CN102641511A - Micromolecule lung cancer targeted radioactive therapeutic agent and preparation method thereof - Google Patents
Micromolecule lung cancer targeted radioactive therapeutic agent and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a micromolecule lung cancer targeted radioactive therapeutic agent. Isotope 131I is marked with eight-peptide molecules with XGXG structures, wherein G shows L glycine, and X shows optional one of 20 amino acids. The invention further discloses a preparation method of the micromolecule lung cancer targeted radioactive therapeutic agent. The micromolecule lung cancer targeted radioactive therapeutic agent has good stability and biological distribution characteristics, can obviously suppress growth of tumour in a human lung cancer nude mouse animal model body, does not have obvious toxic and side effects to vitals such as livers, kidneys, lungs, hearts and the like, is applicable to targeted therapy for patients suffering from non-small cell lung cancer (squamous carcinoma and glandular cancer), and has an important clinical application value in the aspect of molecule targeted treatment for lung cancer.
Description
Technical field
The invention belongs to field of biomedicine technology, be specifically related to a kind of micromolecular lung cancer targeting radiotherapy dose and preparation method thereof.
Background technology
The survey data of the whole nation anticancer association up-to-date announcement shows, pulmonary carcinoma has become the particularly the highest cancer of mortality rate among the urbanite of population of China, is seriously jeopardizing the health and the life of population of China.The main cause of the clinical prognosis difference of pulmonary carcinoma is to have belonged to when about 80% patients with lung cancer is made a definite diagnosis late period; Lost best operative treatment opportunity; This moment, chemotherapy and partial radiotherapy became main Therapeutic Method; But patients with lung cancer is prone to develop immunity to drugs to chemotherapeutics, and chemotherapy is bigger to the globality harm of health simultaneously, is in the pulmonary carcinoma patients with terminal usually because of tolerating the misery abandoning cure of chemotherapy; And radiotherapy is at present mainly as the palliative treatment means of pulmonary carcinoma, like alleviating pain and mitigation symptoms.Therefore, still not having the efficacious therapy method for most of advanced lung cancer patient, become the major obstacle that improves the patients with lung cancer survival rate, is that the pulmonary carcinoma clinical treatment is badly in need of one of emphasis problem that solves.
Molecular targeted agents because of can specific effect in lung carcinoma cell, and toxic reaction is lighter, demonstrates the development trend of good clinical application prospect and lung cancer therapy, for treating the advanced lung cancer patient new way is provided.But because molecular targeted agents such as Iressa, Te Luokai etc., the grace degree etc. used clinically at present; Or EGFR acceptor inhibitor; Or vegf receptor inhibitor; All need patient's life-time service and curative effect only effective to groups of people, the patient is also usually because of finally being difficult to pay great number expenses for medicine abandoning cure.The Iressa of domestic clinical use at present, because clinical trial fails to confirm that it has prolonged patient's life cycle, U.S. FDA strictness limits its clinical practice in the U.S..
With respect to molecular targeted agents, another kind of neoplasm targeted therapy method be radioimmunotherapy (radioimmunotherapy, RIT), along with the RIT agent
90Y-ibritumomabn (trade name Zevalin) and
131I-tositumoma (trade name Bexxar) has obtained significant curative effect in lymphadenomatous treatment, and has obtained the good economic benefit of nearly 1,000,000,000 U.S. dollars of annual sales amount, and RIT becomes another important neoplasm targeted therapy method after chemotherapy.
131I-chTNT (aestheticism is given birth to) is the agent of global first solid tumor RIT, and become continue Zevalin and Bexxar after three global RIT agent at China's official listing in January, 2007; The aestheticism life is the RIT agent that can be used as solid tumors such as pulmonary carcinoma, hepatocarcinoma and cerebroma, and clinical trial shows that the patient of advanced lung cancer has accepted the injection that aestheticism is given birth to, and total effective rate is 33%; But aestheticism is survived and is existed obvious defects, gives birth to the chimeric monoclonal antibody of people Mus because of aestheticism, contains certain Mus derived components; There is potential danger hypersensitive; Also exist macromole antibody simultaneously and be prone to be engulfed and be prone to cause non-specific aggregation, and because of molecular weight is big, penetration power is poor by reticuloendothelial system identification; In insoluble problems such as the inside tumor diffusion are restricted, all influenced its curative effect.
Summary of the invention
To existing deficiency in the prior art, an object of the present invention is to provide a kind of micromolecular lung cancer targeting radiotherapy dose, it is by therapeutic radioisotope labelling small-molecular peptides gained.
Another object of the present invention provides the method for preparing of above-mentioned micromolecular lung cancer targeting radiotherapy dose.
The technical scheme that the present invention adopted is:
A kind of micromolecular lung cancer targeting radiotherapy dose, by gained behind the therapeutic radioisotope labelling small-molecular peptides, said small-molecular peptides is 8 peptide molecules that contain the XGXG structure, and wherein, G representes L type glycine, and X is any in 20 aminoacid.
The aminoacid sequence of said small-molecular peptides is cNGEGQQc (SEQ ID NO:1), and wherein, c representes D type cysteine, and N representes L type agedoite, and G representes L type glycine, and E representes L type glutamic acid, and Q representes L type glutamine.
Said therapeutic radioisotope does
131I,
188Re,
90Among the Y any.
A kind of method for preparing of micromolecular lung cancer targeting radiotherapy dose comprises the steps:
1) the N end with small-molecular peptides connects upward tyrosine;
2) N-end is connected with the small-molecular peptides dissolving of tyrosine after, add therapeutic radioisotope, and then add chloramine-T, concussion reaction 2min is with sodium metabisulfite solution cessation reaction;
Said small-molecular peptides is 8 peptide molecules that contain the XGXG structure, and wherein, G representes L type glycine, and X is any in 20 aminoacid;
Said therapeutic radioisotope does
131I.
The aminoacid sequence of said small-molecular peptides is cNGEGQQc (SEQ ID NO:1), and wherein, c representes D type cysteine, and N representes L type agedoite, and G representes L type glycine, and E representes L type glutamic acid, and Q representes L type glutamine.
The concrete operations of step 1) are: mix small-molecular peptides and tyrosine; Add amino acid condensation agent EDC-HCI [1-ethyl-(3-dimethylaminopropyl) carbonization two amido hydrochlorates]; Reaction was carried out condensation with the amino (N) of small-molecular peptides end with the carboxyl of tyrosine and is connected after 2 hours under the room temperature.
Step 2) concrete operations are: N-holds the small-molecular peptides that is connected with tyrosine with 0.5M PBS (pH=7.4) dilution, treats that small-molecular peptides dissolves the back fully and adds
131I 37MBq/20 μ l, adding final concentration then is the chloramine-T of 0.9 μ g/ μ l, concussion reaction 2min is with 45 μ l (4 μ g/ μ l) sodium metabisulfite solution cessation reaction.
Beneficial effect of the present invention is:
The present invention utilizes therapeutic isotope labeling small-molecular peptides to prepare the agent of micromolecular lung cancer targeting radiation treatment; It has good stable property and bio distribution characteristic; Can obviously suppress growth of tumor in people's pulmonary carcinoma nude mice animal model; Vitals such as liver, kidney, lungs and heart are not had obvious toxic-side effects, be applicable to nonsmall-cell lung cancer (scale cancer and adenocarcinoma) patient's targeted therapy, have great clinical value aspect the molecular targeted treatment of pulmonary carcinoma.
Description of drawings
Fig. 1 is the mass spectral analysis figure of small-molecular peptides cNGEGQQc-Tyr.
Fig. 2 is that paper chromatography is measured
131The radiochemicsl purity figure of I labelling small-molecular peptides cNGEGQQc.
Fig. 3 is
131The HPLC analysis chart of I labelling tyrosine cNGEGQQc.
Fig. 4 is according to obtaining
131I-cNGEGQQc the intravital SPECT dynamic imaging of rabbit desire to make money or profit with ROI region of interest analytical technology obtain each internal organs time-(1 delineates for each internal organs ROI region of interest of rabbit dynamic imaging figure activity curve figure; 2 be heart time-activity curve figure; 3 be spleen time-activity curve figure; 4 be liver time-activity curve figure; 5 be, kidney time-activity curve figure; 6 be bladder time-activity curve figure).
Fig. 5 is
131(1,2 are respectively injection to I-cNGEGQQc at the intravital SPECT dynamic imaging of rabbit figure
13130min rabbit anteposition, position, back total body opacification figure behind the I-cNGEGQQc; 3,4 be respectively injection
1311h rabbit anteposition, position, back total body opacification figure behind the I-cNGEGQQc; 5,6 be respectively injection
1313.5h rabbit anteposition, position, back total body opacification figure behind the I-cNGEGQQc).
Fig. 6 is H1975 pulmonary carcinoma nude mice model tumor growth curve figure.
Fig. 7 is L78 pulmonary carcinoma nude mice model tumor growth curve figure.
The specific embodiment
Below in conjunction with embodiment the present invention is further described, but is not limited thereto.
1 utilizes solid phase synthesis process to prepare small-molecular peptides cNGEGQQc (SEQ ID NO:1)
Concrete grammar is following:
(1) takes by weighing the 1g surface and have NH
2The resin beads of active group with dimethylformamide washing 3 times, is dipped to the abundant swelling of pearl at dimethylformamide then;
(2) add D type cysteine and N, the N'-DIC, reaction is after 2 hours under the room temperature; Wash pearl 5 times with DMF, then add the piperidines of 20% (v/v), at room temperature react 5 min; The DMF that adds 20% (v/v) again reacts 15 min, sloughs Fmoc protection base fully;
(3) set by step (2) method coupling D type aspartic acid-L type glycine-L type isoleucine-L type glycine-L type proline-L type glutamine-D type cysteine successively;
(4) will connect last amino acid whose pearl and wash once distilled water wash 3 times through the trifluoroacetic acid of 25% (v/v);
(5) with anhydrous hydrogen fluoride small-molecular peptides is downcut from resin beads, remove all Side chain protective groups simultaneously.Reduzate is made oxidant with iodine under 30% (v/v) acetic acid high dilution, make 2 cysteine oxidations of intramolecularly form disulfide bond.Through the Sephadex-G-15 column chromatography, dialysis and high performance liquid chroma-tography separation and purification, obtaining at RPHPLC (analytical column) is the high-purity product of simple spike.
2 micromolecular lung cancer targeting radiotherapy doses of the present invention (
131
I-cNGEGQQc) preparation
Composition principle according to above-mentioned small-molecular peptides; Mix small-molecular peptides cNGEGQQc, tyrosine and amino acid condensation agent EDC-HCI [(1-ethyl-3-dimethylaminopropyl) carbonization two amido hydrochlorates] (1:3:3.6 mol ratio); Reaction is after 2 hours under the room temperature; The amino (N) of small-molecular peptides end is carried out condensation with the carboxyl of tyrosine be connected, prepare small-molecular peptides cNGEGQQc-Tyr complex (seeing accompanying drawing 1).
Adopt the chloramine-T labelling method to realize
131I labelling small-molecular peptides cNGEGQQc, concrete grammar is following:
Get the above-mentioned small-molecular peptides 50 μ g that the N-end is connected with tyrosine, dilute with 0.5M PBS (pH=7.4) 50 μ l; Treat that small-molecular peptides dissolves the back fully and adds
131I 37MBq/20 μ l adds chloramine-T 30 μ l (3 μ g/ μ l) then, makes that the chloramine-T final concentration is 0.9 μ g/ μ l; Concussion reaction 2min; With 45 μ l (4 μ g/ μ l) sodium metabisulfite solution cessation reaction, add 0.5M PBS (pH=7.4) solution 200 μ l mixings again, get the reactant liquor behind the labelling; Point sample on chromatographic paper; At developping solution is n-butyl alcohol: ethanol: carry out ply of paper in ammonia (5:1:2) mixed liquor and analyse, utilize the radioactivity thin-layer chromatogram scanner to measure then, calculate mark rate.Reaction mixture is carried out separation and purification through Sephadex G25 chromatographic column, get labelling small-molecular peptides solution behind the purification and carry out paper chromatography and measure radiochemicsl purity (seeing accompanying drawing 2).
The purification process of Sephadex G25 chromatographic column method for preparing and labelling small-molecular peptides: take by weighing 1g Sephadex (polydextran gel) G25 and in PBS (pH7.4), soak 24h; Shake gently and remove fine particle; After treating that it fully expands; The decompression of bleeding adds gel in the glass chromatography pipe then; With PBS (pH7.4) balance chromatographic column, it is saturated to use BSA (20mg is dissolved in the PBS of 1ml) to cross post then earlier, after PBS (pH7.4) washing, above-mentioned labeled reactant liquid is crossed post again, collects the eluent of A280nm absworption peak; Add an amount of BSA and NaN
3, packing is frozen subsequent use.
The mark quality control and the vitro stability of 3 micromolecular lung cancer targeting radiotherapy doses of the present invention are identified
Adopt paper chromatography to measure mark rate; Concrete grammar: with the mixture behind the labelling chromatographic paper one end points appearance; Put into the developing solvent n-butyl alcohol respectively: ethanol: ammonia (5:1:2) mixed liquor, when treating that sample migrates to the other end of chromatographic paper, dry the chromatographic paper taking-up; And cut and put into test tube to chromatographic paper by 10 equal portions; Measure the radioactivity of each test tube with γ immunity enumerator, and calculate mark rate (radiocounting at label peak accounts for the percentage ratio of each peak gross activity counting before the purification) and radiochemicsl purity (radiocounting at label peak accounts for the percentage ratio of each peak gross activity counting behind the purification) in view of the above
131The mobility of I-cNGEGQQc (Rf)=0-0.1, free
131The Rf=0.4-0.6 of I and 0.9-1.0.
131The optimum condition of I labelling cNGEGQQc is: best cNGEGQQc/ chloramine-T mass ratio is 1:1.8, at 20 ℃, pH value 7.4 and response time 2min, under optimum condition, measures mark rate all greater than 90% through paper chromatography.
131The HPLC analysis result of I labelling cNGEGQQc is seen accompanying drawing 3.
Be to estimate the vitro stability of micromolecule radiotherapy dose, adopt paper chromatography measure its at room temperature with human serum in place 0-24h radiochemical purity change, behind the HPLC purification
131I-cNGEGQQc at room temperature places radiation purity behind the 24h all greater than 90%, shows that label has good stability at ambient temperature; For further estimating the stability of micromolecule radiotherapy dose in simulated in vivo environment; The micromolecule radiotherapy dose is placed in people's fresh serum; 37 ℃ of following incubation 24h; Its radiochemical purity progressively drops to 88.2% of 24h by 92.5% of 0h, shows that labelling micromolecule radiotherapy dose has good stability in serum.
Biodistribution analysis in the body of 4 micromolecular lung cancer targeting radiotherapy doses of the present invention
(1) gets 15 of healthy male kunming mices, age in 4-6 week, body weight 19-21g, tail vein injection 0.48MBq (50 μ l)
131I-cNGEGQQc respectively puts to death 3 mices respectively respectively at injection back 1,3,6,12,24h, gets blood and main organs, weighs and measures radiocounting, behind radioactive delay correction, calculates the percentage injection dose rate (%ID/g) of every gram tissue.Adopt the Millennium VG SPECT of GE company, probe is equipped with the low energy high-resolution collimator, can peak center be 364 KeV, window width 20%, and matrix 128 * 128, amplification is 1.
SPECT video picture result sees table 1 for details: in each histoorgan of healthy mice, the radioactivity of kidney is apparently higher than other internal organs, and checkout time is long, shows that micromolecule radiotherapy dose of the present invention is mainly through renal metabolism; Next is a stomach, along with the prolongation of time, each internal organs radioactivity descend gradually, it is more steady that the gastrointestinal radioactivity changes, and explain that the micromolecule radiotherapy dose is stable in vivo, significantly do not dissociate
131I disengages, and muscular tissue and cerebral tissue are minimum to the picked-up of micromolecule radiotherapy dose.
131I-cNGEGQQc sees table 1 for details in the intravital increased radioactivity result of mice.
(2) get 2 of the big ear rabbits of healthy male Japan, dorsal position is fixed on the wooden laboratory table respectively, and probe visual field centrally aligned rabbit breast abdominal part guarantees that whole rabbit body all at probe within sweep of the eye, dilutes through the auricular vein injecting normal saline
131I-cNGEGQQc 0.5 ml (14.8 MBq)/only, carry out dynamic imaging and multidate static image immediately, the DYNAMIC DISTRIBUTION of observing rabbit in-vivo tissue organ radioactivity image changes.Acquisition condition is following: 1 frame/10 second * 6 at first, and 1 frame/1 minute * 4 secondly, 1 frame/5 minute * 5 were then carried out whole body anteposition and position, back static image at last in 30 minutes, 1 hour and 3.5 hours respectively after injection.Simultaneously the serial dynamic acquisition image in position behind the rabbit that obtains is carried out region of interest (ROI) semi-quantitative analysis, pareordia, liver spleen, two kidney and bladder are drawn region of interest, carry out ROI and analyze, set up time-activity curve (seeing accompanying drawing 4-5) separately.
5 micromolecular lung cancer targeting radiotherapy doses of the present invention are to the inhibitory action of pulmonary carcinoma growth
The foundation of people's tumor nude mice animal model.Experiment is respectively with cell: two kinds of people's non-small cell lung cancer cells comprise NCI-H1975 (adenocarcinoma) and L78 (scale cancer); Conventional method is cultured to exponential phase; Trypsinization, the centrifugal Digestive system of removing, PBS washing 2 times; Add serum-free medium and prepare single cell suspension, the adjustment cell concentration is 5 * 10
6/ ml; Respectively at nude mice back subcutaneous injection cell suspension 0.2ml; Set up the animal model of different lung carcinoma cells, every kind of each 12 nude mice model of lung carcinoma cell, the ordinary circumstance of routine observation tumor growth situation and nude mice is like spirit, diet and body weight etc.; When treating that diameter of tumor reaches the 1cm left and right sides, begin to press down the tumor experiment.
Treat that to add final concentration in preceding 3 days in the beginning drinking water be 0.2% liquor kalii iodide,, finish until experiment with the sealing thyroid.12 nude mice models of every kind of pulmonary carcinoma are divided into 3 groups at random, 4 every group, inject respectively in caudal vein: (A)
131I-cNGEGQQc; (B)
131I-cNAQAEQc (negative control small-molecular peptides); (C)
131I; (D) normal saline; Respectively at major diameter and the wide footpath of measuring nude mice body weight and transplanted tumor in the 3rd, 6,9,12,15,18,21,24,27,30 day after the administration, calculate the volume (V=4/3 * π * R1 * R1 * R2 of transplanted tumor; R1＜R2, R1 is short radius, R2 is a greatest radius).
According to each group gross tumor volume situation of change, draw tumor growth curve, the result showed administration after 7 days,
131I-cNGEGQQc group H1975 and L78 transplanted tumor volume begin to dwindle, and other group transplanted tumor volume continues to increase (seeing accompanying drawing 6-7); Continue to observe the life cycle of respectively organizing nude mice, median survival interval is followed successively by (A)
131I-cNGEGQQc group 54 days; (B)
131I-cNAQAEQc group (negative control small-molecular peptides) 45 days; (C)
131I group 42 days; (D) the normal saline group is 43 days.The result shows that micromolecule radiotherapy dose of the present invention has the effect of obvious inhibition tumor growth in vivo.
6 micromolecular lung cancer targeting radiotherapy doses of the present invention are to the evaluation of important organ toxic effect
(1) radiotherapy dose is to the oxicity analysis of people's pulmonary carcinoma nude mice animal model
People's pulmonary carcinoma nude mice animal model gives radiotherapy dose after 3 weeks, puts to death nude mice, leaves and takes important organs such as blood, liver, kidney, the heart, lung, spleen respectively, conventional method analysis hemocyte and liver, kidney biochemical function; The cellular morphology that tissues such as routine pathology cut sections for microscopic examination liver, kidney, microscopically are observed each histoorgan changes; The ultra micro morphosis that the conventional electrical microscopic section is observed each histoorgan cell down changes.
The blood cell analysis result shows
131I-cNGEGQQc group erythrocyte, leukocyte and platelet counts do not have obvious change than the normal saline matched group,
131I-cNAQAEQc group with
131I group quantity of leucocyte reduces than the normal saline matched group; Biochemical studies shows micromolecule radiotherapy dose group reaction liver function index [alanine aminotransferase (ALT), aspartate amino transferase (AST)], and reaction renal function index [creatinine (CRE), blood urea nitrogen (BUN)] all do not see obviously unusual (
P<0.05) (seeing table 2).Routine pathology section and ultra micro electron microscopic examination liver, kidney, heart, lungs are not all seen obvious change.
(2) radiotherapy dose is to the oxicity analysis of healthy rabbit
6 healthy rabbits, diet and active state are good, 3 injection radiotherapy doses, 3 injecting normal salines are injected preceding 15 min, measure each rabbit body temperature between 38.9 ~ 9.3 ℃; In back 24 h of injection, the body temperature of 3 measurements is distinguished as follows: 1 h is between 38.7 ~ 39.2 ℃, and 12 h are between 39.1 ~ 39.6 ℃, and 24 h are between 38.9 ~ 39.1 ℃.Fervescence value in every rabbit 24 h is below 0.7 ℃, and the fervescence total value of measuring for 3 times is below 1.5 ℃.Auricular vein extracts blood 2ml; Promoting the circulation of blood cell and liver, kidney biochemical function are analyzed; With respect to matched group; Except in 24 hours hemocytees of micromolecule radiotherapy dose group platelet counts reduce, the analysis result of all the other time point hemocytees, liver function index (ALT, AST) and reaction renal function index (CRE, BUN) is not all seen obviously unusual (seeing table 3), breathes, independently reaches yet Non Apparent Abnormality performance of central nervous system's behavior.Show that the micromolecule radiotherapy dose does not have the overt toxicity effect to organs such as lungs, liver, kidney, hearts.
Present embodiment adopts the therapeutic radiation property isotope of present wide clinical application
131The pulmonary carcinoma targeting radiopharmaceuticals of I labelling lung carcinoma cell specificity small-molecular peptides preparation, in recent years along with novel isotopic continuous discovery and application, the labeling method of setting up according to the present invention be basic, can constantly change novel isotope as
188Re,
90Y, thus the even more ideal pulmonary carcinoma targeting radiotherapy dose of therapeutic effect obtained.
Above embodiment is merely and introduces preferred case of the present invention, and to those skilled in the art, any conspicuous variation and the improvement in the scope that does not deviate from spirit of the present invention, carried out all should be regarded as a part of the present invention.
< 110>Zhujiang Hospital attached to Nanfang Medical Univ.
< 120>a kind of micromolecular lung cancer targeting radiotherapy dose and preparation method thereof
<130>
<160> 1
<170> PatentIn?version?3.5
<210> 1
<211> 8
<212> PRT
< 213>artificial sequence
< 223>Cys is a D type cysteine
<400> 1
Cys?Asn?Gly?Glu?Gly?Gln?Gln?Cys
1 5
Claims (7)
1. micromolecular lung cancer targeting radiotherapy dose, by gained behind the therapeutic radioisotope labelling small-molecular peptides, said small-molecular peptides is 8 peptide molecules that contain the XGXG structure, and wherein, G representes L type glycine, and X is any in 20 aminoacid.
2. micromolecular lung cancer targeting radiotherapy dose according to claim 1 is characterized in that, the aminoacid sequence of said small-molecular peptides is cNGEGQQc (SEQ ID NO:1); Wherein, C representes D type cysteine, and N representes L type agedoite, and G representes L type glycine; E representes L type glutamic acid, and Q representes L type glutamine.
3. micromolecular lung cancer targeting radiotherapy dose according to claim 1 is characterized in that said therapeutic radioisotope does
131I,
188Re,
90Among the Y any.
4. the method for preparing of a micromolecular lung cancer targeting radiotherapy dose comprises the steps:
1) the N end with small-molecular peptides connects upward tyrosine;
2) N-end is connected with the small-molecular peptides dissolving of tyrosine after, add therapeutic radioisotope, and then add chloramine-T, concussion reaction 2min is with sodium metabisulfite solution cessation reaction;
Said small-molecular peptides is 8 peptide molecules that contain the XGXG structure, and wherein, G representes L type glycine, and X is any in 20 aminoacid;
Said therapeutic radioisotope does
131I.
5. the method for preparing of micromolecular lung cancer targeting radiotherapy dose according to claim 4 is characterized in that, the aminoacid sequence of said small-molecular peptides is cNGEGQQc (SEQ ID NO:1); Wherein, C representes D type cysteine, and N representes L type agedoite, and G representes L type glycine; E representes L type glutamic acid, and Q representes L type glutamine.
6. method for preparing according to claim 4; It is characterized in that; The concrete operations of step 1) are: mix small-molecular peptides and tyrosine; Add amino acid condensation agent EDC-HCI [1-ethyl-(3-dimethylaminopropyl) carbonization two amido hydrochlorates], reaction after 2 hours under the room temperature is carried out condensation with amino (N) end of small-molecular peptides with the carboxyl of tyrosine and is connected.
7. method for preparing according to claim 3 is characterized in that step 2) concrete operations be: be connected with the small-molecular peptides of tyrosine with 0.5M PBS (pH=7.4) dilution N-end, treat that small-molecular peptides dissolves the back fully and adds
131I 37MBq/20 μ l, adding final concentration then is the chloramine-T of 0.9 μ g/ μ l, concussion reaction 2min is with 45 μ l (4 μ g/ μ l) sodium metabisulfite solution cessation reaction.
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| CN201210123590.8A CN102641511B (en) | 2012-04-25 | 2012-04-25 | Micromolecule lung cancer targeted radioactive therapeutic agent and preparation method thereof |
| PCT/CN2012/076102 WO2013159422A1 (en) | 2012-04-25 | 2012-05-25 | Small molecular peptide and use thereof |
| EP12875413.2A EP2873676A4 (en) | 2012-04-25 | 2012-05-25 | Small molecular peptide and use thereof |
| US14/523,986 US9234002B2 (en) | 2012-04-25 | 2014-10-27 | Small peptide specific for lung cancer and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN111574589A (en) * | 2020-06-02 | 2020-08-25 | 南方医科大学南方医院 | Small molecule polypeptide for targeting integrin alpha 3 beta 1 receptor and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009027584A1 (en) * | 2007-08-27 | 2009-03-05 | Elicityl | Method for increasing the resistance of plants to abiotic stress |
| WO2009043984A1 (en) * | 2007-07-19 | 2009-04-09 | Elicityl | Compositions containing a synergic mixture of polyols and xyloglucanes as phytosanitary and bio-fertilising products |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009043984A1 (en) * | 2007-07-19 | 2009-04-09 | Elicityl | Compositions containing a synergic mixture of polyols and xyloglucanes as phytosanitary and bio-fertilising products |
| WO2009027584A1 (en) * | 2007-08-27 | 2009-03-05 | Elicityl | Method for increasing the resistance of plants to abiotic stress |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN111574589A (en) * | 2020-06-02 | 2020-08-25 | 南方医科大学南方医院 | Small molecule polypeptide for targeting integrin alpha 3 beta 1 receptor and preparation method and application thereof |
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