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

Fred C Lam,Tu-Lan Vu Han,Paula T Hammond,Mun Kyung Hwang,Elena Balkanska-Sinclair,Stephen W Morton,Amanda Maffa,Scott R Floyd,Jeffrey Wyckoff,Michael B Yaffe

doi:10.1038/s41467-018-04315-4

Abstract

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.

Highlights

Effective treatment for glioblastoma (GBM) is limited by the presence of the blood–brain barrier (BBB) and rapid resistance to single agent therapies
We show that transferrin-functionalized PEGylated NPs (Tf-NPs) can be used to deliver novel combination therapies across the BBB in two a b c
We first performed biodistribution studies in non-tumor-bearing mice using NPs that were functionalized with a 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)2000] (DSPE-PEG2K) linker conjugated with Cy5.5-Transferrin (Tf-NP) or DSPE-PEG2K-Cy5.5-Folate (Fol-NP) to assess their ability to cross the intact BBB

Summary

Introduction

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. Surface modification of liposomes with PEG imparts a steric barrier to the NPs that decreases their recognition and clearance by the reticuloendothelial system, imparting “stealth-like” properties, thereby increasing circulation time, allowing for accumulation at the tumor site, and minimizing adverse drug toxicities. This is seen with the PEGylated liposomal formulation of doxorubicin (Doxil®), which greatly reduces the cardiotoxicity of doxorubicin[11]. We show that transferrin-functionalized PEGylated NPs (Tf-NPs) can be used to deliver novel combination therapies across the BBB in two a b c

Methods

Results

Conclusion