Local delivery of poly lactic-co-glycolic acid microspheres containing imatinib mesylate inhibits intracranial xenograft glioma growth

Clin Cancer Res. 2009 Feb 15;15(4):1222-31. doi: 10.1158/1078-0432.CCR-08-1316. Epub 2009 Feb 3.

Abstract

Purpose: In an effort to develop new therapeutic strategies to treat malignant gliomas, we have designed poly (lactic-co-glycolic) acid (PLGA) microparticles that deliver imatinib mesylate, a small molecule tyrosine kinase inhibitor. The local continuous release of imatinib mesylate at the tumor site overcomes many obstacles associated with systemic delivery.

Experimental design: Polymeric microspheres were prepared from various compositions of PLGA and loaded with imatinib mesylate. Imatinib release profiles, biological activity, and effect on PDGFR-B phosphorylation were confirmed in vitro. The therapeutic efficacy of imatinib microspheres was examined in two s.c. and orthotopic human glioblastoma xenograft models.

Results: A single local injection of PLGA microspheres loaded with a low concentration of imatinib mesylate led to 88% and 79% reduction in s.c. human (U87-MG) and murine (GL261) glioma tumors, respectively. PLGA-imatinib mesylate administered intracranially led to a 79% reduction in U87MG tumor volume. Immunohistochemical analysis showed a marked decrease in proliferation indices and tumor vessel density in the s.c. model and induction of apoptosis in an intracranial model.

Conclusion: This is the first study to show the therapeutic efficacy of the local delivery of imatinib mesylate using a polymeric delivery system.

MeSH terms

  • Animals
  • Benzamides
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Glioma / drug therapy*
  • Glioma / pathology
  • Humans
  • Imatinib Mesylate
  • Lactic Acid / administration & dosage*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microspheres*
  • Phosphorylation
  • Piperazines / administration & dosage*
  • Polyglycolic Acid / administration & dosage*
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Pyrimidines / administration & dosage*
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Benzamides
  • Piperazines
  • Pyrimidines
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Imatinib Mesylate
  • Receptor, Platelet-Derived Growth Factor beta