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In vivo fate and therapeutic efficacy of PF-4/CTF microspheres in an orthotopic human glioblastoma model

Ofra Benny^*,1, Seung-Ki Kim^,,1, Koby Gvili^*, Inna S. Radzishevsky^*, Amram Mor^*, Luis Verduzco, Lata G. Menon, Peter M. Black, Marcelle Machluf^*,1,2 and Rona S. Carroll^*,2

^* The Faculty of Biotechnology and Food Engineering, The Technion-Israel Institute of Technology, Haifa, Israel;

Department of Neurosurgery, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; and

Department of Neurosurgery, Seoul National University Hospital, Seoul, Korea

²Correspondence: M.M., Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel. E-mail: machlufm{at}tx.technion.ac.il; R.S.C., Department of Neurosurgery, Brigham and Women’s Hospital, 221 Longwood Ave., Boston, MA 02115, USA. E-mail: rcarroll{at}rics.bwh.harvard.edu

The correlation between glioma grade and angiogenesis suggests that antiangiogenic therapies are potentially therapeutically effective for these tumors. However, to achieve tumor suppression, antiangiogenic therapies need to be administered daily using high systemic quantities. We designed a biodegradable polymeric device that overcomes those barriers by providing sustained local delivery of a C-terminal fragment of platelet factor 4 (PF-4/CTF), an antiangiogenic agent. Fluorescent-labeled microspheres composed of poly lactic-coglycolic acid (PLGA) were loaded with rhodamine-labeled PF-4/CTF and formulated to release their contents over time. Fluorescent labeling enabled the correlation between the in vitro to the in vivo kinetic and release studies. PF-4/CTF microspheres were injected into established intracranial human glioma tumors in nude mice. Noninvasive magnetic resonance imaging (MRI) was used to assess the therapeutic response. Tumor size, microvessel density, proliferation, and apoptosis rate were measured by histological analysis. Intracranially, the microspheres were located throughout the tumor bed and continuously released PF-4/CTF during the entire experimental period. MRI and histological studies showed that a single injection of microspheres containing PF-4/CTF caused a 65.2% and 72% reduction in tumor volume, respectively, with a significant decrease in angiogenesis and an increase in apoptosis. Our data demonstrate that polymeric microspheres are an effective therapeutic approach for delivering antiangiogenic agents that result in the inhibition of glioma tumor growth.—Benny, O., Kim, S. K., Gvili, K., Radzishevsky, I. S., Mor, A., Verduzco, L., Menon, L. G., Black, P. M., Machluf, M., Carroll, R.S. In vivo fate and therapeutic efficacy of PF-4/CTF microspheres in an orthotopic human glioblastoma model.

Key Words: angiogenesis • brain tumor • PLGA • local delivery