An in vitro assay designed to assess the effects of extended drug exposure on endothelial cells showed that selective cytotoxic activity against proliferating endothelial cells could explain the effects of liposomal formulations on the angiogenic tumor vasculature.

Keywords:
glioblastoma multiforme; vasculature normalization; liposomal drugs; endothelial cells