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Molecular probe targeting cxcr4 and its use

A targeting and targeting peptide technology, applied in the field of molecular probes targeting CXCR4, can solve the problem of insufficient specific pharmacokinetics of molecular probes, and achieve good specificity and high radioactivity aggregation

Active Publication Date: 2022-01-14
XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] But so far, molecular probes targeting CXCR4 are still insufficient in terms of specificity and in vivo pharmacokinetics

Method used

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  • Molecular probe targeting cxcr4 and its use
  • Molecular probe targeting cxcr4 and its use
  • Molecular probe targeting cxcr4 and its use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1, molecular probe preparation

[0054] Preparation of Cyclic Peptide (Arg-Nal-Gly-D-Tyr-(N-Me)D-Lys)

[0055] 1. Synthetic polypeptide yG5: cyclic peptide (Arg-Nal-Gly-D-Tyr-(N-Me)D-Lys), referred to as yG5, prepared by Fmoc solid-phase peptide synthesis method, wherein D-Lys has a methyl 2. Synthesis of NOTA-yG5: yG5 was conjugated with chelating agent p-SCN-Bn-NOTA, and NOTA-yG5 was obtained after HPLC purification; 3. 68 Ga labeling: Dissolve NOTA-yG5 (20nmol) in sodium acetate buffer (1mL, 0.25M, pH 6.8), add 4mL 68 GaCl 3 0.05M hydrochloric acid solution. The mixture was heated at 100°C for 10 minutes. Purified by C18 solid phase extraction column, rinsed with 2mL 50% ethanol, and passed through a sterile filter membrane into the product bottle, and then rinsed with 8mL normal saline to the product bottle to obtain 68 Ga-NOTA-yG5, abbreviated 68 Ga-yG5. Radiochemical purity was determined by radio-HPLC.

[0056] Preparation of c(Arg-Nal-Gly-D-Ty...

Embodiment 2

[0059] Example 2, Molecular probe in vivo and external stability identification and lipid-water partition coefficient Log P value determination

[0060] Will 68 Ga-yG5 and 68 After Ga-yG6 was incubated with fresh human serum and PBS for 4 hours, it was identified by analytical radio-HPLC. Such as figure 1 with 2 As shown, the proportion of complete probes is still greater than 90%, indicating that 68 Ga-yG5 and 68 Ga-yG6 has good stability in vitro. Normal Balb / c nude mice were used to detect the metabolic stability of the two probes in vivo, and at 2 hours, less than 10% of the 68 Ga-yG5 and 68 Ga-yG6 appeared to be degraded and unlabeled, and the proportion of intact probes was still greater than 90%, indicating that the two probes had better stability in vivo. 68 Ga-yG5, 68 The Log P values ​​of Ga-yG6 were -0.35±0.09, 0.17±0.02, respectively.

[0061] Will 68 After Ga-yG5-RGD was incubated with fresh human serum and PBS for 2 hours, it was identified by analytic...

Embodiment 3

[0062] Example 3, in vitro targeting efficiency detection of molecular probes

[0063] Take the BXPC3 cells growing in the logarithmic phase, count them, and then use 1.5×10 cells per well 5 Cells were seeded in 24-well plates and cultured overnight. The culture medium was discarded, and 800 μL of DMEM medium without serum and double antibody was added to each well to continue culturing for 30 min to 1 h. Then add 50 μL to each well 68 Ga-yG5-RGD (1pmol, 74kBq), 50μL 68 Ga-yG5 (1pmol, 74kBq) and 50μL 68 Ga-RGD (1pmol, 74kBq) was incubated in a 37°C incubator for 30min, 1h and 2h (three replicate wells were set at each time point). At the end of the incubation, collect the supernatant in a test tube, wash each well twice with pre-cooled PBS and collect in the same test tube. Subsequently, 800 μL of NaOH solution (1M) was added to each well to act for 5 minutes to lyse the cells, the cell lysate was collected in another test tube, each well was washed twice with PBS, and co...

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Abstract

The present invention relates to the field of molecular detection, more specifically, to molecular probes targeting CXCR4. The present invention claims a molecular probe targeting CXCR4, and the molecular probe is a compound having the following sequence, or a pharmaceutically acceptable salt or lipid thereof: cyclic peptide (Arg-Nal-Gly-D-Tyr-Tyr- (N-Me)D-Lys)-R n , wherein, R is selected from the group consisting of a linking group, a chelating agent, a radionuclide, another targeting polypeptide or a monoclonal antibody, a monoclonal antibody fragment, and a small molecule inhibitor; wherein, n represents the number of R, and n=0 -4. The probe has good stability in vitro, can be clearly visualized in acute rejection after tumor and heart transplantation, and has good specificity.

Description

technical field [0001] The present invention relates to the field of molecular detection, more specifically, to molecular probes targeting CXCR4. Background technique [0002] Chemokines are a subfamily of cytokines that mainly mediate physiological and pathological processes related to cell homing and migration. Chemokine CXCL12, also known as stromal cell-derived factor-1 (SDF-1), exerts its biological function by binding to cell surface receptor CXCR4. CXCR4 belongs to the seven transmembrane domain G protein-coupled receptor superfamily and is overexpressed in as many as 23 human cancers. Overexpression of CXCR4 in cancer cells contributes to tumor growth, invasion, angiogenesis, metastasis, recurrence, and chemotherapy resistance, and is associated with poor overall prognosis. Studies have shown that CXCR4 antagonism disrupts tumor-stroma interactions, sensitizes cancer cells to cytotoxic drugs, and inhibits tumor growth and metastasis. Integrin α v beta 3 It is ex...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/64A61K51/08A61K103/00
CPCC07K7/64A61K51/08
Inventor 盖永康兰晓莉柳轻瑶蒋亚群李慧玲
Owner XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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