CN101985483A - Iodinated PRTH, and preparation method and application thereof - Google Patents
Iodinated PRTH, and preparation method and application thereof Download PDFInfo
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- CN101985483A CN101985483A CN 201010198151 CN201010198151A CN101985483A CN 101985483 A CN101985483 A CN 101985483A CN 201010198151 CN201010198151 CN 201010198151 CN 201010198151 A CN201010198151 A CN 201010198151A CN 101985483 A CN101985483 A CN 101985483A
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Abstract
The invention discloses iodinated pituitary resistance to thyroid hormone (PRTH), and a preparation method and application thereof, relates to a tumor/cancer diagnosis and treatment reagent, and belongs to the field of medicine and pharmacology. By combining nanotechnology and molecular nuclear medicine, the PRTH is iodinated; and the enhanced permeability and retention (EPR) effect of the PRTH is used for early diagnosis and early treatment of tumor/cancer. The iodinated PRTH has the advantages of simple preparation process, stable marker, safety, no toxicity and good targeting of the tumor/cancer.
Description
Technical field
The present invention relates to a kind of lesion/cancer disease diagnosis, treatment reagent, its preparation method and application belong to the medicine and pharmacology field.
Background technology
Tumour is one of disease of serious harm human health.Annual about 6,000,000 people in the whole world die from malignant tumour, and are every year and increase progressively trend.The non-operative treatment of tumour comprises radiation and chemotherapy, is purpose with the kill tumor cell, but all lacks the specificity to tumour cell.The targeted therapy of tumour is that therapeutic action is optionally concentrated on tumor tissues, tumour cell, oncogene, can reduce to minimum to the untoward reaction of healthy tissues.
Molecular nuclear medicine carries out the live body tomography by advanced persons' such as SPECT, PET, MicroPET, SPECT/CT, PET/CT, MicroPET/CT molecular imaging apparatus to the human or animal, can on molecular level, realize the live body of biological organism physiology, pathological change, real-time, dynamic, noninvasive three-dimensional imaging, have high specific, highly sensitive and high resolving power.For providing information, research specific gene function, biology growing growth, disease development and drug effect effect assessment and pharmacokinetics etc. obtain effective means with analyzing and processing.
Interior radio nuclide therapy method is the characteristic of tumour nuclear medicine, and its action principle is to utilize radiopharmaceuticals that nucleic is passed to diseased tissue.
131I is by the treatment radiopharmaceutical agent of widespread use, and for being used for the treatment of thyroid carcinoma and hyperthyroidism;
123I and
124I is respectively applied for SPECT and PET video picture.
The early diagnosis and therapy that appears as tumour of nanotechnology has brought new hope.Nano material is because its unique physics and chemical property, surface effects, the high surface that micro-dimension effect, quantum effect and structure thereof had, unique photoelectric property, special surface effect and volume effect etc. have broad application prospects it in the research in fields such as environment, biology, medical science.It is modern science (engineering science, biology, physics and chemistry etc.) and modern technologies (microtronics technology, computer technology, high resolution microtechnique, nuclear analytical technology etc.) bonded product.Made a breakthrough at aspects such as the diagnosis of disease and treatments in conjunction with the nanosecond medical science that forms by nanotechnology and medical science, shown powerful growth momentum.
University Of Suzhou discloses a kind of nano-high molecule polymer P RTH, and its structural formula is as follows:
It is the high molecular polymer that has fluorophor and tyrosine group simultaneously, and this polymkeric substance has better biocompatibility, non-immunogenicity, and can modify structure according to different application targets, makes corresponding nanoparticle.Because the rate of permeation that the lymphokinesis of tumor locus is more normally organized is low, in a single day nanometer polymer enters, be difficult to leave by lymphokinesis, but tendency is stranded in tumour cell, be called " strengthen and see through retention effect (the enhanced permeability andretention effect, EPR effect) ".After the mode with intravenously administrable was injected into nanoparticle, nanoparticle can overflow from tumour is misunderstanded each other the endothelial tissue blood vessel that leaks and be trapped in the tumour, thus the retention time of prolong drug in tumour.Utilize the EPR effect, adopt the PRTH nanoparticle can be, thereby reduce side effect, the concentration of raising medicine in tumour chemotherapy and radiotherapy drug targeting tumor tissues.
Summary of the invention
The technical problem to be solved in the present invention is the defective that overcomes existing lesion/cancer disease diagnosis and treatment, treatment technology, and nanotechnology is combined with molecular nuclear medicine, and PRTH is carried out structure of modification, utilizes its EPR effect, is used for the early diagnosis and the treatment of lesion/cancer disease.
In order to solve the problems of the technologies described above, the invention provides following technical scheme:
A kind of I
*-PRTH, for having the compound of following general structure:
In the formula, iodine I
*The expression radionuclide
123I,
124I,
125I,
131Among the I any; 0＜x＜2,3≤y≤4,300≤z≤400.
Above-mentioned I
*The preparation method of-PRTH adopts oxidation style to carry out radioiodination PRTH, and it comprises the steps:
(1) in phosphate buffer, with PRTH and an amount of NaI
*And oxygenant is 10-50 ℃ of vibration mixing down;
(2) add the excessive reductant termination reaction;
(3) reactant uses column chromatography purifying;
In the step (1), the NaI of 20 μ g PRTH and 0.05-10mCi
*Reaction; Described oxygenant is a kind of among chloramine-T, hydrogen peroxide or the Iodogen;
The described reductive agent of step (2) is a kind of in Sulfothiorine, the Sodium Metabisulfite;
The described column chromatography material of step (3) comprises that Sephadex G-10 is to G-100.
Iodate is usually used in mark peptide class, protein and enzyme etc., and its principle is to adopt chemistry or enzymatic oxidn reaction directly will
125I etc. are incorporated into and are labeled in the thing molecule on tyrosine residues or the histamine residue.
With chloramine-T (ch-T) method be example illustrate its iodate principle: ch-T be to toluene sulfo group acid amides N-chlorine derivative sodium salt, in water, easily resolve into the hypochlorous acid of tool oxidisability, it can with
125I
-Be oxidized to positively charged
125I
+, the latter can replace two hydrogen atoms that are labeled in the thing molecule hydroxyl neck position on the tyrosine residues phenyl ring, makes protein or polypeptide by iodate, but adds reductive agent Sodium Metabisulfite stopped reaction.Its iodination reaction process is as follows:
The Ch-T oxidation:
The tyrosine residues mark:
Above-mentioned I
*-PRTH is as the application of lesion/cancer disease diagnosis, medicine, especially as the diagnosis of mammary cancer, liver cancer, lung cancer, thyroid carcinoma, lymphoma, melanoma or intestinal canal tumour, the application of therapeutical agent, or as the application of SPECT or PET diagnostic reagent.Particularly,
123I-PRTH can be used for lesion/cancer disease SPECT video picture,
124I-PRTH can be used for lesion/cancer disease PET video picture,
131I-PRTH both can be used for the SPECT video picture of lesion/cancer disease, can be used for the target radiotherapy of lesion/cancer disease again.
The advantage of the technology of the present invention is:
(1) preparation technology is simple, and marker is stable, is convenient to the further application of clinical, scientific research and drug development;
(2) I
*-PRTH safety non-toxic, good to the target of lesion/cancer disease, have a good application prospect.
Embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for description and interpretation the present invention, and be not used in qualification the present invention.
Embodiment 1
1, I
*The preparation of-PRTH:
10 μ l PRTH (2mg/ml) add 7 μ l NaI
*(0.05-10mCi), 20 μ l 0.2mol/L PB (pH8.0), 10 μ l chloramine-Ts (3mg/ml), vortex vibration 30-60s adds 20 μ l Sodium Metabisulfites (6mg/ml), vortex vibration 2-5min termination reaction.The 0.02mol/L PBS (pH7.2 contains 0.3%BSA) that adds 20 μ l in the reaction solution is added to the PD-10 post with 0.02mol/L PBS (pH7.2 contains 0.3%BSA) pre-equilibration behind the mixing, above-mentioned buffer solution elution, and 1ml/min, every pipe 0.5ml collects.
2, I
*The evaluation of-PRTH
Adopt thin-layer chromatography and phosphorus screen imaging system to measure:
(1) thin-layer chromatography: the polyamide 66 film is a upholder, and developping agent is 70% ethanol.Wait behind the point sample to launch to finish, polyamide layer is cut into 10 sections, γ-calculating instrument is measured each section radiocounting, I
*-PRTH marker is at the Rf=0.7-0.9 place, and impurity such as free-iodine are at Rf≤0.1 place.
(2) phosphorus screen imaging system: the polyamide 66 film is a upholder, and developping agent is 70% ethanol.Wait behind the point sample to launch to finish, polyamide layer is observed with phosphorus screen imaging system.The result shows: I
*-PRTH marker is at the Rf=0.7-0.9 place, and free-iodine is at Rf≤0.1 place.
3, I
*The cellular uptake of-PRTH
Collect normal liver cell L-02 and liver cancer cell 7402,10
6Individual/pipe, add
131I-PRTH, 37 ℃ of water-bath 1h, the centrifugal 10min of 2000rpm removes supernatant, and precipitation is surveyed cpm.The result shows: 7402 pairs of liver cancer cells
131The picked-up height of the picked-up L-02 cell of I-PRTH, explanation
131I-PRTH has target preferably to tumour cell.
4, I
*-PRTH SPECT video picture
Get HepA liver cancer model ICR mouse, intraperitoneal injection of ketamine is behind the anesthesia 10min, in tail vein injection 0.1-0.2mCi
125I-PRTH carried out the SPECT video picture after 20min, 40min, 1h, 2h, 18h, 26h, 50h hour.The result shows: tumor locus shows as high dense poly-, after 1 hour target this than being 5.98.
5, the cellular uptake of PRTH
Collect normal liver cell L-02, liver cancer cell 7402 and melanoma cell HT-144 cell, be taped against in 96 orifice plates 10
4Individual/hole, be positioned over 37 ℃, contain 5%CO
2Spend the night in the incubator.Every hole adds 100 μ g PRTH, washs the change in fluorescence of fluorescence microscope cell 3 times with 0.02mol/L PBS pH7.2 behind 37 ℃ of placement 30min.The result shows: the fluorescence in the normal liver cell L-02 very a little less than, and fluorescence intensity illustrates that apparently higher than normal liver cell PRTH has target picked-up preferably to tumour cell in liver cancer cell 7402 and the melanoma cell HT-144 cell.
It should be noted that at last: the above only is the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (5)
1. I
*-PRTH, for having the compound of following general structure:
In the formula, iodine I
*The expression radionuclide
123I,
124I,
125I,
131Among the I any; 0＜x＜2,3≤y≤4,300≤z≤400.
2. the preparation method of the described I*-PRTH of claim 1 adopts oxidation style to carry out radioiodination PRTH, and it comprises the steps:
(1) in phosphate buffer, with PRTH and an amount of NaI
*And oxygenant is 10-50 ℃ of vibration mixing down;
(2) add the excessive reductant termination reaction;
(3) reactant uses column chromatography purifying;
In the step (1), the NaI of 20 μ g PRTH and 0.05-10mCi
*Reaction; Described oxygenant is a kind of among chloramine-T, hydrogen peroxide or the Iodogen;
The described reductive agent of step (2) is a kind of in Sulfothiorine, the Sodium Metabisulfite;
The described column chromatography material of step (3) comprises that Sephadex G-10 is to G-100.
3. the described I of claim 1
*-PRTH is as the application of the diagnosis of lesion/cancer disease, medicine.
4. application according to claim 3 is characterized in that: described lesion/cancer disease is mammary cancer, liver cancer, lung cancer, thyroid carcinoma, lymphoma, melanoma or intestinal canal tumour.
5. application according to claim 3 is characterized in that: described I
*-PRTH is as the application of SPECT or PET diagnostic reagent.
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| CN 201010198151 CN101985483A (en) | 2010-06-11 | 2010-06-11 | Iodinated PRTH, and preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103383392A (en) * | 2012-05-02 | 2013-11-06 | 上海方恩医疗用品有限公司 | Novel iodine solution, preparation method of the novel iodine solution, and use of the novel iodine solution in human squamous epithelial cell mucosa and human squamous epithelial cell mucosa precancerosis staining diagnosis |
| CN105396148A (en) * | 2015-11-26 | 2016-03-16 | 江苏诚品生物科技有限公司 | Esophageal-mucosa staining combination set |
| CN107118198A (en) * | 2017-06-08 | 2017-09-01 | 福州大学 | Have rhodamine B derivative of antitumaous effect and fluorescence property and preparation method thereof concurrently |
| CN111303265A (en) * | 2020-03-24 | 2020-06-19 | 中奥生物医药技术(广州)有限公司 | One kind contains131I-labeled Caerin1.1 polypeptide and application thereof |
-
2010
- 2010-06-11 CN CN 201010198151 patent/CN101985483A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103383392A (en) * | 2012-05-02 | 2013-11-06 | 上海方恩医疗用品有限公司 | Novel iodine solution, preparation method of the novel iodine solution, and use of the novel iodine solution in human squamous epithelial cell mucosa and human squamous epithelial cell mucosa precancerosis staining diagnosis |
| CN105396148A (en) * | 2015-11-26 | 2016-03-16 | 江苏诚品生物科技有限公司 | Esophageal-mucosa staining combination set |
| CN107118198A (en) * | 2017-06-08 | 2017-09-01 | 福州大学 | Have rhodamine B derivative of antitumaous effect and fluorescence property and preparation method thereof concurrently |
| CN107118198B (en) * | 2017-06-08 | 2019-07-09 | 福州大学 | Have the rhodamine B derivative and preparation method thereof of antitumaous effect and fluorescence property concurrently |
| CN111303265A (en) * | 2020-03-24 | 2020-06-19 | 中奥生物医药技术(广州)有限公司 | One kind contains131I-labeled Caerin1.1 polypeptide and application thereof |
| CN111303265B (en) * | 2020-03-24 | 2020-10-02 | 中奥生物医药技术(广州)有限公司 | One kind contains131I-labeled Caerin1.1 polypeptide and application thereof |
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Open date: 20110316 |