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Continuous Delivery of Endogenous Inhibitors from Poly(Lactic-Co-Glycolic Acid) Polymeric Microspheres Inhibits Glioma Tumor Growth

¹ Laboratory of Cancer Drug Therapeutics and Mammalian Cell Technology, Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel; ² Molecular Mechanisms of Angiogenesis, Universite de Bordeaux I, Talence, France; ³ Department of Neurological Sciences, University of Milan, Milan, Italy; and ⁴ Laboratory of Neurosurgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Marcelle Machluf, Laboratory of Cancer Drug Therapeutics and Mammalian Cell Technology, Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel. Phone: 972-4-8294916/3079; Fax: 972-4-8293399; E-mail: machlufm{at}tx.technion.ac.il.

Purpose: There is an urgent need for modalities that can localize and prolong the administration of the antitumor agents, particularly antiangiogenic, to achieve long-term tumor inhibition. However, one of the major obstacles is designing a device in which the biological activity of sensitive endogenous inhibitors is retained. We have designed a biodegradable polymeric device, which provides a unique and practical means of localizing and continuously delivering hemopexin (PEX) or platelet factor 4 fragment (PF-4/CTF) at the tumor site while maintaining their biological activity. The potential and efficacy of this system is shown in vitro and in vivo in a human glioma mouse model.

Experimental Design: Polymeric microspheres made of poly(lactic-co-glycolic acid) (PLGA) were loaded with very low amounts of PEX and PF-4/CTF. The release profiles of these factors from PLGA and their biological activity were confirmed in vitro using proliferation assays done on endothelial and tumor cells. Tumor inhibition using this system was studied in nude mice bearing a human s.c. glioma.

Results: PEX and PF-4/CTF released in vitro from PLGA microspheres were biologically active and significantly inhibited the proliferation of human umbilical vein endothelial cells, bovine capillary endothelial cells, and U87-MG cells. A single local s.c. injection of PLGA microspheres loaded with low amounts of PEX or PF-4/CTF resulted in an 88% and 95% reduction in glioma tumor volume 30 days post-treatment. Immunohistochemical analysis of the treated tumors showed a marked decrease in tumor vessel density compared with untreated tumors.

Conclusion: Our findings show that polymeric microspheres are a very promising approach to locally and efficiently deliver endogenous inhibitors to the tumor site leading to a significant inhibition of the tumor.

Key Words: Brain tumor • angiogenesis • PEX • PF-4/CTF • controlled delivery

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