Nanoformulation of a vascular disrupting agent for the treatment of glioma with MRI monitoring

Anti-angiogenesis therapy VEGF-VEGF receptors axis alone or in combination with other therapeutic agents have demonstrated mixed results, with the majority of reports indicating that glioblastoma (GBM) developed resistance against anti-angiogenesis therapy as well as small molecular receptor tyrosine kinase inhibitors. This result is perhaps not unexpected, because angiogenesis is obviously complex, involving dozens of different growth factors that trigger a cascade of subsequent events. Even if a drug effectively blocks one angiogenic growth factor, such as VEGF, blood vessels may still develop via activating alternative pathways. Yet without a sufficient blood supply, cancerous tumors can\u27t grow larger than the head of a pin and are unlikely to become lethal. Therefore, tumor vascularization is a critical process that determines tumor growth, progression and metastasis. Thus, tumor vasculature has become an emerging target for new chemotherapeutic drugs. Vascular disrupting agents (VDAs) for example, combretastatin (CA4), represent a new class of chemotherapeutic agent that targets the newly formed vasculature in solid tumors. Preclinical and early phase trials have demonstrated the promising therapeutic benefits of CA4. Nevertheless, the clinical translation of CA4 has been significantly hampered due to its poor systemic bioavailability and the non-specific distribution of CA4 throughout the body when administered intravenously. Thus, it is reasonable to explore novel formulations of CA4 that overcome the limitations mentioned above. We have engineered dendrimer-based nanosized CA4 conjugate which demonstrates high water solubility. Preliminary intravenous (i.v.) delivery of nano-combretastatin in an orthotropic glioma model demonstrated a necrosis at the core of the tumor leaving a rim of viable tissue. The MRI-determined tissue parameters Ktrans, blood flow (CBF), DWI, ADC map, distribution volume and tumor size indicated the effectiveness of nano-combretastatin treatment. The overall therapeutic effect from G3-CA4 alone or in combination with SRS/TMZ will be evaluated by image-guided MRI monitoring of long-term survival rats