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Compositions and methods for cancer imaging and radiotherapy

A compound and chelate technology, which can be used in the detection, labeling, staging or treatment of cancer, cancers that overexpress low-density lipoprotein receptors, and can solve problems such as unmet medical needs

Pending Publication Date: 2019-12-03
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] There is a clear unmet medical need in the area of ​​effective imaging and targeted agents

Method used

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  • Compositions and methods for cancer imaging and radiotherapy
  • Compositions and methods for cancer imaging and radiotherapy
  • Compositions and methods for cancer imaging and radiotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0420] Example 1: LDL-receptor (LDLR) expression in mouse and human tissues

[0421] To assess membrane expression of LDLR in mouse and human cell lines of interest, membrane extracts were prepared from human and mouse cancer cell lines using the kit ProteoExtract Subcellular Proteome Extraction Kit (Calbiochem, La Jolla, CA, USA) things.

[0422] Membrane extracts were quantified using the BioRad DC protein assay (Bio-Rad, Hercules, CA, USA) following the manufacturer's instructions. 1, 10 μg or 20 μg of cell membrane proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) on a 4-12% polyacrylamide gel and transferred to a nitrocellulose membrane (Amersham Biosciences) superior. The membrane was probed with a goat anti-LDLR antibody (R&D Systems, (1 / 500)) followed by a peroxidase-conjugated donkey anti-goat secondary antibody (Jackson Immunoresearch). Finally, the protein is detected using chemiluminescence.

[0423] Such as figu...

Embodiment 2

[0424] Example 2: Synthesis of fluorescent LDLR targeting conjugates: Conjugate A, Conjugate B, Conjugate C and Conjugate D

[0425] In the following examples, the production and use of conjugates A, B, C and D are disclosed. As shown below, conjugates A, B, C and D contain peptides A (SEQ ID NO: 1), B (SEQ ID NO: 13), C (SEQ ID NO: 6) and D (SEQ ID NO: 14).

[0426] compound composition Conjugate A Fc-peptide A-A680 Conjugate B Fc-peptide B-A680 Conjugate C Fc-peptide C-A680 Conjugate D Fc-peptide D-A680

[0427] Production of Conjugate C and Conjugate D Fusion Proteins

[0428] Peptides C and D were cloned as fusions to the Fc fragment of IgGl.

[0429] For the production of Fc fragments fused to peptides C or D, plasmid constructs were generated based on the plasmid pINFUSEhIgG1-Fc2 (InvivoGen) used as template. Use oligonucleotides to synthesize large primers called Primer C or Primer D by PCR:

[0430] - Forward primer:...

Embodiment 3

[0456] Example 3: Affinity of Conjugates A, B, C and D to LDLR (K D ) determined by surface plasmon resonance (SPR). Binding / endocytic properties of conjugates to h / mLDLR stably expressed by CHO cells and cancer cell lines.

[0457] The affinity of the conjugate to LDLR (K D )

[0458] Recombinant human LDLR (His-tagged) was purchased from Sino Biological (Beijing, China). Interaction of conjugates with LDLR was tested at 25°C using Biacore T200 (GE Healthcare) and 50 mM HEPES-NaOH pH 7.4, 150 mM NaCl, 0.005% Tween-20, 50 μM EDTA as running buffer. Add hLDLR at 35-60 fmol / mm 2 The densities of were immobilized on a NiHC sensor chip (Xantec, Dusseldorf, Germany). Binding of conjugates to LDLR-coated flow cells was corrected for non-specific binding to uncoated flow cells. A one-cycle kinetic approach was used to measure ligand affinity to LDLR. Ligands were diluted in running buffer and injected sequentially at 30 μl / min for 2 minutes using increasing concentrations...

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Abstract

The present invention relates to a conjugated compound comprising a marker M pharmaceutically acceptable, and a peptide or pseudo-peptide P having at most 30 amino acid residues and able to bind the Low-Density Lipoprotein Receptor (LDLR) and to its use in a method of labelling and / or detecting and / or treating cancerous cells in a subject by administration of the conjugated compound to the subjectan analysis of the presence and / or the amount of marker.

Description

technical field [0001] The present invention relates to compositions and methods for cancer imaging, detection and radiation therapy. In particular, the present invention relates to conjugated compounds comprising peptides targeting LDLR and pharmaceutically acceptable markers, and their use in labeling, detecting, staging or treating cancer, especially overexpressed low-density lipoprotein receptor (LDLR) use in cancer. Background technique [0002] Cancer is one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths in 2012, according to Cancer Research UK and WHO. [0003] Although many forms of cancer are now treatable, some of them remain difficult to treat. For example, pancreatic cancer remains one of the deadliest cancers, with a 75% mortality rate within the first year and a 5-year survival rate of only 6%. Every year approximately 12,000 people are diagnosed with pancreatic cancer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/08A61K49/00A61P35/00A61K101/02A61K103/00A61K103/20A61K103/30A61K103/32C07K7/02C07K7/04C07K7/64
CPCA61K49/0056A61K51/048A61K51/08A61K51/088A61K2121/00A61K2123/00C07K7/06C07K7/08C07K14/705C07K19/00G01N33/57438G01N33/60G01N33/92A61P35/00
Inventor 塞德里克·马利塞帕斯卡利娜·勒科尔谢乔纳森·诺瓦克马里恩·大卫贾马尔·铁姆萨曼尼米歇尔·克莱斯特查蒂斯基
Owner ヴェクトオール
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