Glioblastoma multiforme (GBM), the most common primary brain cancer, has a 5-year survival rate of <12%. GBM treatment is severely limited by the fact that chemotherapeutic drugs reach the brain in very low concentrations due to the blood brain barrier (BBB). Current strategies to circumvent the BBB (i.e. Gliadel wafers and convection enhanced delivery) are invasive and lead to only moderate improvements in survival. Clearly, less-invasive strategies that provide sustained and well-dispersed drug delivery to brain tumors are needed. To address this need, we propose an innovative image guided drug-delivery approach that couples magnetic resonance (MR)-targeted BBB opening via focused ultrasound (FUS) and microbubbles (MBs) with drug-loaded nanoparticles that have been engineered with extremely dense polyethylene glycol (PEG) coatings to rapidly penetrate brain tissue (i.e. "brain penetrating nanoparticles" or BPNs). We hypothesize that this approach will improve brain cancer treatment by enhancing drug delivery across the BBB to FUS-targeted tumors, providing sustained drug delivery deep within tumors, and minimizing systemic side effects. We will test this hypothesis with 4 aims.
In Aim 1, we will optimize BPN size and surface chemistry for brain tumor penetration and long circulation time. Tracer BPNs will be used to determine the nanoparticle size range and surface chemistry required to produce BPNs with controlled particle penetration depths in freshly obtained brain tumors ex vivo. Subsequently, BPNs with these optimal characteristics will be generated from biodegradable polymers and tested.
In Aim 2, running in parallel with Aim 1, we will determine FUS pressure thresholds for safe and reversible MR-guided BBB opening to gadolinium in intracranial 9L rat brain tumors as a function of MB diameter. Then, FUS pressure thresholds will be used as a basis for determining optimal FUS and MB parameters for delivering the most promising BPN formulation from Aim 1 to brain tumors. These FUS and MB parameters will be carried to Aim 3, wherein we will evaluate whole-body and brain biodistributions of biodegradable BPNs via Fluorescence Molecular Tomography (FMT). BPN dispersion into the brain after delivery across the BBB will be further analyzed in detail using confocal microscopy. Brain tissue inflammation, which is expected to be negligible or absent, will be assessed histologically.
In Aim 4, we will first determine the maximum tolerated dose (MTD) of paclitaxel-loaded BPNs, followed by an evaluation of drug pharmacokinetics (PK). Finally, we will determine the overall efficacy of drug-loaded BPN delivery with MR- guided FUS and MBs to invasive brain tumors by measuring reduced tumor growth and enhanced animal survival after treatment. If these pre-clinical studies proceed as expected, we are well-positioned for translation to the clinic. Our next step would be to test the safety of the MR-guided BPN delivery approach in large animals (pig) using the University of Virginia's clinical Insightec Exablate system, followed by the initiation of a clinical trial.

Public Health Relevance

Chemotherapy is often ineffective when treating brain tumors because the interface between the bloodstream and the brain, which is called the blood-brain barrier, is not permeable to drugs in the bloodstream. We are testing the ability of a new technology, which uses MR imaging and specialized ultrasound equipment to open the blood-brain barrier around brain tumors, to permit the delivery of specially designed drug-carrying nanoparticles for improved brain cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA164789-03
Application #
8638777
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Farahani, Keyvan
Project Start
2012-05-07
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$600,359
Indirect Cost
$103,259
Name
University of Virginia
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Berry, Sneha; Mastorakos, Panagiotis; Zhang, Clark et al. (2016) Enhancing Intracranial Delivery of Clinically Relevant Non-viral Gene Vectors. RSC Adv 48:41665-41674
Mead, Brian P; Mastorakos, Panagiotis; Suk, Jung Soo et al. (2016) Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound. J Control Release 223:109-17
Mastorakos, Panagiotis; Song, Eric; Zhang, Clark et al. (2016) Biodegradable DNA Nanoparticles that Provide Widespread Gene Delivery in the Brain. Small 12:678-85
Moyer, Linsey C; Timbie, Kelsie F; Sheeran, Paul S et al. (2015) High-intensity focused ultrasound ablation enhancement in vivo via phase-shift nanodroplets compared to microbubbles. J Ther Ultrasound 3:7
Hsiang, Y-H; Song, J; Price, R J (2015) The partitioning of nanoparticles to endothelium or interstitium during ultrasound-microbubble-targeted delivery depends on peak-negative pressure. J Nanopart Res 17:
Schuster, Benjamin S; Ensign, Laura M; Allan, Daniel B et al. (2015) Particle tracking in drug and gene delivery research: State-of-the-art applications and methods. Adv Drug Deliv Rev 91:70-91
Timbie, Kelsie F; Mead, Brian P; Price, Richard J (2015) Drug and gene delivery across the blood-brain barrier with focused ultrasound. J Control Release 219:61-75
Schneider, Craig S; Perez, Jimena G; Cheng, Emily et al. (2015) Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells. Biomaterials 42:42-51
Mastorakos, Panagiotis; Zhang, Clark; Berry, Sneha et al. (2015) Highly PEGylated DNA Nanoparticles Provide Uniform and Widespread Gene Transfer in the Brain. Adv Healthc Mater 4:1023-33
Nance, Elizabeth; Timbie, Kelsie; Miller, G Wilson et al. (2014) Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound. J Control Release 189:123-32

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