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Radioactive phospholipid metal chelates for cancer imaging and therapy

Inactive Publication Date: 2018-01-25
WISCONSIN ALUMNI RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The technical effects of this patent are not specifically mentioned in this section. Further analysis of the patent's objectives and features will be required to determine the technical effects of this invention.

Problems solved by technology

There are currently a variety of radiopharmaceuticals available for tumor imaging, but these are limited by non-specificity for malignancy, the inability to distinguish cancer from inflammation, short biological half-life, and generally poor spatial resolution associated with PET and SPECT scanning modalities.
There are a few recognized issues with using compounds that include radioactive iodine isotopes for targeted radiation cancer therapy and / or imaging.
For example, I-124, suffers from poor positron output (only about 24% of the emissions are positrons), and it suffers further from a confounding gamma emission (600 KeV) which actually interferes with normal 511 keV PET detection.
The beta particle range of I-131 is also quite long, which contributes to off target toxicity.

Method used

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  • Radioactive phospholipid metal chelates for cancer imaging and therapy
  • Radioactive phospholipid metal chelates for cancer imaging and therapy
  • Radioactive phospholipid metal chelates for cancer imaging and therapy

Examples

Experimental program
Comparison scheme
Effect test

example 1

of Metal Chelated DO3A-404

[0119]In this Example, we show the synthetic scheme used to synthesize one exemplary phospholipid chelate, Gd-DO3A-404. Analogs incorporating various radioactive isotopes could be synthesized in a similar manner, where the radioactive isotope in questions is substituted for Gd.

[0120]Scheme for synthesizing Gd-DO3A-404 (the disclosed radioactive metal isotopes can be readily substituted for Gd):

example 2

maging Proof of Concept

[0121]In this example, we demonstrate the successful in vivo MRI imaging of a tumor, using Gd-DO3A-404 as the MRI contrast agent. The data demonstrates that the backbone phospholipid and chelating agent are taken up and retained by solid tumors, demonstrating that such chelates incorporating various radioactive metals, as disclosed herein, would exhibit similar properties

[0122]For proof-of-concept in vivo imaging of tumor uptake of the Gd-DO3A-404 agent, nude athymic mouse with a flank A549 tumor (non small cell lung cancer) xenograft was scanned. The Gd-DO3A-404 agent (2.7 mg) was delivered via tail vein injection. Mice were anesthetized and scanning performed prior to contrast administration and at 1, 4, 24, 48, and 72 hours following contrast delivery. Imaging was performed on a 4.7T Varian preclinical MRI scanner with a volume quadrature coil. T1-weighted images were acquired at all imaging time points using a fast spin echo scan with the following pulse s...

example 3

ancer Imaging in Multiple Tumor Models

[0125]In this extension of Example 2, we demonstrate selective uptake and in vivo MRI imaging in two distinct flank tumor types, using Gd-DO3A-404 as the MRI contrast agent.

[0126]To test uptake and retention in rodent models of human cancer, flank xenografts were established in mice for two distinct tumor types, A549 (human non small cell lung cancer, NSCLC) and U87 (human glioma). N=3 for each model. For pre-contrast imaging, T1-W images of the tumor and abdomen (FIG. 4; 2 leftmost images) and T1 maps of the tumor were obtained.

[0127]At time zero (“contrast”), 2.5 mg of Gd-DO3A-404 (˜12 mmol / kg body mass) was delivered into the mice by intravenous injection. Animals were scanned pre-contrast and at various time points between one hour and seven days post-contrast (after one hour, 24 hours, 48 hours, three days, four days and seven days). T1 maps of the tumor were acquired for each time point, along with T1-weighted images of the tumor and the a...

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Abstract

Alkylphosphocholine analogs incorporating a chelating moiety that chelates a radioactive metal isotope are disclosed herein. The alkylphophocholine analogs, which can be used to treat or detect solid tumors, have the formula:R1 includes a chelating agent that is chelated to a metal atom, wherein the metal atom is a positron or single photon emitting metal isotope with a half life of greater than or equal to 4 hours, or an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days; a is 0 or 1; n is an integer from 12 to 30; m is 0 or 1; Y is —H, —OH, —COOH, —COOX, —OCOX, or —OX, wherein X is an alkyl or an arylalkyl; R2 is —N+H3, —N+H2Z, —N+HZ2, or —N+Z3, wherein each Z is independently an alkyl or an aroalkyl; and b is 1 or 2.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional Application No. 62 / 366,344 filed on Jul. 25, 2016, which is incorporated by reference herein in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]Not applicable.FIELD OF THE DISCLOSURE[0003]This disclosure relates generally to disease treatment and medical diagnosis / imaging. In particular, the disclosure is directed to the alkylphosphocholine analogs that include chelated radioactive metal isotopes to target and treat a wide range of pediatric and adult malignant solid tumors, and to detect / image malignant solid tumor cells.BACKGROUND[0004]There are currently a variety of radiopharmaceuticals available for tumor imaging, but these are limited by non-specificity for malignancy, the inability to distinguish cancer from inflammation, short biological half-life, and generally poor spatial resolution associated with PET and SPECT scanning modalities.[0005]W...

Claims

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Application Information

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IPC IPC(8): C07F9/6524G01N33/60A61N5/10A61K51/04
CPCC07F9/6524A61K51/0482A61N5/10G01N33/60A61K51/0489C07B59/004G01N33/574A61P35/00A61K2121/00C07B2200/05C07F5/003C07F9/091G01N2800/52
Inventor WEICHERT, JAMEYPINCHUK, ANATOLYHERNANDEZ, REINIER
Owner WISCONSIN ALUMNI RES FOUND
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