Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles.
Fred C LamStephen W MortonJeffrey WyckoffTu-Lan Vu HanMun Kyung HwangAmanda MaffaElena Balkanska-SinclairMichael B YaffeScott R FloydPaula T HammondPublished in: Nature communications (2018)
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.
Keyphrases
- dna damage
- oxidative stress
- high fat diet induced
- drug delivery
- cancer therapy
- high grade
- blood brain barrier
- high resolution
- cell death
- bone marrow
- mesenchymal stem cells
- risk factors
- high throughput
- photodynamic therapy
- signaling pathway
- combination therapy
- wild type
- metabolic syndrome
- atomic force microscopy
- replacement therapy
- single molecule
- human health