caa a22 4500 605479976 CHVBK 20210128100412.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s10544-015-9969-2 doi (NATIONALLICENCE)springer-10.1007/s10544-015-9969-2 The effect of AZD2171- or sTRAIL/Apo2L-loaded polylactic-co-glycolic acid microspheres on a subcutaneous glioblastoma model [Elektronische Daten] [Anna Shivinsky, Tomer Bronshtein, Tom Haber, Marcelle Machluf] 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 2weeks. 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. Springer Science+Business Media New York, 2015 AZD2171 nationallicence sTRAIL nationallicence Brain/central nervous system cancers nationallicence Controlled release nationallicence Novel drug delivery systems nationallicence PLGA microspheres nationallicence Shivinsky Anna Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology (IIT), 3200003, Haifa, Israel aut Bronshtein Tomer Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology (IIT), 3200003, Haifa, Israel aut Haber Tom Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology (IIT), 3200003, Haifa, Israel aut Machluf Marcelle Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology (IIT), 3200003, Haifa, Israel aut Biomedical Microdevices Springer US; http://www.springer-ny.com 17/4(2015-08-01), 1-15 1387-2176 17:4<1 2015 17 10544 https://doi.org/10.1007/s10544-015-9969-2 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10544-015-9969-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Shivinsky Anna Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology (IIT), 3200003, Haifa, Israel aut NATIONALLICENCE 700 1- Bronshtein Tomer Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology (IIT), 3200003, Haifa, Israel aut NATIONALLICENCE 700 1- Haber Tom Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology (IIT), 3200003, Haifa, Israel aut NATIONALLICENCE 700 1- Machluf Marcelle Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology (IIT), 3200003, Haifa, Israel aut NATIONALLICENCE 773 0- Biomedical Microdevices Springer US; http://www.springer-ny.com 17/4(2015-08-01), 1-15 1387-2176 17:4<1 2015 17 10544