CN103497235B - Small molecular peptide probe and preparation method and application thereof - Google Patents
Small molecular peptide probe and preparation method and application thereof Download PDFInfo
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- CN103497235B CN103497235B CN201310302559.5A CN201310302559A CN103497235B CN 103497235 B CN103497235 B CN 103497235B CN 201310302559 A CN201310302559 A CN 201310302559A CN 103497235 B CN103497235 B CN 103497235B
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Abstract
The invention discloses a small molecular peptide probe and a preparation method and an application thereof. The small molecular peptide WAVGHLM of the invention can be specifically bound with lung cancer cells, providing a new method for specific diagnosis and treatment of lung cancer. The small molecular peptide is marked with an auxiliary group of 18F-NFP to obtain the small molecular peptide probe of 18F-FP-WAVGHLM marked with radioisotope 18F. The probe has good targeting to lung adenocarcinoma LTEP-a-2 in vivo, has better imaging effect than 18F-FDG, has long imaging maintenance time, and thus can be used for preparation of diagnostic imaging agents for lung cancer, early diagnosis of lung cancer and tumor, and monitoring of tumor treatment effect.
Description
Technical field
The invention belongs to field of biomedicine technology, particularly a kind of Small molecular peptide probe and its preparation method and application.
Background technology
As everyone knows, pulmonary carcinoma is the malignant tumor that mortality rate is the highest in the world, reaches 135.2 ten thousand according to World Health Organization's annual new cases of the statistical result showed of 2005, and it is 96.5 ten thousand examples that male falls ill every year, and women is 38.7 ten thousand examples.Lung cancer in China sickness rate in 2008, male is 49.0/10 ten thousand, and women is 22.9/10 ten thousand.Britain oncologist R.Peto foretells: if China controls smoking and air pollution not in time, more than 1,000,000, will become the first in the world pulmonary carcinoma big country to the annual lung cancer morbidity number of China in 2025.Pulmonary carcinoma onset is hidden, and still lacking effective examination and method of early diagnosis both at home and abroad at present, has been middle and advanced stage when making a definite diagnosis.The current diagnostic method of pulmonary carcinoma comprises expectorative cytology inspection, chest x-ray, CT, bronchoscope, B ultrasonic or CT Guided Percutaneous Transthoracic Biopsy, pulmonary function, cardiac work up, the scanography at the positions such as liver, spleen, bone brain, exploratory thoracotomy or thoracoscopic operation etc.Due to the appearance of PET-CT, the especially appearance of small animal position emission tomography (PET), provide effective technology platform, and this diagnosis being pulmonary carcinoma provides sensitiveer, accurate, special method for we find the specific developer of pulmonary carcinoma.Small animal position emission tomography (PET) is the tomography device being specifically designed to toy grown up based on PET clinical diagnosis technology, has volume little, compact conformation, superelevation spatial resolution, can carry out accurate PET video picture to toy.Be used frequently to now in biologic pharmacological science research, such as metabolic imaging, tumor imaging, gene expression video picture, the aspect such as rii receptor and drug research.
Molecular probe is the key factor of molecular imaging, and be also the prerequisite of molecular imaging research, PET and molecular biological combination, developer molecule image probe is feasible, also holds out broad prospects.The monoclonal antibody fragment, human mouse chimeric antibody, the bioactive substance of gene recombinaton, micromolecular biological polypeptide, antisense oligonucleotide etc. of radioisotope labeling have all entered Small-molecule probe research field.Small-molecule probe, relative to macromole antibody probe, has molecular weight little, and penetration into tissue is good, more easily reach target cell, non-immunogenicity, can synthesize in enormous quantities, be easy to the features such as labelling, therefore, Small-molecule probe comparatively macromole probe has better potential applicability in clinical practice.
18f-fluorodeoxyglucose (
18f-FDG) be a kind of carbohydrate metabolism type PET developer the most frequently used at present, it is successfully applied to clinical each side, as the malignant and benign lesion of tumor, the grade malignancy evaluating tumor and oncotherapy effect monitoring etc.But
18also there is poor specificity, some tumor cell and not absorb it and inflammatory cell also has the problems such as picked-up in F-FDG, thus causes and there will be certain false positive or false negative result to the Differential Diagnosis of tumor.
Gastrin-releasing peptide precursor is the front body structure of gastrin releasing peptide (gastrin-releasing peptide, GRP).McDonald etc. separated GRP in 1978 from the non-hole portion gastric epithelial cell of pig, and GRP is mammiferous Magainin analog, is present in normal brain, the nerve fiber of gastrointestinal and the neuroendocrine tissue of Fetal Lung.Mankind GRP gene encoding production is the parent (preproGRP) of 148 amino acid whose gastrin-releasing peptide precursors, be made up of signal peptide, GRP1-27 and C-end GRP31-125, then preproGRP changes into Pro-GRP1-125, generate ripe GRP1-27, GRP18-27 and C-terminal extension peptide by endogenous protein decomposition and amidatioon, C-terminal extension peptide continues generation and contains C-end ProGRP molecule.Existing research confirms, GRP and the ProGRP that the tumor cell of relapsed small cell lung cancer (SCLC) patient produces is proportionate.The present invention is devoted to research and develop a kind of high specific Small-molecule probe being applicable to pulmonary carcinoma.
Summary of the invention
The object of this invention is to provide a kind of can with the small-molecular peptides of lung carcinoma cell specific binding.
Another object of the present invention is to provide a kind of specific small molecule peptide probes and preparation method thereof being applicable to the diagnosis of pulmonary carcinoma molecular image.
Another object of the present invention is to provide the application of above-mentioned Small molecular peptide probe in preparation pulmonary carcinoma molecular image diagnostic reagent.
The technical solution used in the present invention is:
A kind of small-molecular peptides, its aminoacid sequence is WAVGHLM(SEQ ID NO.1).
A kind of Small molecular peptide probe, obtained by labelled with radioisotope small-molecular peptides, the aminoacid sequence of described small-molecular peptides is WAVGHLM(SEQ ID NO.1).
Preferably, described radiosiotope is
18f.
The application of above-mentioned Small molecular peptide probe in preparation pulmonary carcinoma molecular image diagnostic reagent.
The invention has the beneficial effects as follows:
Micromolecule Toplink of the present invention and lung carcinoma cell specific binding, for the specific diagnosis of pulmonary carcinoma and treatment provide new method.
The present invention's auxiliary group
18f-NFP labelling small-molecular peptides, obtains radiosiotope
18the Small molecular peptide probe of F labelling
18f-FP-WAVGHLM, this probe has good targeting to adenocarcinoma of lung LTEP-a-2 in vivo, and imaging results is better than
18f-FDG, video picture is held time length, and therefore, this probe can be used for the diagnosing developing agent preparing pulmonary carcinoma, carries out early diagnosis and the monitoring oncotherapy curative effect of lung cancer tumor.
Accompanying drawing explanation
Fig. 1 is the HPLC figure of small-molecular peptides WAVGHLM;
Fig. 2 is the mass spectrum of small-molecular peptides WAVGHLM;
Fig. 3 is Small molecular peptide probe
18the radiochemicsl purity testing result figure of F-FP-WAVGHLM;
Fig. 4 is the HE coloration result figure of lung adenocarcinoma cell LTEP-a-2 tumor;
Fig. 5 is nude mice model injection
18the PET figure of different time sections after F-FP-WAVGHLM;
Fig. 6 is nude mice model injection
18the PET figure of 60min after F-FDG;
Fig. 7 is nude mice model injection
18the ROI value change histogram of different time sections after F-FP-WAVGHLM.
Detailed description of the invention
A kind of small-molecular peptides, its aminoacid sequence is WAVGHLM(SEQ ID NO.1).
A kind of Small molecular peptide probe, obtained by labelled with radioisotope small-molecular peptides, the aminoacid sequence of described small-molecular peptides is WAVGHLM(SEQ ID NO.1).Preferably, described radiosiotope is
18f.
The preparation method of Small molecular peptide probe, comprises the following steps:
1) with containing K
222and K
2cO
3acetonitrile solution drip washing
18f
-the QMA post of enrichment, obtain leacheate, nitrogen dries up; Then successively with 2 bromopropionic acid ethyl ester, potassium hydroxide, two (p-nitrophenyl) carbonate reaction, after cooling, add acetic acid aqueous solution, through half preparative HPLC detached dowel eluting, obtain
18f acetylated precursor 4-Nitrobenzol-2-
18f-propionic ester, for
18f-NFP;
2) will
18f-NFP and small-molecular peptides WAVGHLM(SEQ ID NO.1) coupling, obtain Small molecular peptide probe
18f-FP-WAVGHLM.
Preferably, step 2) comprising: step 1) is obtained
18the aqueous solution dilution of F-NFP trifluoroacetic acid, by Oasis HLB post, will
18f-NFP is adsorbed on post, washes with water, after drying up, then uses absolute ether eluting
18f-NFP, and dewater further through anhydrous sodium sulfate post; After drying up absolute ether with nitrogen, add diisopropyl ethyl amine and the small-molecular peptides WAVGHLM(SEQ ID NO.1 being dissolved in dimethyl sulfoxide), after reacting 8min at 40 DEG C, add acetic acid aqueous solution dilution, by C18 post, washing, eluting, dry up after, add water wiring solution-forming, cross microporous filter membrane, obtain Small molecular peptide probe
18f-FP-WAVGHLM.
Set forth content of the present invention further below in conjunction with embodiment, but be not limited to this.
Main agents used and equipment in embodiment: CTC-resin(Tianjin Nankai is biological); N, N-DIC (DIC) (U.S. Alfa Aesar); DIPEA (DIPEA) (U.S. Alfa Aesar); 2 bromopropionic acid ethyl ester; NPC(Sigma, the U.S.); K
222(ABX, the U.S.); 1640 culture medium (U.S. Gibco); Trypsin U.S. Gibco); Hyclone (U.S. Gibco); Shanghai cell institute of the Lu-csf-1 LTEP-a-2(Chinese Academy of Sciences); Cell superclean bench (Suzhou purification); CO
2incubator (U.S. Thermo); Fluorine multifunctional chemistry synthesis module PET-MF-2V-IT-I(sends in Beijing special biological company limited, China); Agilent 1200 type analysis type high-efficient liquid phase analysis instrument (Agilent, the U.S.); High performance liquid chroma-tography radiacmeter (Bioscan, the U.S.); Cyclone10/5 cyclotron (IBA, Belgium); Micro PET (Siemens, Germany); Sep Pak QMA, Sep Pak HLB, Sep Pak C18 (Water, the U.S.) etc.
embodiment 1
1, small-molecular peptides WAVGHLM(SEQ ID NO.1) synthesis:
Adopt solid-phase synthesis, polypeptide is held growth from C to N, until reach required peptide chain length.Finally slough protecting group, the ester bond between hydrolysis peptide chain and solid phase carrier, through purification, obtains required polypeptide.Concrete steps are as follows:
1) get 6gCTC resin in Solid phase peptide synthssis bottle, dimethyl formamide (DMF) swelling 20min, drains, and takes off Fmoc, drain with 20% piperidines/DMF, and DMF washes 6 times, 1min/ time, drains;
2) DIC of the methionine being equivalent to resin 3 times of equivalents, the I-hydroxybenzotriazole (HOBT) of 4.5 times of equivalents, 6 times of equivalents is taken, add after mixing in resin, blistering reaction 3h, whether complete with 5% 1,2,3-indantrione monohydrate test reaction, DMF washs, drain, 20% piperidines/DMF takes off Fmoc, drains, and DMF washes 6 times, 1min/ time, drain;
3) 2 are repeated), until on aminoacid is all connected;
4) preparation is equivalent to the lysate (TFA/TIS/H of dry resin 10 times of equivalents
2o=95/2.5/2.5), mix in flask, ice bath, magnetic agitation, when being stabilized in about 5 DEG C to solution temperature, slowly resin is added, ice bath is removed after continuing ice bath 5min, stirred at ambient temperature reaction 3h, reactant liquor is drained, and with the trifluoroacetic acid being equivalent to resin 3 times of equivalents (TFA) washing resin 3 times, drain, retain filtrate, 40 DEG C of concentrated by rotary evaporation filtrates, to about 30mL, concentrated solution is poured in the diisopropyl ether that ice bath crosses, now adularescent Precipitation, all reactants are moved into centrifuge bottle, 3500rpm, 3min is centrifugal, abandoning supernatant, diisopropyl ether washs, recentrifuge, so repeatedly until supernatant pH is greater than 4, nitrogen dries up, weigh, through high performance liquid chromatograph purification, obtain small-molecular peptides object product.Adopt the object product of HPLC to synthesis to measure, its purity is about 95%(and sees Fig. 1).Carry out LC-MS qualification to object product, its mass spectrum as shown in Figure 2.
Small-molecular peptides WAVGHLM(SEQ ID NO.1) there is following structure:
。
2, Small molecular peptide probe
18the synthesis of F-FP-WAVGHLM:
18f labeling polypeptide mainly contains direct labelling and indirect labelling two kinds of mark modes, and in indirect labelling mode.Wherein, Indirect Labelling has
18f-acylation reaction,
18the reaction of F-amidation process, sulfydryl, oximation reaction etc.
18f-SFB is first and is really used for labeling polypeptide compounds
18f precursor, and be used for labelling neurotensin (NT), RGD, annexin V etc.Except
18outside F-SFB, conventional carboxyl class
18f acetylated precursor also has 4-nitrophenyl-2-
18f-fluoropropionate(4-Nitrobenzol-2-[
18f] propionic ester,
18f-NFP), N-succinimidyl-4-
18f-(fluoromethyl)-Benzoate (
18f-SFMB).In fact, in labeling polypeptide and polypeptide hormone
18f-NFP ratio
18f-SFB is better, has higher metabolic stability in vivo, and has less fluorine mark group, less to the characteristics influence of polypeptide itself.Therefore the present invention selects
18f-NFP precursor markers small-molecular peptides.
Labelling route is as follows:
。
Concrete steps are as follows:
Spread out of from accelerator
18f
-be attracted on SEP-PAK QMA post, use K
222(12 mg are dissolved in 0.9mL acetonitrile) and K
2cO
3under (2.7 mg are dissolved in the water of 0.1 mL) mixed solution drip washing
18f
-.Mixed solution dries up with nitrogen at 116 DEG C, then to add under acetonitrile (1.5mL) similarity condition evaporate to dryness again and dewater.Then add 2 bromopropionic acid ethyl ester solution (5mg/1mL acetonitrile), at 100 DEG C, react 10min, after cooling reaction bulb, add potassium hydroxide solution (0.2mol/L, 0.2mL), continue 100 DEG C of reaction 10min.The solvent of evaporate to dryness reactant liquor at 100 DEG C, adds two (p-nitrophenyl) carbonic ester (30mg is dissolved in 1mL acetonitrile), cools after reacting 10min at 100 DEG C in residual solids, adds the acetic acid solution (1mL) of 5%.Mixed reaction solution is expelled on half preparative HPLC detached dowel, and HPLC column is anti-phase C
18post (5 μm, 4.6 × 150 mm), with A (0.1% TFA/H
2o) and the ratio of B (0.1% TFA/MeCN) 45:55 be mobile phase isocratic elution, flow velocity is 4 mL/min, and determined wavelength is 254nm.
Collection obtains
18the aqueous solution (40mL) of F-NFP containing 0.1% trifluoroacetic acid dilutes, then by Oasis HLB post, and radioactivity
18f-NFP is attracted on Oasis HLB post, and uses 1mL water washing, dries up, with absolute ether under eluting Oasis HLB post
18f-NFP also dewaters further through anhydrous sodium sulfate post.After at room temperature drying up absolute ether with nitrogen, add diisopropyl ethyl amine (60 μ L) and WAVGHLM(0.1mg is dissolved in 0.2mL DMSO solution), after reacting 8min at 40 DEG C, add acetic acid aqueous solution (0.7mL) and the water (10mL) of 5%.Reactant liquor after dilution by C18 post, and with water (10mL) washing, then under using ethanol (1mL) eluting, 40 DEG C dry up ethanol after to add water wiring solution-forming, obtain after mistake microporous filter membrane
18f-FP-WAVGHLM probe.
3, radiochemicsl purity detects:
Radiochemical purity is detected, anti-phase C18 post (4.6 × 150 mm, 5 μm with radioactivity high-efficient liquid phase analysis; Agilent), mobile phase is A (0.1% TFA/H
2o) and B (0.1% TFA/MeCN) gradient elution, flow velocity is 1mL/min, and determined wavelength is 210nm.Gradient program is the A gradient elution 8min of A to 90% of 98%, the A of the 20% A gradient elution 25min to 80%.Result as shown in Figure 3.
embodiment 2
Laboratory animal: healthy Balb-c nude mice (4-5 age in week, body weight 18-22g male femalely not to limit) purchased from Zhongshan University's animal center, the quality certification number: SCXK(Guangdong) 2011-0029.Zoopery is by the approval of Ethics Committee of school.
Independent ventilation systems (IVC) facility of animal feeding in SPF level laboratory animal room.Group support, freely drinks water, takes food, and laboratory temperature is 20 ~ 25 DEG C, and humidity is 40 ~ 70%.Animal housing's condition remains stable, ensures the reliability of experimental result.
1) foundation of cell culture and animal model:
Human lung adenocarcinoma cell line LTEP-a-2 is inoculated in interpolation 100 IU/ml penicillin, 100 μ g/ml streptomycins containing 10% serum 1640 culture medium in, containing 5% CO
2place in 37 DEG C of constant incubators and cultivate, every other day change liquid once.Get be in exponential phase cell with trypsinization, the centrifugal 90s of 1000rpm, removes supernatant, and with serum-free 1640 culture medium re-suspended cell, cell counting count board counts and adjusts cell density and is about 1 × 10
7individual/ml, axil subcutaneous vaccination before nude mice, 0.2ml/ only.After about 10 days, diameter of tumor grows to about 5 × 5mm, without festering, in good condition, and utilizes HE dyeing to confirm that (see figure 4) is set up in the success of tumor model, can be used for test.
2) toy video picture:
By diagnostic reagent---Small molecular peptide probe prepared by normal saline dilution embodiment 1
18f-FP-WAVGHLM, get in lotus human lung adenocarcinoma LTEP-a-2 nude mouse that 150 μ Ci are set up by tail vein injection step 1), isoflurane inhalation anesthesia tumor bearing nude mice, put on small animal position emission tomography (PET) bed board, continue isoflurane inhalation anesthesia, and pass into oxygen, adhesive tape is fixed, location, carries out whole body PET/CT scanning at once, the scanogram (Fig. 5) of record 30min, 60min, 90min, 120min.As seen from Figure 5, along with the growth of time, the radioactive probe of tumor uptake is more and more higher.Show thus,
18f-FP-WAVGHLM is along with the growth of time, and what be combined with the polypeptide receptor of tumor locus is more and more, is optimum time of developing (white arrow sensing tumor locus) during 120min.
Fig. 6 is the injection of lotus human lung adenocarcinoma LTEP-a-2 nude mice model
18the video picture figure of 60min after F-FDG, clearly finds out that FDG is mainly accumulated in thoracic cavity with bladder position, and that accumulates in tumor is also few.
Fig. 7 is the injection of lotus human lung adenocarcinoma LTEP-a-2 nude mice model
18the change histogram of the ROI value of F-FP-WAVGHLM, visible radioactive probe in tumor along with the prolongation of time assemble more, fewer and feweri in muscle, brain, liver and heart.And the radioactivity in liver, heart is about 2 times of muscle, is greater than 2 times in tumor; Its picked-up in tumor is the highest, close with muscle in brain, shows
18f-FP-WAVGHLM is not easily through blood brain barrier, less to central nervous system effects, is applicable to the diagnosing developing agent being developed as pulmonary carcinoma, can not as the diagnostic reagent of brain diseases.During 120min, the radioactivity of tumor is obviously very high, and being about 3 times of muscle, is the best visualization time.
The present invention with auxiliary group [
18f] GRP polypeptide WAVGHLM nitrogen position that NFP labelling utilizes solid-phase synthesis to synthesize, obtain nitrogen position 2-
18the polypeptide probe of F-propiono labelling---
18f-FP-WAVGHLM, this probe has good targeting to adenocarcinoma of lung LTEP-a-2, and imaging results is better than
18f-FDG, video picture is held time longer, and the radioactivity of brain is more weak, is unsuitable for the video picture of brain diseases.Therefore, the present invention designs
18f-FP-WAVGHLM molecular probe may become the developer of good adenocarcinoma of lung and even various pulmonary carcinoma future.
<110> Guangdong Pharmaceutical University
<120> Small molecular peptide probe and its preparation method and application
<130>
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 7
<212> PRT
<213> artificial sequence
<400> 1
Trp Ala Val Gly His Leu Met
1 5
Claims (1)
1.
18the application of Small molecular peptide probe in preparation pulmonary carcinoma molecular image diagnostic reagent of F labelling, the aminoacid sequence of described Small molecular peptide probe is as shown in SEQ ID NO.1, and described pulmonary carcinoma is adenocarcinoma of lung.
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