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Folic acid composite used for imageology diagnosis of tumor and lymphatic metastasis tumor

A technology for tumor imaging and lymphatic metastasis, which is applied in preparations for in vivo experiments, MRI/MRI contrast agents, radioactive carriers, etc., can solve the problems of low spatial resolution, limited application, poor specificity, etc., and achieve high Effects of resolution, enhanced sensitivity, and high targeting

Inactive Publication Date: 2012-06-27
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with 99m Tc as an imaging diagnosis has the disadvantages of low spatial resolution and poor specificity
It has been reported that PAMMA is used as an intermediate to connect multiple chelating agents to increase the number of nuclides connected to a single molecule, but the toxicity of PAMMA itself limits its further clinical application (Noriko Sato et al, 3D-Micro-MR Angiography of Mice Using Macromolecular MR Contrast Agents With Polyamidoamine Dendrimer Core With Reference to Their Pharmacokinetic Properties, Hisataka Kobayashi. Magnetic Resonance in Medicine 2001, 45: 454-460)

Method used

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  • Folic acid composite used for imageology diagnosis of tumor and lymphatic metastasis tumor
  • Folic acid composite used for imageology diagnosis of tumor and lymphatic metastasis tumor
  • Folic acid composite used for imageology diagnosis of tumor and lymphatic metastasis tumor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1Folate-PEG-CKK 2 - Preparation of multiDTPA

[0058] 1. CKK 2 (CpL followed by 3 lysines) Preparation

[0059] Weigh 0.4167 g of Boc-Cys(Mbzl)-PAM resin (degree of substitution: 0.6 mmol / g) into a peptide bottle, swell the resin with DMF, and drain it after 20 minutes. Add about twice the resin volume of TFA and stir for 1 min, remove the TFA, then add TFA and operate in the same way once to remove the Boc protecting group. After washing the resin with DMF, add Boc-Lys (Boc) activation solution (1.1mmol Boc-Lys (Boc) is activated with 2ml 0.5mmol / ml HBTU in DMF and 0.5mL DIPEA for 2min), and shake for 40min. After the reaction was completed, the reaction solution was removed, and the resin was washed with DMF. Then add TFA for deprotection according to the above method, add Boc-Lys (Boc) activation solution after DMF washing (2.2mmol Boc-Lys (Boc) is activated with 4ml 0.5mmol / ml HBTU DMF solution and 1mL DIPEA for 2min), and shake for 60min . After th...

Embodiment 2

[0070] Embodiment 2Folate-PEG-CKK 2 -Cell verification of multiDTPA

[0071] 1. Folate-PEG-CKK 2 - Preparation of multiDTPA(I) fluorescent marker

[0072] Folate-PEG-CKK 2 -Dissolve 5mg of multiDTPA(I) with 2mg EDC·HCl, 2mg HOBt in DMSO, stir at room temperature for 1h, add appropriate amount of FITC-EDA, react at 40°C for 2h, monitor the process by HPLC, after the reaction is basically completed, add 200μL dH 2 O diluted reaction solution has precipitation, centrifuges to get supernatant, and with 150mL dHO 2O washed the precipitate three times and combined the supernatant, separated and purified on G-15 gel column, collected the corresponding product, and lyophilized to obtain 1.95 mg of dark yellow solid.

[0073] 2. Folate-PEG-CKK 2 -Folic acid receptor affinity evaluation of multiDTPA(I) fluorescent marker

[0074] Take the monolayer cultured SGC7901 cells in the logarithmic growth phase, digest the monolayer cultured cells with 0.25% trypsin and 0.025% disodium ede...

Embodiment 3

[0080] Example 3 Folate-PEG-CpL-multiDTPA fluorescein and radioactivity 99m Validation of Tc markers in animals

[0081] 1. Folate-PEG-CKK 2 -Distribution of multiDTPA(I) fluorescent marker in tumor-bearing nude mice

[0082] Four KB tumor-bearing nude mice were given Folate-PEG-CKK by tail vein injection 2 -multiDTPA(I)-FITC, the dose is 1mg / mouse, the mice were killed after 2h, observed in the NightOWLIILB983 living animal imaging system, and the heart, lung, liver, spleen, kidney and tumor were taken as live animals The distribution in each organ was observed in the imaging system ( Figure 9 ).

[0083] 2. Folate-PEG-CKK 2 -Radioactivity of multiDTPA(II) 99m Lymphatic system-directed validation of Tc markers

[0084] (1) Folate-PEG-CKK 2 -Radioactivity of multiDTPA(II) 99m Tc tag

[0085] 5mg Folate-PEG-CKK 2 -multiDTPA(II) was dissolved in 208 μL pH7.2 isotonic phosphate buffer, and 35 μg / 35 μL of SnCl was added to the solution 2 2H 2 O solution, then add 500...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, relating to a folic acid-polyethyleneglycol composite which can be combined with imageology nuclide for tumor diagnosis, wherein the folic acid composite folic acid, the polyethyleneglycol, functional oligomerized polylysine and a plurality of DTPA are connected in a covalent bond mode. After applying the folic acid composite to animal nuclear magnetic resonance or radioactive video picture diagnosis, experiment results show that the type of the composite is lead to lymphatic system without transmitting blood capillaries at tissue spaces, is dynamically concentrated and eliminated at lymph glands, combines with high-expressive tumor cells of folate receptors in a competitiveness mode, and presents excellent lymph guiding property and accumulative property of tumor locations. The invention can be effectively used for target diagnosis of tumors and metastatic tumors of the lymphatic system, and has high targeting property and high resolution of the tumor and lymphoma diagnosis.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy and relates to a folic acid compound used for tumor imaging diagnosis, in particular to a folic acid-polyethylene glycol compound which can be combined with imaging radionuclides for tumor diagnosis. Such substances can be effectively used in the targeted diagnosis of tumors and metastatic tumors of the lymphatic system. Background technique [0002] With the deterioration of the human living environment, there are more and more factors that induce cancer, and the incidence of cancer is on the rise. The main biological characteristics of cancer are invasion and metastasis. Once the tumor metastasizes, it will bring great benefits to the treatment. Therefore, the early diagnosis of tumor is of great significance, whether early diagnosis and treatment is the key to cure cancer. Therefore, early diagnosis of cancer is very important. [0003] Tumor metastasis is the main reason why most cancers are...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K49/06A61K49/12A61K51/00A61K51/06A61K103/10
Inventor 陆伟跃顾炳谢操刘敏朱建华
Owner FUDAN UNIV
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