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Local Intracerebral Delivery of Endogenous Inhibitors by Osmotic Minipumps Effectively Suppresses Glioma Growth in Vivo¹

Neurosurgery, Department of Neurological Sciences, University of Milano, Ospedale Maggiore Policlinico, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy [C. G., G. C., M. P., F. C., M. M., G. T., R. V., L. B.]; Department of Pharmacology, University of Milano, Milan 20122, Italy [V. L,., M. P., D. C.]; and Institut National de la Santé et de la Recherche Médicale Unit 0113, Molecular Mechanisms of Angiogenesis, University of Bordeaux I, Talence, France [A. B.]

The systemic administration of endogenous inhibitors significantly reduced the growth of human glioma in vivo, but required the production of a large amount of biologically active protein. In this study we reduced the amount of protein needed and optimized the therapeutical response by delivering the endogenous inhibitors locally into the brain by osmotic minipumps. Human hemopexin fragment of MMP-2 or COOH-terminal fragment of platelet factor-4 were delivered locally and continuously into the brain of mice implanted intracranially with glioma cells, by osmotic minipumps connected to an intracranial catheter. Local delivery of human hemopexin fragment of MMP-2 and COOH-terminal fragment of platelet factor-4 significantly inhibited the growth of well-established malignant glioma in nude and BALB/C mice. When the inhibitors were given at the same concentration, the efficacy of the local delivery was much higher than that reached with the systemic administration, both when the inhibitor was administered daily or continuously by s.c. minipumps. Moreover, the local delivery reduced the amount of protein needed to reach a significant therapeutic response. Intracerebral delivery maintained a long-term control of glioma growth and inhibited glioma recurrence in a surgical resection model. Treatment showed no side effects. Histochemical analysis of tumors showed that the tumor growth inhibition was the result of a decrease in tumor vasculature and a change in tumor vessel morphology. Our data demonstrate that local intracerebral delivery of endogenous inhibitors effectively inhibits malignant glioma growth and reduces the amount of protein needed to reach a therapeutical response.

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