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Chlorotoxin-labeled nanoparticle compositions and methods for targeting primary brain tumors

a technology of chlorotoxin and nanoparticles, which is applied in the direction of drug compositions, peptide/protein ingredients, instruments, etc., can solve the problems of severe limitations in the effectiveness of tumor resection in neurosurgery, none of the targeted tumors have been shown to specifically target the vast majority of gliomas, and the difficulty of malignant gliomas to be treated

Inactive Publication Date: 2007-07-05
FRED HUTCHINSON CANCER RES CENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0054]FIG. 5A is a TEM image of representative nanoparticles useful in preparing the chlorotoxin / fluorophore-labeled nanoparticles of the invention;
[0055]FIG. 5B is an X-ray diffraction pattern of representative nanoparticles useful in preparing the chlorotoxin / fluorophore-labeled nanoparticles of the invention;

Problems solved by technology

Gliomas are currently the most common and lethal type of primary brain tumor and are one of the leading causes of cancer-related deaths.
Treating malignant gliomas remains a formidable challenge due to the difficulty in differentiating between tumor and healthy brain tissue; the rapid growth rate of invasive gliomas; the sensitivity of normal brain tissue to current therapies; the intrinsic cellular resistance of gliomas to drugs; and the blood brain barrier's ability to prevent the passage of substances including drugs and contrast agents.
However, none have been shown to specifically target the vast majority of glioma tumors.
The effectiveness of tumor resection in neurosurgery is severely limited by the poor visual contrast between neoplastic and normal brain tissue.
Gross tumor resection restricts both patient quality of life and patient survival, while limited resection leaves residual glioma cells that have the ability to proliferate and migrate rapidly.
However, using these probes, preoperative diagnostic images cannot be correlated with intraoperative pathology.
Currently, the major limitation of the multimodal probes is their low specificity and limited internalization by glioma cells.

Method used

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  • Chlorotoxin-labeled nanoparticle compositions and methods for targeting primary brain tumors
  • Chlorotoxin-labeled nanoparticle compositions and methods for targeting primary brain tumors
  • Chlorotoxin-labeled nanoparticle compositions and methods for targeting primary brain tumors

Examples

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example 1

The Preparation of Representative Chlorotoxin-Labeled Nanoparticles

[0146] In this example, the preparation of representative chlorotoxin-labeled nanoparticles (e.g., a chlorotoxin-labeled nanoparticle referred to herein as “NPC”) of the invention is described.

[0147] Materials. All chemicals were obtained from Sigma-Aldrich (St. Louis, Mo.) and all reagents for cell culture were obtained from Invitrogen (Carlsbad, Calif.) unless otherwise noted. Chlorotoxin (Cltx) was purchased from Alomone (Jerusalem, Israel).

[0148] Synthesis of nanoparticle-PEG-chlorotoxin conjugates (NPC). A schematic illustration of the preparation is shown in FIG. 1A. Iron oxide nanoparticles (NPs) were first surface-modified with a trifluoroethylester-terminal PEG silane which was then converted to an amine terminated PEG silane as described in Zhang et al., J. Am. Chem. Soc. 2004, 126:7206-7211, expressly incorporated herein by reference in its entirety. Cltx was conjugated to the amino end groups of nanopa...

example 2

The Uptake of Representative Chlorotoxin-Labeled Nanoparticles

[0151] Cell culture. Rat gliosarcoma (9L, ATCC, Manassas, Va.) and rat cardiomyocytes (rCM, Cell Applications, San Diego, Calif.) cells were grown in DMEM and rCM medium respectively, supplemented with 1% streptomycin / penicillin and 10% fetal bovine serum FBS. On the day of experiment, cells were incubated with pre-warmed cell culture medium containing NPs. Following incubation, cells were washed twice with cell culture medium and twice with PBS, then trypsinized and suspended in a 4:1 (v / v) solution of PBS and cell culture medium.

[0152] Quantification of nanoparticle uptake. Nanoparticle uptake by cells was determined through the measurement of iron concentrations by inductively coupled plasma atomic emission spectroscopy (ICP-AES). Cell samples were prepared by dissolving the cell pellets in 200 μl of concentrated hydrochloric acid (HC1) for 1 hr at 60° C. and then analyzed on a Jarrell Ash 955 ICP-AES spectrophotomet...

example 3

Therapeutic Effect of Representative Chlorotoxin-Labeled Nanoparticles

[0157] The therapeutic effect of free chlorotoxin is due to its ability to limit further expression of the surface-bound MMP-2 and inhibit its enzymatic activity, subsequently inhibiting tumor migration and invasion. FIG. 1C illustrates conceptually the binding of a NPC to a glioma cell, in which the NPC inhibits the activity of MMP-2 endopeptidase and its further expression by glioma cells. Upon binding of chlorotoxin to the endopeptidase, the cellular invasion pathway by endopeptidase is blocked. At the same time, this interaction induces a second physiological response through down regulation of further MMP-2 expression. This dual action alters the invasive behavior of glioma cells.

[0158] To evaluate the therapeutic potential of NPCs and retention of chlorotoxin therapeutic functionality after nanoparticle conjugation, a transwell migration assay was performed.

[0159] Transwell migration assay. The assay was ...

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Abstract

Chlorotoxin-labeled nanoparticles that target primary brain tumors, compositions that include the nanoparticles, methods of imaging tissues using the nanoparticles, and methods for treating tissues using the nanoparticles.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] The present application is a continuation of U.S. patent application Ser. No. 11 / 385,985, filed Mar. 20, 2006, which claims the benefit of U.S. Patent Application Ser. No. 60 / 674,280, filed Apr. 22, 2005, each application which is expressly incorporated herein by reference in its entirety.STATEMENT OF GOVERNMENT LICENSE RIGHTS [0002] This invention was made with government support under Grant No. N01-C037122 awarded by National Institutes of Health—National Cancer Institute. The government has certain rights in the invention.BACKGROUND OF THE INVENTION [0003] Gliomas are currently the most common and lethal type of primary brain tumor and are one of the leading causes of cancer-related deaths. Treating malignant gliomas remains a formidable challenge due to the difficulty in differentiating between tumor and healthy brain tissue; the rapid growth rate of invasive gliomas; the sensitivity of normal brain tissue to current therapies; the i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/574
CPCA61K47/48261A61K49/0032A61K49/0041A61K49/0056C07K14/43522G01N33/57492A61K49/0017A61K49/005A61K51/08A61B17/22A61K38/16A61K47/6415A61P35/00
Inventor ZHANG, MIQINOLSON, JAMES M.SZE, RAYMONDELLENBOGEN, RICHARD G.VEISEH, OMIDSUN, CONROYGUNN, JONATHAN WHITNEY
Owner FRED HUTCHINSON CANCER RES CENT
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