In vivo MRI detection of gliomas by chlorotoxin-conjugated superparamagnetic nanoprobes.

Converging advances in the development of nanoparticle-based imaging probes and improved understanding of the molecular biology of brain tumors offer the potential to provide physicians with new tools for the diagnosis and treatment of these deadly diseases. However, the effectiveness of promising nanoparticle technologies is currently limited by insufficient accumulation of these contrast agents within tumors. Here a biocompatible nanoprobe composed of a poly(ethylene glycol) (PEG) coated iron oxide nanoparticle that is capable of specifically targeting glioma tumors via the surface-bound targeting peptide, chlorotoxin (CTX), is presented. The preferential accumulation of the nanoprobe within gliomas and subsequent magnetic resonance imaging (MRI) contrast enhancement are demonstrated in vitro in 9L cells and in vivo in tumors of a xenograft mouse model. TEM imaging reveals that the nanoprobes are internalized into the cytoplasm of 9L cells and histological analysis of selected tissues indicates that there are no acute toxic effects of these nanoprobes. High targeting specificity and benign biological response establish this nanoprobe as a potential platform to aid in the diagnosis and treatment of gliomas and other tumors of neuroectodermal origin.

[1]  P. Gutin,et al.  The 9L rat brain tumor: Description and application of an animal model , 2004, Journal of Neurology.

[2]  Nathan Kohler,et al.  Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. , 2002, Biomaterials.

[3]  R. Béliveau,et al.  Expression of matrix metalloproteinases and their inhibitors in human brain tumors , 2004, Clinical & Experimental Metastasis.

[4]  J. Nazzaro,et al.  The role of surgery in the management of supratentorial intermediate and high-grade astrocytomas in adults. , 1990, Journal of neurosurgery.

[5]  Donghoon Lee,et al.  Optical and MRI multifunctional nanoprobe for targeting gliomas. , 2005, Nano letters.

[6]  M. Ferrari.  Cancer nanotechnology: opportunities and challenges , 2005, Nature Reviews Cancer.

[7]  R. Weissleder.  Molecular Imaging in Cancer , 2006, Science.

[8]  R Weissleder,et al.  Improvement of MRI probes to allow efficient detection of gene expression. , 2000, Bioconjugate chemistry.

[9]  Rolf F. Barth,et al.  Rat brain tumor models in experimental neuro-oncology:The 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 Gliomas , 2004, Journal of Neuro-Oncology.

[10]  Francesco M Veronese,et al.  PEGylation, successful approach to drug delivery. , 2005, Drug discovery today.

[11]  Ralph Weissleder,et al.  Long-circulating iron oxides for MR imaging , 1995 .

[12]  Nathan Kohler,et al.  A bifunctional poly(ethylene glycol) silane immobilized on metallic oxide-based nanoparticles for conjugation with cell targeting agents. , 2004, Journal of the American Chemical Society.

[13]  J. Riemer,et al.  Colorimetric ferrozine-based assay for the quantitation of iron in cultured cells. , 2004, Analytical biochemistry.

[14]  Miqin Zhang,et al.  Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI. , 2006, Journal of biomedical materials research. Part A.

[15]  M. Berens,et al.  Molecular targets of glioma invasion , 2007, Cellular and Molecular Life Sciences.

[16]  S M Moghimi,et al.  Long-circulating and target-specific nanoparticles: theory to practice. , 2001, Pharmacological reviews.

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

[18]  M. Kuttel,et al.  Glycosidic linkage rotations determine amylose stretching mechanism. , 2005, Journal of the American Chemical Society.

[19]  Anna Moore,et al.  In vivo imaging of siRNA delivery and silencing in tumors , 2007, Nature Medicine.

[20]  Jin-Sil Choi,et al.  In vivo magnetic resonance detection of cancer by using multifunctional magnetic nanocrystals. , 2005, Journal of the American Chemical Society.

[21]  James I. Cohen,et al.  Comparison of two superparamagnetic viral-sized iron oxide particles ferumoxides and ferumoxtran-10 with a gadolinium chelate in imaging intracranial tumors. , 2002, AJNR. American journal of neuroradiology.

[22]  A. Mamelak,et al.  Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601) , 2007, Expert opinion on drug delivery.

[23]  H. Maeda.  The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. , 2001, Advances in enzyme regulation.

[24]  D. Reardon,et al.  Molecularly targeted therapy for malignant glioma , 2007, Cancer.

[25]  Conroy Sun,et al.  Self-Assembled Coatings on Individual Monodisperse Magnetite Nanoparticles for Efficient Intracellular Uptake , 2004, Biomedical microdevices.

[26]  R. Weissleder,et al.  Tumor Cell Endocytosis Imaging Facilitates Delineation of the Glioma–Brain Interface , 1997, Experimental Neurology.

[27]  C Zimmer,et al.  MR imaging of phagocytosis in experimental gliomas. , 1995, Radiology.

[28]  E. Neuwelt,et al.  Imaging of iron oxide nanoparticles by MR and light microscopy in patients with malignant brain tumours , 2004, Neuropathology and applied neurobiology.

[29]  H. Sontheimer,et al.  Chlorotoxin, a scorpion‐derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin , 2002, Glia.

[30]  R Weissleder,et al.  Improved delineation of human brain tumors on MR images using a long‐circulating, superparamagnetic iron oxide agent , 1999, Journal of magnetic resonance imaging : JMRI.

[31]  Kiyoshi Sato,et al.  Prognostic implications of the extent of surgical resection in patients with intracranial malignant gliomas , 1995, Cancer.