Folic acid dimer compound combined with folate receptor targeting and application thereof

A technology of folic acid dimer and compound, which is applied in the medical field to achieve the effect of increasing concentration and good effect

Inactive Publication Date: 2015-08-05
NANJING FIRST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, there is no radionuclide-labeled folic acid dimer with high radioactive uptake in tumor sites on the market

Method used

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  • Folic acid dimer compound combined with folate receptor targeting and application thereof
  • Folic acid dimer compound combined with folate receptor targeting and application thereof
  • Folic acid dimer compound combined with folate receptor targeting and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] 1. DOTA-FA 2 Synthesis and quality control of:

[0063] 1. Synthesis of folic acid-NHS (succinimide) ester

[0064] (1) Weigh 440 mg of folic acid and dissolve it in 40 ml of DMSO, add EDC.HCl (1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride) 200 mg and react in an ice bath for 1 h;

[0065] (2) Weigh 120 mg of NHS and add it into the reaction system, and react overnight at room temperature after 1 h in ice bath;

[0066] (3) Filtrate, evaporate the organic solvent, wash with distilled water, centrifuge, freeze-dry for later use, marked as A.

[0067] 2. Solid Phase Synthesis of Folic Acid-Lys(DOTA)

[0068] (1) Weigh 1.0g wang resin (wang Resin Tianjin Nankai synthetic 1% DVB, 100-200mesh, 0.8-1.0mmol / g) into a clean and dry reaction tube, add appropriate amount of DMF, swell and activate for about 30min, then weigh The first amino acid Fmoc-Lys(Dde)-OH(N-fluorenylmethoxycarbonyl-N'-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl] -Lysine) 0.2mmol, DMAP...

Embodiment 2

[0095] Example 2: 68 Ga-DOTA-FA 2 Preparation and in vivo and in vitro experiments

[0096] one, 68 Ga-DOTA-FA 2 preparation of

[0097] Formulating DOTA-FA 2 The solution is 2mg / ml, HEPES is 1M (pH: 7), GaCl 3 1-10mCi / ml, take 25μl of 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) solution (concentration 1M, preparation method: dissolve 23.8g HEPES in about 90ml of water, adjust the pH to 6.8 to 8.2 with NaOH, Then dilute to 100ml with water), add 0.7-5μL DOTA-FA in turn 2 solution (2mg / ml) and 100μl of 68 GaCl 3 (radioactive concentration 1-10mCi / ml), placed in a water bath at 95°C and heated for 15-20min to obtain 68 Ga-DOTA-FA 2 . Take 20 μL for HPLC inspection, the parameters are the same as before, and the results are shown in image 3 .

[0098] image 3 show 68 Ga-DOTA-FA 2 As a result of HPLC examination, the radiochemical purity was 99.1%.

[0099] two, 68 Ga-DOTA-FA2 in vitro experiment

[0100] 68 After Ga-DOTA-FA2 was synthesized, it was d...

Embodiment 3

[0110] Example 3: 64 Cu-DOTA-FA 2 Preparation and in vivo and in vitro experiments

[0111] In addition to radionuclides for 64 CuCl 2 Outside, all the other are with embodiment 2.

[0112] Result 1: 64 Cu-DOTA-FA 2 The radiochemical purity of the drug label was (97.3±2.56%) immediately, and it was placed in saline in vitro and incubated at 37°C for 2h, 4h, and 6h, and then HPLC was performed to check its radiochemical purity to investigate its in vitro stability, and the results were not found. 64 The Cu free peak indicates that it has good stability in vitro, and its radiochemical purity is (96.5±1.62%) at 6 hours.

[0113] Result 2: Ovarian cancer tumor-bearing mice 64 Cu-DOTA-FA 2 After tail vein injection, the biological distribution in vivo and 68 Ga-DOTA-FA 2 Similarly, considering that the main reason is that the biological distribution characteristics in the body mainly depend on DOTA-FA 2 It is mainly excreted through the urinary system (kidney and bladder...

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Abstract

The invention belongs to the medical field and discloses folic acid dimer compound combined with folate receptor targeting and an application thereof. The compound is X2-Y-Z-A, wherein X2 is lysine and folic acid connecting dimer or lysine and folic acid derivative connecting dimer; Y is conjugate with (polyethylene glycol or polyethylene glycol derivative) m-lysine structure, and m is equal to 1, 2, 3, 4 or 5; Z is DOTA, NOTA, CB-TE2A, DTPA, NODAGA, the like substance or the derivative thereof; A is radionuclide, magnetic resonance imaging agent, chemical medicine or chemical medicine-loaded nano particle; the X, Y, Z and A are connected by covalent bond. The compound can be used for preparing tumor targeted imaging and treatment medicine, and the compound can effectively improve the gathering of the radionuclide in the tumor and metastasis thereof and improve the diagnosis efficiency and treatment effect.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a folic acid dimer complex targetedly combined with a folic acid receptor and an application thereof. Background technique [0002] Ovarian cancer is the malignant tumor with the highest fatality rate in women. Surgery combined with platinum and taxane chemotherapy is a common method at present. However, multiple drug resistance to ovarian cancer chemotherapy drugs is common, and the postoperative recurrence rate and lymphatic metastasis rate are high. There is no effective treatment, and the 5-year survival rate is less than 30%. [1] Finding new treatment methods to improve the curative effect and survival rate of ovarian cancer has become a clinical problem. [0003] Folate receptor (FR) is a glycosylphosphatidylinositol-coupled protein, mainly including α, β, γ and δ subtypes. Among them, FRα receptors can also be seen in low and moderate expression in normal tissues such as choroid pl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K51/06A61K51/04A61K49/12A61K31/337A61P35/00
Inventor 邵国强王自正王峰谢静燕汤翠菊樊宏伟徐友娣
Owner NANJING FIRST HOSPITAL
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