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

Abstract

BackgroundChemotherapy 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.MethodsLiposomal 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.ResultsThe 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).ConclusionThe 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.

The Potential and Challenges of siRNA-Based Targeted Therapy for Treatment of Patients with Glioblastoma

“…Treatment also increased the quantity of vessel in the center of tumors, suggesting a more homogeneous distribution of blood across the entire tumor (Verreault et al, 2011c). Further, IrC TM significantly reduced K trans values calculated from Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) studies (Verreault et al, 2011c), which was also suggestive of a decrease in vessel permeability (O'Connor et al, 2007). Taken together, these observations strongly suggested an improvement in vascular function: the tumor blood vessels in tumors from animals treated with IrC TM were behaving more like vessels in the normal brain.…”

“…As described in section 8, the therapeutic activity of irinotecan is improved by the extended exposure of tumor cells to the drug provided by the drug carrier (Verreault et al, 2011b). Moreover, the effects of the formulation on the tumor micro-environment may increase the delivery and efficacy of a second agent (Verreault et al, 2011c). This dual mechanism may provide an opportunity for designing a therapy which would encompass the cytotoxic activity of an optimized chemotherapeutic agent together with the increase in tumor delivery of an antibody-coupled carrier encapsulating siRNAs specific to promalignancy genes.…”

“…IrC TM treatment restored the basement membrane architecture of the tumor vasculature, reduced blood vessel diameters and reduced vessel permeability to the fluorescent dye Hoechst 33342, suggesting a restoration of the vessel architecture and function to a more normal state (Verreault et al, 2011c). Treatment also increased the quantity of vessel in the center of tumors, suggesting a more homogeneous distribution of blood across the entire tumor (Verreault et al, 2011c). Further, IrC TM significantly reduced K trans values calculated from Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) studies (Verreault et al, 2011c), which was also suggestive of a decrease in vessel permeability (O'Connor et al, 2007).…”

“…It was suggested that SU5416 restored capillary architecture and decreased interstitial fluid pressure (Ma et al, 2003), allowing for an increase in TMZ delivery to the tumor tissue. Our laboratory has recently reported that IrC TM therapy (once weekly for three weeks) can lead to normalization of GBM blood vessel structure and function (Verreault et al, 2011c). IrC TM treatment restored the basement membrane architecture of the tumor vasculature, reduced blood vessel diameters and reduced vessel permeability to the fluorescent dye Hoechst 33342, suggesting a restoration of the vessel architecture and function to a more normal state (Verreault et al, 2011c).…”

“…Our laboratory has recently reported that IrC TM therapy (once weekly for three weeks) can lead to normalization of GBM blood vessel structure and function (Verreault et al, 2011c). IrC TM treatment restored the basement membrane architecture of the tumor vasculature, reduced blood vessel diameters and reduced vessel permeability to the fluorescent dye Hoechst 33342, suggesting a restoration of the vessel architecture and function to a more normal state (Verreault et al, 2011c). Treatment also increased the quantity of vessel in the center of tumors, suggesting a more homogeneous distribution of blood across the entire tumor (Verreault et al, 2011c).…”