511 Iron Oxide Nanoplatform HMC-FMX for Targeted Chemotherapeutic Treatment of Glioblastoma

Abstract

INTRODUCTION: Glioblastoma multiforme (GBM), is the most common and aggressive form of primary brain tumors in adults with a high mortality rate. Despite the emergence of potent chemotherapies, clinical efficacy has been limited in part due to the blood-brain barrier (BBB). Therefore, recurrence rate is high, limiting life expectancy. Our nanoplatform is based on ferumoxytol (FMX), an FDA-approved MRI-sensitive supramagnetic iron oxide nanoparticle conjugated to heptamethine cyanine (HMC), a near infrared-flourescent ligand that specifically targets organic anion transporter polypeptides (OATP) expressed in GBM and endothelial cells. METHODS: To show the specificity of OATP-targeting by HMC-FMX nanoplatform, cells were pre-incubated with OATP inhibitors and then incubated with HMC-FMX. Fluorescent intensity and HMC uptake were assesed by flow cytometry. Cytotoxicity of the drug-loaded nanoparticles, HMC-FMX(SN38) and HMC-FMX(CPT) compared to SN38 and Camptothecin (CPT) in U87 cells was assessed by flow cytometry following cell staining with Annexin and 7-AAD. RESULTS: The HMC-FMX nanoplatform is successfully taken up by both U87 and endothelial cells. OATP inhibition significantly decreased HMC uptake (10%-30%) in comparison to control in U87 and endothelial cells. In addition, HMC-FMX(SN38) and HMC-FMX(CPT) exerted increased cytotoxic effect on U87 cells compared with SN38 and CPT alone. Furthermore, majority of apoptotic cells were observed in the HMC-positive cells in contrast to HMC-negative cells. CONCLUSIONS: HMC-FMX can encapsulate chemotherapeutic drugs, such as SN38 and CPT. HMC-FMX as a nanoplatform demonstrates specific, safe and efficient drug delivery through the BBB into GBM cells in vitro.