Introduction: Development of rapid treatment resistance to single agent therapies and the presence of the blood-brain barrier (BBB) have limited significant improvements in outcomes for patients with gliomablastomas (GBM). To address these issues, we developed dual-drug loaded transferrin-functionalized nanoparticles containing the novel combination of temozolomide and the bromodomain inhibitor JQ1 and tested their safety and efficacy in U87MG and GL261 intracranial orthotopic GBM mouse models.
Methods: In vivo multiphoton imaging through a cranial window was performed to assess tumor uptake of nanoparticles. Mice containing U87MG or GL261 intracranial orthotopic tumors stable expressing GFP and luciferase were treated for 5 consecutive days with IV injections of either free drug or drug-loaded Tf-NPs. Tumor response to treatment was tracked every 3 to 5 days using bioluminescence imaging. Serial daily blood profiling was performed to assess systemic drug toxicity. Brains were harvested, fixed, and stained to detect markers of DNA damage (gamma-H2AX), apoptosis (cleaved caspase 3), and proliferation (Ki67) following treatment.
Results: In vivo multiphoton imaging demonstrated the ability of Tf-NPs to cross intact BBB and achieve durable tumor uptake in mice containing U87MG and GL261 gliomas. Mice treated with Tf-NPs loaded with TMZ and JQ1 led to increases in tumor cell DNA damage and apoptosis that correlated with decreased tumor burden and significant survival benefits compared to equivalent free-drug dosing. Finally, immunocompetent mice treated with Tf-NP-loaded drugs showed protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this versatile NP platform for use in the delivery of novel drug combinations to treat gliomas.
Conclusions: Our tumor-targeting nanoparticle offers the potential to deliver novel combination therapies across the BBB to overcome rapid rewiring of resistance pathways as well as avert effects of systemic drug toxicity to improve treatment outcomes for patients with GBM.
Patient Care: Bromodomain inhibitors have shown in vivo efficacy across multiple tumor types and are currently in clinical trials for the treatment of hematological malignancies. There are also small-scale clinical trials testing the safety and efficacy of nanoparticles for delivery of TMZ across the BBB in glioma patients. Our research suggests that the novel combination of TMZ and a bromodomain inhibitor delivered using our nanoparticles can be translated for use to improve survival benefits and alleviate systemic side-effects of treatment for GBM patients.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Identify limiting factors to effective delivery of therapies to CNS tumors; 2) Discuss the use of emerging targeted nanotechnologies to improve delivery of novel therapies across the BBB for the treatment of GBM; and 3) Identify novel combination therapies using current FDA-approved drugs and preclinical small molecule inhibitors that that can potentially be used to overcome treatment resistance for GBM.