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Polypeptide for targeting combination with PSMA extracellular domain and application of polypeptide

A targeted, extramembranous region technology, applied in the medical field, can solve the problems of poor prognosis and high mortality of PCa, and achieve good results

Inactive Publication Date: 2015-03-25
NANJING FIRST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Untreated PCa cells are mostly androgen-dependent, that is, blocking androgen promotes the apoptosis of androgen-dependent cancer cells, but after a period of endocrine therapy (average 14-30 months) androgen-dependent PCa, most Most of them turn into hormone-independent prostate cancer (AIPC), and eventually into hormone-refractory prostate cancer (Hormone refractory prostate cancer, HRPC). Currently, there is no effective treatment for HRPC and its metastases. Clinically referred to as refractory prostate cancer, it is the main cause of poor prognosis and high mortality in PCa

Method used

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  • Polypeptide for targeting combination with PSMA extracellular domain and application of polypeptide
  • Polypeptide for targeting combination with PSMA extracellular domain and application of polypeptide
  • Polypeptide for targeting combination with PSMA extracellular domain and application of polypeptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1. Synthesis and quality control of polypeptide DOTA-PTP

[0033] 1. Synthesis of linear polypeptide PTP by solid-phase method and coupling with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)

[0034] ① Polypeptides are synthesized from the C-terminus to the N-terminus. First, hang the first amino acid on the resin, weigh 2.0g of the resin into a clean and dry reaction tube, add an appropriate amount of dimethylformamide (DMF), activate it for about 30 minutes, and then Weigh the first amino acid Fmoc-Ser(But)-OH 0.5mmol, 4-dimethylaminopyridine (DMAP) 75mg, N,N'-diisopropylcarbodiimide (DIC) 1ml into the reaction tube , DMF as a solvent reaction for 3h. After the reaction, wash with DMF for 4 to 6 times, add appropriate amount of pyridine and methanol, the volume ratio is 1:1, and react for 30 minutes. After the reaction, wash with DMF 4 to 6 times. Then use piperidine solution to remove the Fmoc of amino acid, remove twice for a total of 15min, 10m...

Embodiment 2

[0056] Example 2: 68 Preparation of Ga-DOTA-PTP and its in vivo and in vitro experiments

[0057] one, 68 Preparation of Ga-DOTA-PTP

[0058] Configure DOTA-PTP polypeptide solution as 2mg / ml, HEPES as 1M (pH: 7), 68 GaCl 3 1-10mCi / ml.

[0059] Take 25 μl of HEPES solution (a non-ionic amphoteric buffer, composed of 4-hydroxyethylpiperazineethanesulfonic acid, distilled water and sodium hydroxide) (concentration 1M), and add 0.7-5 μl DOTA-PTP polypeptide solution in sequence ( 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-PTP.

[0060] two, 68 Ga-DOTA-PTP in vitro experiment

[0061] 68 After Ga-DOTA-PTP was synthesized, it was detected by radioactive-HPLC. The method and parameters were the same as before, and the results showed that 68 The HPLC peak of Ga-DOTA-PTP and the radioactive peak appear at the same time, see image 3 and 4 , radiochemically pure (98.4 ±...

Embodiment 3

[0072] Example 3: 64 Preparation of Cu-DOTA-PTP and its in vivo and in vitro experiments

[0073] In addition to radionuclides for 64 CuCl 2 Outside, all the other are with embodiment 2.

[0074] Result 1: 64 The radiochemical purity of Cu-DOTA-PTP was (98.3±1.31%), and it was incubated in normal saline at 37°C. After 2 hours, 4 hours, and 6 hours, 20ul were taken for HPLC inspection, 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±0.76%) at 6 hours.

[0075] Result 2: Prostate cancer tumor-bearing mice 64Cu-DOTA-PTP after tail vein injection, the biological distribution in vivo and 68 Ga-DOTA-PTP is similar, and the main reason is that the biological distribution characteristics in the body mainly depend on DOTA-PTP, which is mainly excreted through the liver and kidney, and cleared quickly. After 60 minutes, the radioactivity uptake in the liver and kidneys can be significantly red...

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Abstract

The invention belongs to the field of medicine, and discloses a polypeptide for targeting combination with a PSMA (Prostate Specific Membrane Antigen) extracellular domain and application of the polypeptide. The amino acid sequence of the polypeptide is as shown in SEQ ID No:1. The polypeptide is marked by radionuclide mediated by a coupling agent, and can be used for preparing a targeting drug for treating or diagnosing prostatic cancer.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a polypeptide targetedly combined with the outer region of PSMA and its application. Background technique [0002] Prostate cancer (PCa) has become the main malignant tumor that endangers the health of men around the world. In the early stage, surgery and radiotherapy are mainly used, but early detection is difficult, and most of them have metastasized to distant places when they go to the doctor. Untreated PCa cells are mostly androgen-dependent, that is, blocking androgen promotes the apoptosis of androgen-dependent cancer cells, but after a period of endocrine therapy (average 14-30 months) androgen-dependent PCa, most Most of them turn into hormone-independent prostate cancer (AIPC), and eventually into hormone-refractory prostate cancer (Hormone refractory prostate cancer, HRPC). Currently, there is no effective treatment for HRPC and its metastases. Clinically referred to as refracto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/13A61K47/42A61K51/08A61P35/00
Inventor 邵国强王自正刘现忠贾瑞鹏梁凯曹红勇刘子君洪灵芝
Owner NANJING FIRST HOSPITAL
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