The difficulty in delineating brain tumor margins is a major obstacle in the path toward better outcomes for patients with brain tumors. Current imaging methods are often limited by inadequate sensitivity, specificity and spatial resolution. Here we show that a unique triple-modality magnetic resonance imaging–photoacoustic imaging–Raman imaging nanoparticle (termed here MPR nanoparticle) can accurately help delineate the margins of brain tumors in living mice both preoperatively and intraoperatively. The MPRs were detected by all three modalities with at least a picomolar sensitivity both in vitro and in living mice. Intravenous injection of MPRs into glioblastoma-bearing mice led to MPR accumulation and retention by the tumors, with no MPR accumulation in the surrounding healthy tissue, allowing for a noninvasive tumor delineation using all three modalities through the intact skull. Raman imaging allowed for guidance of intraoperative tumor resection, and a histological correlation validated that Raman imaging was accurately delineating the brain tumor margins. This new triple-modality–nanoparticle approach has promise for enabling more accurate brain tumor imaging and resection.
At a glance
- Near complete surgical resection predicts a favorable outcome in pediatric patients with nonbrainstem, malignant gliomas: results from a single center in the magnetic resonance imaging era. Cancer 101, 817–824 (2004). et al.
- Changing paradigms—an update on the multidisciplinary management of malignant glioma. Oncologist 11, 165–180 (2006). et al.
- Intraoperative optical spectroscopy identifies infiltrating glioma margins with high sensitivity. Neurosurgery 57, 382–391, discussion 382–391 (2005). et al.
- The brain tumor window model: a combined cranial window and implanted glioma model for evaluating intraoperative contrast agents. Neurosurgery 66, 736–743 (2010). et al.
- Course of brain shift during microsurgical resection of supratentorial cerebral lesions: limits of conventional neuronavigation. Acta Neurochir. (Wien) 146, 369–377, discussion 377 (2004). et al.
- Pharmacokinetic analysis of glioma compartments with dynamic Gd-DTPA-enhanced magnetic resonance imaging. Magn. Reson. Imaging 18, 1201–1214 (2000). , &
- Low-field interventional MRI in neurosurgery: finding the right dose of contrast medium. Neuroradiology 43, 254–258 (2001). , , &
- Surgically induced intracranial contrast enhancement: potential source of diagnostic error in intraoperative MR imaging. AJNR Am. J. Neuroradiol. 20, 1547–1553 (1999). et al.
- Ex vivo and in vivo diagnosis of C6 glioblastoma development by Raman spectroscopy coupled to a microprobe. Anal. Bioanal. Chem. 398, 477–487 (2010). , , &
- Bromophenol blue staining of tumors in a rat glioma model. Neurosurgery 57, 1041–1047, discussion 1041–1047 (2005). et al.
- Fluorescence-guided resection of glioblastoma multiforme by using high-dose fluorescein sodium. Technical note. J. Neurosurg. 99, 597–603 (2003). et al.
- Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 7, 392–401 (2006). et al.
- A comparison between time domain and spectral imaging systems for imaging quantum dots in small living animals. Mol. Imaging Biol. 12, 500–508 (2010). et al.
- Multiphoton excitation fluorescence microscopy of 5-aminolevulinic acid induced fluorescence in experimental gliomas. Lasers Surg. Med. 40, 273–281 (2008). et al.
- Carbon nanotubes as photoacoustic molecular imaging agents in living mice. Nat. Nanotechnol. 3, 557–562 (2008). et al.
- Multiscale photoacoustic microscopy and computed tomography. Nat. Photonics 3, 503–509 (2009).
- Raman's “effect” on molecular imaging. J. Nucl. Med. 52, 1839–1844 (2011). , &
- Noninvasive molecular imaging of small living subjects using Raman spectroscopy. Proc. Natl. Acad. Sci. USA 105, 5844–5849 (2008). et al.
- Noninvasive Raman spectroscopy in living mice for evaluation of tumor targeting with carbon nanotubes. Nano Lett. 8, 2800–2805 (2008). et al.
- Multiplexed imaging of surface enhanced Raman scattering nanotags in living mice using noninvasive Raman spectroscopy. Proc. Natl. Acad. Sci. USA 106, 13511–13516 (2009). et al.
- Nanomaterial standards for efficacy and toxicity assessment. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2, 99–112 (2010). , &
- Fluorescent nanoparticle uptake for brain tumor visualization. Neoplasia 8, 302–311 (2006). et al.
- AMIDE: a free software tool for multimodality medical image analysis. Mol. Imaging 2, 131–137 (2003). &
- The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation. Proc. Natl. Acad. Sci. USA 107, 6459–6464 (2010). et al.
- Laser optoacoustic imaging system for detection of breast cancer. J. Biomed. Opt. 14, 024007 (2009). et al.
- Initial results of in vivo non-invasive cancer imaging in the human breast using near-infrared photoacoustics. Opt. Express 15, 12277–12285 (2007). et al.
- Photoacoustic ocular imaging. Opt. Lett. 35, 270–272 (2010). et al.
- Ultrahigh sensitivity carbon nanotube agents for photoacoustic molecular imaging in living mice. Nano Lett. 10, 2168–2172 (2010). et al.
- Advanced contrast nanoagents for photoacoustic molecular imaging, cytometry, blood test and photothermal theranostics. Contrast Media Mol. Imaging 6, 346–369 (2011). , , , &
- Weight of evidence approach for the relative hazard ranking of nanomaterials. Nanotoxicology 5, 445–458 (2011). et al.
- Noninvasive cell-tracking methods. Nat. Rev. Clin. Oncol. 8, 677–688 (2011). , &
- The fate and toxicity of Raman-active silica-gold nanoparticles in mice. Sci. Transl. Med. 3, 79ra33 (2011). et al.
- Oxidative stress mediates the effects of Raman-active gold nanoparticles in human cells. Small 7, 126–136 (2011). et al.
- Preclinical evaluation of Raman nanoparticle biodistribution for their potential use in clinical endoscopy imaging. Small 7, 2232–2240 (2011). et al.
- Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Release 65, 271–284 (2000). , , , &
- Raman spectroscopic characterization of porcine brain tissue using a single fiber-optic probe. Anal. Chem. 79, 557–564 (2007). et al.
- Development and preliminary results of an endoscopic Raman probe for potential in vivo diagnosis of lung cancers. Opt. Lett. 33, 711–713 (2008). et al.
- RT_Image: an open-source tool for investigating PET in radiation oncology. Technol. Cancer Res. Treat. 6, 111–121 (2007). , &
- American National Standards Institute. American national standard for the safe use of lasers. in ANSI Standard Z136.1–2000 (ANSI, Inc., New York, 2000).