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68Ga-marked NOTA modified EGFR molecular imaging probe and preparation and application

A 68ga, 68ga-nota-zegfr technology, applied in the fields of radiopharmaceutical chemistry and clinical nuclear medicine, can solve the problems of inappropriate antibody probes, poor tumor penetration, and inability to perform delayed imaging, achieving good tumor imaging quality, Satisfied with the effect of the imaging effect

Pending Publication Date: 2020-07-03
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Small-molecule probes are safe, have good pharmacokinetics, and have high affinity and specificity in addition to ideal size. However, small-molecule probes target the intracellular segment of EGFR and cannot be used to Molecular Targeted Therapy of the Outer Segment
EGF is the natural ligand of EGFR with high specificity, but delayed imaging cannot be performed due to its fast metabolism
Antibody-based probes have high affinity but poor imaging quality due to their larger size, poor tumor penetration, high nonspecific uptake, and long metabolic cycle
In addition, in some quantitative PET imaging studies of EGFR with radiometal-labeled antibodies, there was no correlation between the evaluation of EGFR expression and the PET signal at all, suggesting that bulky antibody probes may not be suitable for quantitative EGFR imaging

Method used

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  • 68Ga-marked NOTA modified EGFR molecular imaging probe and preparation and application
  • 68Ga-marked NOTA modified EGFR molecular imaging probe and preparation and application
  • 68Ga-marked NOTA modified EGFR molecular imaging probe and preparation and application

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Embodiment 1 preparation 68 Ga-NOTA-Z EGFR:1907

[0042] by itG 68 Ge / 68 Ga generator, rinse with 0.05M HCl hydrochloric acid solution to get 185~370MBq (5~10mCi) 68 GaCl 3 Hydrochloric acid solution 1mL. 100 μg of NOTA-Z EGFR:1907 (Ac-Cys-Z chemically synthesized according to the amino acid sequence EGFR:1907 Vortex 2h with MMA-NOTA in DMSO solution) Dissolve in 250μL of 0.38M sodium acetate buffer (NaOAc), then add 1mL of 68 GaCl 3 Hydrochloric acid solution (185~370MBq, 5~10mCi). After the mixture was shaken, it was reacted at 80°C for 15 minutes under airtight conditions, and cooled to room temperature;

[0043] Slowly inject the above reaction solution into the pre-activated Sep-Pak C18-light column, then rinse with 10ml deionized water to remove unreacted free 68 Ga ion and water-soluble impurity, 20mL air is blown dry and rinses with 500μL of 70% ethanol aqueous solution, obtains the structure as follows figure 1 shown 68 For Ga-labeled peptide prod...

Embodiment 268

[0045] Example 2 68 Ga-NOTA-Z EGFR:1907 Cellular uptake, release and blocking experiments of probes

[0046] to prove 68 Ga-NOTA-Z EGFR:1907 For the specific binding ability of EGFR, in vitro cell uptake, release and blocking experiments were performed before in vivo imaging to determine the targeting of the probe. Five non-small cell lung cancer cell lines were selected for this experiment: HCC827 for high expression of EGFR, H1975 for medium and high expression of EGFR, A549 for medium expression of EGFR, H358 for low expression of EGFR, and H520 for negative expression of EGFR.

[0047] Cell uptake experiment: HCC827, H1975, A549, H358, H520 (1×10 5 / well) in a 12-well plate overnight. On the day of the experiment, the cells were washed twice with serum-free medium, and incubated with radioactive probes (1 μCi / well) for 15 min-2 h in a sterile incubator at 37°C. At the time points of 15, 30, 60 and 120 min, the culture medium was discarded and washed three times with ...

Embodiment 3

[0053] Example 3 probe 68 Ga-NOTA-Z EGFR:1907 in vivo targeted validation

[0054] The NSCLC cell line HCC827 with high expression of EGFR was selected for the target verification experiment in vivo to establish a subcutaneous xenograft tumor model (BALB / c female mice, 4-5 weeks old, about 18-20 g, 5×10 6 The number of cells was subcutaneously implanted in the right shoulder, and the tumor volume was about 300mm after about 4 weeks 3 for in vivo imaging experiments), injected via the tail vein of rats 68 Ga-NOTA-Z EGFR:1907Probe (injection dose is about 3.7MBq, 100μCi), under 2.5%-3% isoflurane-oxygen anesthesia, PET / CT scanning (Discovery 790Elite, GE healthcare) for 30min, 60min and 120min, the total scanning time is about 5min, image post-processing using AW4.6 workstation (GE Healthcare).

[0055] Imaging results such as image 3 As shown in A, the HCC827 xenograft tumor can be clearly displayed 30 minutes after injection, and the tumor imaging quality in the later s...

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Abstract

The invention relates to the technical field of radioactive medicinal chemistry and clinic nuclear medicine and particularly relates to a 68Ga marked EGFR targeted tracer agent 68Ga-NOTA-ZEGFR:1907 and a preparation method and application thereof. The molecular imaging probe 68Ga-NOTA-ZEGFR:1907 is specific and targeted to combination of EGFR; a HCC827 hetero-transplanted tumor can be displayed clearly after injection of 30 min, and tumor imaging quality is good in a later period (tumor uptake values are 2.58% ID / g and 2.69% ID / g after injection of 1 h and 2 h respectively); the tumor uptake values are higher than uptake values of most other organs, and satisfactory imaging effects can be obtained; and an autoradiography grey level of 68Ga-NOTA-ZEGFR:1907 in a human tumor tissue specimen is in positive linear correlation with an EGFR expression degree (R2=0.62, P (0.0001).

Description

Technical field: [0001] The invention relates to the technical field of radiopharmaceutical chemistry and clinical nuclear medicine, in particular to a 68 Ga-labeled EGFR targeting tracer 68 Ga-NOTA-Z EGFR:1907 Its preparation method and application. Background technique: [0002] Epidermal growth factor receptor (EGFR) is one of the four members of the human epidermal growth factor receptor (HER) tyrosine kinase HER / ErbB family. It is a cell surface transmembrane protein, including extracellular ligand binding domain, The transmembrane region and intracellular tyrosine kinase region are involved in various physiological processes such as growth, proliferation, differentiation and apoptosis of normal cells. Studies have shown that EGFR also plays an important role in the formation, progression, metastasis and angiogenesis of cancer, and its overexpression or abnormal expression is widely found in solid tumors, such as: non-small cell lung cancer, esophageal cancer, gastri...

Claims

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Application Information

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IPC IPC(8): A61K51/04A61K51/08
CPCA61K51/0482A61K51/08
Inventor 孙夕林陈维芝苗爽刘杨王凯杨丽丽王春和刘想
Owner HARBIN MEDICAL UNIVERSITY
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