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Design, synthesis and application of near-infrared fluorescence imaging agent for targeted tumor VEGFR-3 molecule

A technology of VEGFR-3 and fluorescent imaging agent, applied in the field of medical imaging imaging, can solve the problem of low tumor specificity, and achieve the effect of good specificity and wide application prospect.

Active Publication Date: 2018-11-06
WUHAN KDWS BIOLOGICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In order to overcome the shortcomings of low tumor specificity of traditional ICG imaging, the present invention provides a novel near-infrared fluorescence imaging agent ICG-OSu-(PEG4)n-TMVP1 targeting tumor VEGFR-3 molecules, which is based on the original Based on the design and modification of the targeting polypeptide TMVP1 (LARGR), a fluorescent imaging agent with the structural formula ICG-OSu-(PEG)n-G (CGLARGRGC) was obtained. This imaging agent is not only used for tumor diagnosis, but also for fluorescence Precise resection of guided lesions in laparoscopic surgery, used to guide cervical biopsy sampling in fluorescent colposcopy

Method used

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  • Design, synthesis and application of near-infrared fluorescence imaging agent for targeted tumor VEGFR-3 molecule
  • Design, synthesis and application of near-infrared fluorescence imaging agent for targeted tumor VEGFR-3 molecule
  • Design, synthesis and application of near-infrared fluorescence imaging agent for targeted tumor VEGFR-3 molecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Synthesis of ICG-OSu-PEG4-TMVP1 and corresponding quality inspection

[0030] see figure 1 a, PEG-G (CGLARGRGC) was first synthesized using a polypeptide solid phase carrier, and then reacted with ICG-OSu to obtain the imaging agent shown in the present invention. figure 1 b is the purity (>95%) of the imaging agent detected by high performance liquid chromatography (HPLC, Agilent 1200, USA). figure 1 c and 1d are detected by liquid phase mass spectrometry and chromatography (LC-MS, Agilent 1200HPLC&6410Triple Quad, USA) to prove the correct synthesis of the imaging agent shown in the present invention.

Embodiment 2

[0031] Example 2 Cytotoxicity Experiment

[0032] 1. Cell culture

[0033] The mouse breast cancer cell line 4T1 (purchased from ATCC Cell Bank, USA) was cultured in RPMI-1640 medium (Gibco, ThermoFish Company, USA) containing 10% fetal bovine serum by volume. The mouse embryonic fibroblast cell line 3T3 (purchased from ATCC Cell Bank, USA) was cultured in DMEM medium (Gibco, ThermoFish Company, USA) containing 10% fetal bovine serum by volume fraction. All the above cells were kept at 37°C with 5% CO 2 incubator culture.

[0034] 2. CCK-8 test

[0035] 4T1, 3T3 cells were divided into 1*10 4 Species / well density in 96-well plate at 37°C, 5% CO 2 After culturing in the incubator for 24 hours, replace them with fresh medium containing 0, 3.125, 6.5, 12.5, 25, 50ug / ml ICG-OSu-PEG4-TMVP1 respectively, and set 3 auxiliary wells for each group. After incubation for 24 h, the medium was aspirated and replaced with CCK-8 reagent (Dojindo Molecular Technologies, Japan). After in...

Embodiment 3

[0037] Example 3 Experiment of tumor cell binding efficiency under different PEG numbers

[0038] Synthesize the imaging agent with different numbers of PEG, taking n=2, 4, 6, 8, 10, 20 respectively. 4T1 cells were cultured as shown in Example 2, and the 4T1 cells were divided into 1*10 5 Plant a 24-well plate at a density of one per well. After culturing overnight, add 500ul of 1μM ICG-OSu-(PEG)n-TMVP1 or ICG with different PEG numbers to each well, and add PBS to the well as a blank control, and incubate on ice for 20 Minutes later, wash 3 times with cold PBS, and place under a small animal in vivo imager to collect fluorescence pictures of the well plate. Then, the fluorescence value of each well was quantitatively analyzed by the ROI tool of the IVIS imaging software.

[0039] For experimental results, see image 3 , image 3 a is the fluorescence image of 4T1 cells incubated with different PEG numbers of this imaging agent, image 3 b is the quantitative analysis of ...

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Abstract

The invention relates to design, synthesis and application of a near-infrared fluorescence imaging agent for a targeted tumor VEGFR-3 molecules, of which the structural formula is ICG-OSu-(PEG)n-G(CGLARGRGC), wherein ICG is near-infrared fluorescence imaging agent indocyanine green, ICG-OSu is sulfonic acid group indocyanine green activated ester, the core LARGR of cyclic polypeptide G(CGLARGRGC)is polypeptide TMVP1 of a targeted VEGFR-3 molecule, which has carboxyl reactivity, and both are bridged through polyethylene glycol (PEG), wherein n is an integer from 2-20. According to the near-infrared molecule imaging agent provided by the invention, the specificity of ICG development cervical cancer, breast cancer focus and lymphatic metastasis focus thereof is greatly improved, and good instructions are provided for later clinical diagnosis of cervical cancer and breast cancer as well as elimination of tumor metastasis lymph node by applying a fluorescent endoscope.

Description

technical field [0001] The invention relates to the technical field of medical imaging imaging, in particular to the precise resection of malignant tumors under fluorescent laparoscopy. Background technique [0002] In recent years, malignant tumors have become the primary disease that threatens human health. According to the World Cancer Report in 2014, there were 3.07 million newly diagnosed cancer cases in China, accounting for 21.8% of the global total. The number of cancer deaths is about 2.2 million, accounting for 26.9% of the global cancer deaths. At present, the treatment of patients with solid tumors is still dominated by surgical resection, supplemented by chemotherapy, radiotherapy and molecular targeted therapy, but the most critical factors affecting the treatment effect and prognosis of cancer patients are early detection, early diagnosis and early intervention. Existing imaging examinations such as CT / MR / B-ultrasound have been well applied to the diagnosis o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K49/00
CPCA61K49/0034A61K49/0056
Inventor 马丁魏军成陈刚罗丹枫李飞周颖
Owner WUHAN KDWS BIOLOGICAL TECH CO LTD
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