SCDT-42. ENHANCED IN VIVO EFFICACY AND SAFETY OF COMBINATION TEMOZOLOMIDE AND BROMODOMAIN INHIBITOR THERAPY FOR GLIOMAS USING A TARGETED DUAL DRUG-LOADING STEALTH LIPOSOMAL CARRIER

摘要

Effective treatment for gliomablastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse the intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 led to increased DNA damage and apoptosis in tumor tissue that correlated with decreased tumor burden and significant survival benefits compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also showed protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this platform to deliver novel combination therapies for gliomas and other central nervous system tumors.