Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles

• Published in: Nature communications Vol. 9; no. 1; pp. 1991 - 11
• Main Authors: Lam, Fred C, Morton, Stephen W, Wyckoff, Jeffrey, Vu Han, Tu-Lan, Hwang, Mun Kyung, Maffa, Amanda, Balkanska-Sinclair, Elena, Yaffe, Michael B, Floyd, Scott R, Hammond, Paula T
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.05.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animal models; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents, Alkylating - chemistry; Apoptosis; Apoptosis - drug effects; Azepines - administration & dosage; Azepines - chemistry; Biodistribution; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - physiopathology; Brain tumors; Cancer therapies; Cell Line, Tumor; Central nervous system; Chemotherapy; Deoxyribonucleic acid; DNA; DNA damage; Drug delivery systems; Drug Delivery Systems - instrumentation; Drug Delivery Systems - methods; Endothelium; Glioblastoma; Glioma; Glioma - drug therapy; Glioma - metabolism; Glioma - physiopathology; Humans; Inhibitors; Ligands; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Nanoparticles - chemistry; Nervous system; Neuroimaging; Polyethylene glycol; Temozolomide; Temozolomide - administration & dosage; Temozolomide - chemistry; Toxicity; Transferrin; Transferrins; Triazoles - administration & dosage; Triazoles - chemistry; Tumors; Vitamin B; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04315-4

Effective treatment for glioblastoma (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 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 leads to increased DNA damage and apoptosis that correlates with a 1.5- to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors.