Studies with AZD2171-a new anti-
angiogenic inhibitor of
tyrosine kinases associated with
VEGF signaling-have shown great promise for treating
glioblastoma. Unfortunately,
AZD2171 success is limited by low permeability through the blood-brain barrier. Due to
AZD2171's short half-life and high toxicity, its local administration will require multiple intracranial procedures, making this approach clinically unfeasible. In this study, we investigated the potential of the highly hydrophobic
AZD2171, released from modified polylactic-co-
glycolic acid microspheres (PLGA-MS), to treat
glioblastoma. To further demonstrate the versatile loading capacity of this system, the same PLGA formulation, which was found optimal for the loading and release of
AZD2171, was tested with sTRAIL/Apo2L-a
biologic drug that is very different than
AZD2171 in its molecular weight, solubility, and charge.
AZD2171 released from PLGA-MS was at least effective as the free
drug in inhibiting endothelial growth and proliferation (in vitro), and, surprisingly, had a profound cytotoxic effect also towards in vitro cultured
glioblastoma cell-lines (U87 and A172). Complete
tumor inhibition was achieved following a single treatment with AZD2171-loaded PLGA-MS (6 (mg)/kg) administered locally adjacent to human U87
glioma tumors inoculated subcutaneously in nude mice. This improved effect, compared to other therapeutic approaches involving
AZD2171, was shown to affect both
tumor vasculature and the
glioma cells. sTRAIL-loaded
microspheres, administered at very low doses (0.3 (mg)/kg), led to 35 % inhibition of
tumor growth in 2 weeks. Collectively, our results provide pre-clinical evidence for the potential of PLGA formulations of
AZD2171 and sTRAIL to serve as an effective treatment for
glioblastoma.