Topical Application of Activity-based Probes for Visualization of Brain Tumor Tissue

Several investigators have shown the utility of systemically delivered optical imaging probes to image tumors in small animal models of cancer. Here we demonstrate an innovative method for imaging tumors and tumor margins during surgery. Specifically, we show that optical imaging probes topically applied to tumors and surrounding normal tissue rapidly differentiate between tissues. In contrast to systemic delivery of optical imaging probes which label tumors uniformly over time, topical probe application results in rapid and robust probe activation that is detectable as early as 5 minutes following application. Importantly, labeling is primarily associated with peri-tumor spaces. This methodology provides a means for rapid visualization of tumor and potentially infiltrating tumor cells and has potential applications for directed surgical excision of tumor tissues. Furthermore, this technology could find use in surgical resections for any tumors having differential regulation of cysteine cathepsin activity.

[1]  Kinneret Keren,et al.  Dynamic imaging of protease activity with fluorescently quenched activity-based probes , 2005, Nature chemical biology.

[2]  Anthony Asher,et al.  Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. , 2003, Journal of neurosurgery.

[3]  Georges von Degenfeld,et al.  Noninvasive optical imaging of cysteine protease activity using fluorescently quenched activity-based probes. , 2007, Nature chemical biology.

[4]  Bonnie F. Sloane,et al.  Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis. , 1995, Journal of neurosurgery.

[5]  Veit Rohde,et al.  EXTENT OF RESECTION AND SURVIVAL IN GLIOBLASTOMA MULTIFORME: IDENTIFICATION OF AND ADJUSTMENT FOR BIAS , 2008, Neurosurgery.

[6]  Bonnie F. Sloane,et al.  Cysteine cathepsins: multifunctional enzymes in cancer , 2006, Nature Reviews Cancer.

[7]  Jan Grimm,et al.  A spatially and temporally restricted mouse model of soft tissue sarcoma , 2007, Nature Medicine.

[8]  Ralph Weissleder,et al.  A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation. , 2003, Cancer research.

[9]  F. Jolesz,et al.  Survival rates in patients with low‐grade glioma after intraoperative magnetic resonance image guidance , 2005, Cancer.

[10]  M. Bogyo,et al.  Comparative Assessment of Substrates and Activity Based Probes as Tools for Non-Invasive Optical Imaging of Cysteine Protease Activity , 2009, PloS one.

[11]  J. Joyce,et al.  Cysteine cathepsin proteases as pharmacological targets in cancer. , 2008, Trends in pharmacological sciences.

[12]  John V Frangioni,et al.  Intraoperative Near-infrared Fluorescence Imaging in Perforator Flap Reconstruction: Current Research and Early Clinical Experience , 2009, Journal of reconstructive microsurgery.

[13]  T. Strojnik,et al.  Cathepsin L in glioma progression: comparison with cathepsin B. , 2005, Cancer detection and prevention.

[14]  M M Bonsanto,et al.  Clinical evaluation and follow-up results for intraoperative magnetic resonance imaging in neurosurgery. , 2000, Neurosurgery.

[15]  Vasilis Ntziachristos,et al.  Shedding light onto live molecular targets , 2003, Nature Medicine.

[16]  P. Low,et al.  Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results , 2011, Nature Medicine.

[17]  Peter L. Choyke,et al.  Rapid Cancer Detection by Topically Spraying a γ-Glutamyltranspeptidase–Activated Fluorescent Probe , 2011, Science Translational Medicine.

[18]  C R Wirtz,et al.  Surgically induced intracranial contrast enhancement: potential source of diagnostic error in intraoperative MR imaging. , 1999, AJNR. American journal of neuroradiology.

[19]  Vasilis Ntziachristos,et al.  Deep tissue optical and optoacoustic molecular imaging technologies for pre-clinical research and drug discovery. , 2012, Current pharmaceutical biotechnology.

[20]  R. Weissleder,et al.  Near infrared thoracoscopy of tumoral protease activity for improved detection of peripheral lung cancer , 2006, International journal of cancer.

[21]  Ralph Weissleder,et al.  Quantitative real-time catheter-based fluorescence molecular imaging in mice. , 2007, Radiology.

[22]  R Weissleder,et al.  Preparation of a cathepsin D sensitive near-infrared fluorescence probe for imaging. , 1999, Bioconjugate chemistry.

[23]  M. Prados,et al.  Survival and functional status after resection of recurrent glioblastoma multiforme. , 1998, Neurosurgery.

[24]  T. Lah,et al.  Proteases in brain tumour progression , 2003, Acta Neurochirurgica.

[25]  F. Zanella,et al.  Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. , 2006, The Lancet. Oncology.

[26]  R. Sawaya.  Fifty years of neurosurgery argue in favor of glioma resection. , 2001, Clinical neurosurgery.

[27]  P. Low,et al.  Tumor detection using folate receptor-targeted imaging agents , 2008, Cancer and Metastasis Reviews.

[28]  M M Haglund,et al.  Enhanced optical imaging of human gliomas and tumor margins. , 1996, Neurosurgery.

[29]  J. Frangioni,et al.  An Operational Near-Infrared Fluorescence Imaging System Prototype for Large Animal Surgery , 2003, Technology in cancer research & treatment.

[30]  Bonnie F. Sloane,et al.  Cathepsin B and glioma invasion , 1999, International Journal of Developmental Neuroscience.

[31]  Ralph Weissleder,et al.  Protease sensors for bioimaging , 2003, Analytical and bioanalytical chemistry.

[32]  H. Wakimoto,et al.  Intra-arterial delivery of p53-containing adenoviral vector into experimental brain tumors , 2002, Cancer Gene Therapy.

[33]  M. Berger,et al.  The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere. , 1999, Surgical neurology.

[34]  Ralph Weissleder,et al.  Colonic adenocarcinomas: near-infrared microcatheter imaging of smart probes for early detection--study in mice. , 2007, Radiology.

[35]  M. Stepp,et al.  Cdk5 regulates activation and localization of Src during corneal epithelial wound closure , 2004, Journal of Cell Science.

[36]  C. McPherson,et al.  Technologic advances in surgery for brain tumors: tools of the trade in the modern neurosurgical operating room. , 2005, Journal of the National Comprehensive Cancer Network : JNCCN.

[37]  R. Kikinis,et al.  Development and implementation of intraoperative magnetic resonance imaging and its neurosurgical applications. , 1997, Neurosurgery.

[38]  Vasilis Ntziachristos,et al.  Clinical translation of optical and optoacoustic imaging , 2011, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[39]  V. Ntziachristos.  Going deeper than microscopy: the optical imaging frontier in biology , 2010, Nature Methods.

[40]  A. Blejec,et al.  Comparison of potential biological markers cathepsin B, cathepsin L, stefin A and stefin B with urokinase and plasminogen activator inhibitor-1 and clinicopathological data of breast carcinoma patients. , 2002, Cancer detection and prevention.

[41]  L. Ngo,et al.  The FLARE™ Intraoperative Near-Infrared Fluorescence Imaging System: A First-in-Human Clinical Trial in Breast Cancer Sentinel Lymph Node Mapping , 2009, Annals of Surgical Oncology.

[42]  D. Hanahan,et al.  Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. , 2006, Genes & development.

[43]  M M Haglund,et al.  Enhanced optical imaging of rat gliomas and tumor margins. , 1994, Neurosurgery.

[44]  D. Hanahan,et al.  Multiple Roles for Cysteine Cathepsins in Cancer , 2004, Cell cycle.

[45]  Gabriele Schackert,et al.  Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients. , 2008, Neuro-oncology.

[46]  Nina M. Muñoz,et al.  Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. , 2007, Cancer research.