Nimg-19. tumor parameters affected by nanocombrestatin therapy in an experimental rat model of glioma

Abstract INTRODUCTION: of polymeric nanoparticles in cancer therapeutics is widely investigated since nanomedicine often enables the intratumoral delivery of drugs with increased efficacy with minimal side effects. In this study magnetic resonance imaging (MRI) monitoring was employed to study the therapeutic effect of nanocombretastatin (G3-CA4) in an orthotopic glioma model. Water insoluble combretastatin (CA4) was conjugated to a small-sized water soluble G3-succinimic acid PAMAM dendrimer. Tumor growth and vascular parameters were assessed non-invasively using MRI. In the brain, intravenously (iv) administered magnetic resonance (MR) contrast agents (CAs) can be used to measure the biomarkers of tumor perfusion - the blood-to-brain transvascular transfer constant (K-trans), tumor plasma volume (Vp), the extravascular extracellular space (Ve) and the blood volume (VD) in cerebral tumors. K-trans, Vp, Ve and VD showed the discrimination of tumorous vasculature responding to CA4 and G3-CA4 therapies from tumorous tissues. The average K-trans, Vp, Ve and VD decreased significantly 24 hours after G3-CA4 treatment. The results showed that G3-CA4 caused a change in tumor vasculature as measured with DCE-MRI. These effects were homogenous throughout the U-251 tumor. However, CA4 did not show any change in tumor vasculature. Imaging, histological and molecular signatures of the primary glioblastoma were compared. Large necrotic area was found together with destroyed blood vessels at the core of the tumor leaving viable tissue at the rim of the tumor. In vivo studies proved that the cytotoxicity of G3-CA4 conjugate was more effective against human U-251 tumor while CA4 alone was ineffective. Therefore, we have accomplished the effective transvascular delivery of G3-CA4 into human U251 glioma tumor with a compromised blood brain tumor barrier. In vivo studies proved that the cytotoxicity of G3-CA4 conjugate is more effective against human U-251 tumor than that of free CA4.