Glioblastoma multiforme (GBM) is both the most common and most lethal primary malignant brain tumor in adults. Patients with GBM have a mean survival of 15 months or less, despite current therapy (surgery, chemotherapy, and radiation). Surgery is a mainstay of GBM treatment and the extent of tumor resection has been shown to correlate with patient survival. However, complete GBM resections are usually not possible because of the inability to visualize the full extent of the infiltrating tumor, and becaue wide margin resections are prohibitive in the brain. Tumor cells migrate through the normal brain parenchyma and a clear delineation of the tumor margins is not always possible. Infiltrating tumor cells extend beyond what is usually depicted with contrast-enhanced MRI, and cannot be seen with the unaided eye during surgery. An imaging method sensitive enough to detect residual tumor cells during the operative procedure could guide neurosurgeons to perform more complete resections and improve survival. The overall goal of this project is to develop a novel approach to brain tumor management that allows preoperative staging, intraoperative 3D high-resolution imaging and photothermal ablation of GBMs using a single nanoprobe. We propose to accomplish this with a novel theranostic triple-modality MRI-Photoacoustic- Raman nanoparticle (MPR-Nanostars). MPR-Nanostars can be detected with these three modalities, and each has unique complementary strengths. This enables preoperative staging with MRI, 3D real-time bulk tumor visualization with Photoacoustic Imaging, and ultrahigh sensitivity detection of small tumor clusters with Raman imaging. Because of the stable retention of MPR-Nanostars within the tumor, pre- and intraoperative imaging can be performed with a single intravenous injection. We will first optimize the MPR-Nanostars to further improve their tumor targeting properties. Next we will characterize the behavior of the nanoparticles in vivo. Here we will use non-invasive dynamic positron emission tomography imaging and conventional methods to quantify biodistribution, and will perform detailed toxicity studies. We will then assess the accuracy of delineating GBMs by nanoparticle-MRI preoperatively and by nanoparticle-Photoacoustic Imaging and -Raman imaging intraoperatively. This will be followed by the optimization of the MPR-Nanostar's ability to destroy microscopic residual tumor via photothermal ablation. All in vivo experiments will be performed in two different GBM mouse models that closely recapitulate human disease. Because the MPR-Nanostars are made of inert gold and silica uniquely built around an FDA-approved iron oxide nanoparticle core, this theranostic nanotechnology approach has a significant potential for clinical translation. The results obtained from this proposal could significantly accelerate the translation of this novel strategy into the clinic, and ultimately lead to improved survival of brain tumor patients.

Public Health Relevance

The proposed research aims at developing a novel triple-modality nanoparticle approach for combined preoperative and intraoperative brain tumor visualization and treatment. It harnesses the complimentary strengths of Magnetic Resonance Imaging, Photoacoustic Imaging and Raman Imaging to allow both deep tissue imaging and ultrahigh sensitivity detection of glioblastomas. This novel theranostic approach has the potential to significantly improve the clinical outcome of glioblastoma patients, by combining optimal preoperative staging with more accurate image-guided resection and the ability to destroy unresectable tumor via photothermal ablation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
1R01EB017748-01A1
Application #
8761985
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Krosnick, Steven
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
City
New York
State
NY
Country
United States
Zip Code
10065
Andreou, Chrysafis; Neuschmelting, Volker; Tschaharganeh, Darjus-Felix et al. (2016) Imaging of Liver Tumors Using Surface-Enhanced Raman Scattering Nanoparticles. ACS Nano 10:5015-26
Neuschmelting, Volker; Burton, Neal C; Lockau, Hannah et al. (2016) Performance of a Multispectral Optoacoustic Tomography (MSOT) System equipped with 2D vs. 3D Handheld Probes for Potential Clinical Translation. Photoacoustics 4:1-10
Spaliviero, Massimiliano; Harmsen, Stefan; Huang, Ruimin et al. (2016) Detection of Lymph Node Metastases with SERRS Nanoparticles. Mol Imaging Biol 18:677-85
Shaffer, Travis M; Harmsen, Stefan; Khwaja, Emaad et al. (2016) Stable Radiolabeling of Sulfur-Functionalized Silica Nanoparticles with Copper-64. Nano Lett 16:5601-4
Huang, Ruimin; Harmsen, Stefan; Samii, Jason M et al. (2016) High Precision Imaging of Microscopic Spread of Glioblastoma with a Targeted Ultrasensitive SERRS Molecular Imaging Probe. Theranostics 6:1075-84
Neuschmelting, Volker; Lockau, Hannah; Ntziachristos, Vasilis et al. (2016) Lymph Node Micrometastases and In-Transit Metastases from Melanoma: In Vivo Detection with Multispectral Optoacoustic Imaging in a Mouse Model. Radiology 280:137-50
Harmsen, Stefan; Bedics, Matthew A; Wall, Matthew A et al. (2015) Rational design of a chalcogenopyrylium-based surface-enhanced resonance Raman scattering nanoprobe with attomolar sensitivity. Nat Commun 6:6570
Harmsen, Stefan; Huang, Ruimin; Wall, Matthew A et al. (2015) Surface-enhanced resonance Raman scattering nanostars for high-precision cancer imaging. Sci Transl Med 7:271ra7
Shaffer, Travis M; Wall, Matthew A; Harmsen, Stefan et al. (2015) Silica nanoparticles as substrates for chelator-free labeling of oxophilic radioisotopes. Nano Lett 15:864-8
Andreou, Chrysafis; Kishore, Sirish A; Kircher, Moritz F (2015) Surface-Enhanced Raman Spectroscopy: A New Modality for Cancer Imaging. J Nucl Med 56:1295-9

Showing the most recent 10 out of 12 publications