The effect of AZD2171- or sTRAIL/Apo2L-loaded polylactic-co-glycolic acid microspheres on a subcutaneous glioblastoma model
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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.
KeywordsAZD2171 sTRAIL Brain/central nervous system cancers Controlled release Novel drug delivery systems PLGA microspheres
A172 human glioblastoma cells were kindly provided by Prof. David Givol, Weizmann Institute of Science, Rehovot, Israel. bFGF was kindly donated by Prof. Gera Neufeld, Technion—Israel Institute of Technology, Haifa, Israel. The financial support of the Russell Berrie Nanotechnology Institute (RBNI) and The Lorry I. Lokey Center is thankfully acknowledged. The financial support and contribution of the Bert Richardson Foundation is greatly appreciated.
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. All animal experiments were performed in compliance with the Ministry of Health’s guidelines for the care and use of laboratory animals (Ethics Committee approval No. IL-089-09-2006).
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