CN101474415A - RGD polypeptide radiopharmaceutical for integrin alphav beta3 positive tumor and preparation method thereof - Google Patents

RGD polypeptide radiopharmaceutical for integrin alphav beta3 positive tumor and preparation method thereof Download PDF

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CN101474415A
CN101474415A CNA2009100770392A CN200910077039A CN101474415A CN 101474415 A CN101474415 A CN 101474415A CN A2009100770392 A CNA2009100770392 A CN A2009100770392A CN 200910077039 A CN200910077039 A CN 200910077039A CN 101474415 A CN101474415 A CN 101474415A
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rgd
rgdxk
dimer
product
pkm
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CN101474415B (en
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王凡
史继云
贾兵
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Guangdong ruidio Technology Co.,Ltd.
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Peking University
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Abstract

The invention relates to a RGD polypeptide radiopharmaceutical used for integrin alphavbeta3 positive tumor. The RGD polypeptide radiopharmaceutical comprises RGD polypeptide, difunctional Chelator and radioactive Nuclide. The RGD polypeptide is RGD cyclic peptide dimer which is RGD cyclic peptide dimer E(L-c(RGDxK))2 which is synthesized by connecting the coupling agent L with RGD polypeptide monomer c(RGDfK) and dimerizing two RGD polypeptide monomer L-c(RGDfK) which are connected with the coupling agent L. The radioactive nuclide marks the RGD cyclic peptide dimer by one difunctional Chelator, and pharmacokinetic modifying molecule PKM is connected between the RGD cyclic peptide dimer and the difunctional chelator. The RGD polypeptide radiopharmaceutical is Nuclide-Chelator-PKM-E(L-c(RGDxK))2, and the RGD polypeptide radiopharmaceutical is colorless transparent liquid injection.

Description

Be used for integrin α vβ 3Rgd peptide radiopharmaceutical of positive tumor and preparation method thereof
Technical field
The present invention relates to the radiopharmaceutical of diagnosing tumor and treatment, particularly be used for integrin α vβ 3Rgd peptide radiopharmaceutical of positive tumor and preparation method thereof.
Background technology
The key link is a tumor-blood-vessel growth in the tumor growth process.There is not the just continued growth again after length arrives several centimetres of sizes of new angiogenesis tumor.Tumor-blood-vessel growth is regulated and control by various protein moleculars, comprising integrin α vβ 3Integrin α vβ 3Be a kind of extracellular matrix receptor, the heterodimer transmembrane glycoprotein that it is made up of α and two subunits of β.Integrin α vβ 3Be the important forming member of integrin family, as one of molecular marker relevant with new vessels, its high expressed is at new vessels endothelial cell surface and some tumor cell surface (neuroblastoma, osteosarcoma, glioblastoma, breast carcinoma and carcinoma of prostate etc.), and do not express in already present blood vessel and normal structure or express very low.Integrin α vβ 3Limitation in height in tumor growth and transfer process is expressed, and makes it become a target spot that haves a great attraction, and is used for the diagnosis and the treatment of tumor.
Studies confirm that the part and the integrin α that contain RGD (Arg-Gly-Asp, arginine-glycine-aspartic acid) sequence vβ 3Have high-affinity and specificity.The RGD sequence part of different radioisotope labelings, the video picture and the treatment that have been used to tumor as the existing RGD cyclic peptide dimer and the tetramer etc. are studied.The RGD dimer or the tetramer have higher integrin α than monomer whose vβ 3Affinity mainly comes from two factors, and one is that two RGD blocks (motif) can be simultaneously and the integrin α of cell surface vβ 3Combine, or RGD block and integrin α vβ 3In conjunction with after increased the local RGD concentration of cell surface binding site.If between two RGD blocks apart from long enough, they can be simultaneously and integrin α so vβ 3In conjunction with; If the distance between two RGD blocks is not a long enough, they can only increase local RGD concentration so.The RGD cyclic peptide dimer E[c (RGDxK) of present report] 2(E represents glutamic acid, and c represents cyclisation, and R represents arginine, and G represents glycine, and D represents aspartic acid, and x is f or y, represents phenylalanine or tyrosine respectively), the distance between two RGD block is 6 keys, owing to distance falls short of, so E[c (RGDxK)] 2Two RGD blocks be difficult to two simultaneously adjacent integrin α with cell surface vβ 3Receptors bind (referring to Fig. 1).In this sense, two RGD blocks (motif) can be simultaneously and the integrin α of cell surface vβ 3Combine and have more important role.For this reason, be necessary to propose novel rgd peptide dimer, make between two RGD blocks in the dimer molecule apart from long enough with can be simultaneously and the adjacent integrin α of cell surface expression vβ 3Receptor combines, and strengthens rgd peptide and integrin α vβ 3Affinity, improve the picked-up of tumor, and invention is used for integrin α on this basis to medicine vβ 3The rgd peptide radiopharmaceutical of positive tumor is to reach better diagnosis and treatment effect.
Summary of the invention
The object of the present invention is to provide a kind of integrin of being used for α vβ 3Rgd peptide radiopharmaceutical of positive tumor and preparation method thereof.This medicine is at first with three glycine molecule (G 3, G=glycine) or four peg molecule (PEG 4, PEG=Polyethylene glycol) be connected with the RGD monomer, and then with the synthetic novel RGD cyclic peptide dimer E[L-c (RGDxK) of this dimerization] 2, make between two RGD blocks in the dimer molecule apart from long enough so that it can be simultaneously and the adjacent integrin α of cell surface expression vβ 3Receptor combines (referring to Fig. 2), promptly with two valency forms and integrin α vβ 3In conjunction with, can further strengthen binding affinity and tumor like this to the picked-up of medicine, reach better diagnostic and therapeutic effect.This medicine by DOTA, DTPA, NOTA and derivant thereof as bifunctional chelating agent with radionuclide 111In, 90Y, 177Lu, 68Ga reaches 64Labellings such as Cu are to novel RGD cyclic peptide dimer molecule, and the targeting of labeled drug by rgd peptide is dense poly-to tumor locus in vivo, utilize the single photon tomography technology of nuclear medicine and positron emission tomography (PET) technology to integrin α vβ 3Positive tumor carries out localization diagnosis, can also be by the β of radionuclide radiation -The particle killing tumor cell is to integrin α vβ 3Positive tumor radiates targeted therapy.When passing through bifunctional chelating agent DOTA or DTPA or derivatives thereof labelling radionuclide 111During In, rgd peptide radiopharmaceutical of the present invention is used for integrin α vβ 3The single photon tomography diagnosis of positive tumor.When passing through bifunctional chelating agent DOTA or NOTA or derivatives thereof labelling radionuclide 68During Ga, rgd peptide radiopharmaceutical of the present invention is used for integrin α vβ 3The positron emission tomography (PET) diagnostic of positive tumor.When passing through bifunctional chelating agent DOTA or TETA or derivatives thereof labelling radionuclide 64During Cu, rgd peptide radiopharmaceutical of the present invention is used for integrin α vβ 3The positron emission tomography (PET) diagnostic of positive tumor.When passing through bifunctional chelating agent DOTA or DTPA or derivatives thereof labelling radionuclide 90Y or 177During Lu, rgd peptide radiopharmaceutical of the present invention is used for integrin α vβ 3The radiation targeted therapy of positive tumor.
The objective of the invention is to be achieved through the following technical solutions:
A kind of integrin α that is used for vβ 3The rgd peptide radiopharmaceutical of positive tumor, comprise rgd peptide, bifunctional chelating agent (Chelator) and radionuclide (Nuclide), described rgd peptide is a RGD cyclic peptide dimer, described RGD cyclic peptide dimer is that bridging agent L is connected with rgd peptide monomer c (RGDfK), again with two rgd peptide monomer L-c (RGDfK) dimerizations that are connected with bridging agent L and synthetic RGD cyclic peptide dimer E[L-c (RGDxK)] 2Described radionuclide is by the described RGD cyclic peptide of a bifunctional chelating agent labelling dimer, also be connected with pharmacokinetics decorating molecule PKM between described RGD cyclic peptide dimer and the described bifunctional chelating agent, described rgd peptide radiopharmaceutical is Nuclide-Chelator-PKM-E[L-c (RGDxK)] 2Described rgd peptide radiopharmaceutical is the colourless transparent liquid injection.
Described bridging agent L is PEG 4Or G 3
Described pharmacokinetics decorating molecule PKM is G 2Or G 3Or G 4Or PEG 4(G 2Represent two glycine molecules, G 4Be four glycine molecules).
Described radionuclide is 111In, described radionuclide 111In is by the described RGD cyclic peptide of a kind of labelling dimer in bifunctional chelating agent DOTA and DTPA and the derivant thereof.
Described radionuclide is 64Cu, described radionuclide 64Cu is by the described RGD cyclic peptide of a kind of labelling dimer in bifunctional chelating agent DOTA and TETA and the derivant thereof.
Described radionuclide is 68Ga, described radionuclide 68Ga is by the described RGD cyclic peptide of a kind of labelling dimer in bifunctional chelating agent DOTA and NOTA and the derivant thereof.
Described radionuclide is 90Y or 177Lu, described radionuclide 90Y or 177Lu is by the described RGD cyclic peptide of a kind of labelling dimer in bifunctional chelating agent DOTA and DTPA and the derivant thereof.
The described integrin α that is used for vβ 3The radiopharmaceutic preparation method of the rgd peptide of positive tumor may further comprise the steps:
(L is PEG in the preparation of a, L-c (RGDxK) 4Or G 3)
The bridging agent L of Boc (t-Butyl carbamate, tertbutyloxycarbonyl) protection is dissolved among the 1mL DMF (dimethyl formamide), adds NHS (N-hydroxy-succinamide also is HOSu) and DCC (dicyclohexylcarbodiimide), stirring reaction is 2 hours under the room temperature; Rgd peptide monomer c (RGDxK) is joined in the above-mentioned reactant liquor, pH regulator is arrived 8.0-8.5, stirred overnight at room temperature with DIEA (N, N-diisopropylethylamine); In reactant liquor, add 3mL0.5M NH 4OAc buffer solution (pH=7.0) also filters, and filtrate is collected the fraction of object through Zorbax C18 semi-preparative column HPLC separation and purification, merges and collects liquid and lyophilizing; Obtain product and confirm as expection product B oc-L-c (RGDxK) through the ESI-MS mass spectral analysis; Boc-L-c (RGDxK) is joined among the 3.0mL TFA (trifluoroacetic acid) room temperature reaction 30 minutes; Revolve and boil off except that TFA, residue is dissolved in 2mL0.5M NH 4OAc buffer solution (pH=7.0) through the separation and purification of Zorbax C18 semi-preparative column HPLC method, is collected the fraction of object, merges and collects liquid and lyophilizing; Obtain product and confirm as expection product L-c (RGDxK) through the ESI-MS mass spectral analysis;
B, E[L-c (RGDxK)] 2Preparation
The glutamic acid (E) of Boc protection is dissolved in 5mL DMF, adds NHS and DCC, stirring at room 10 hours; Filter by-product DCU (1,3-Dicyclohexylurea), the filtrate evaporated in vacuo obtains crude product; Use 3mL CH 2Cl 2The dissolving crude product filters insoluble matter, and filtrate is concentrated into about 1mL; Slowly dropwise join in the 30mL ether, separate out white precipitate, filtering also, vacuum drying obtains product; Obtain the product warp 1H NMR nuclear-magnetism analysis of spectrum is confirmed as expection product B oc-E (OSu) 2With Boc-E (OSu) 2Be dissolved among the anhydrous 1mL DMF, add L-c (RGDxK); Use DIEA to regulate pH value to 8.0-9.0, stirred overnight at room temperature through Zorbax C18 semi-preparative column HPLC separation and purification, merges and collects liquid and lyophilizing, obtains product and confirms as expection product B oc-E[L-c (RGDxK) through the ESI-MS mass spectral analysis] 2Soak Boc-E[L-c (RGDxK) with anhydrous TFA] 25 minutes, remove the Boc-blocking group; Thick product merges and collects liquid and lyophilizing through Zorbax C18 semi-preparative column HPLC separation and purification, obtains product and confirms as expection product E[L-c (RGDxK) through the ESI-MS mass spectral analysis] 2C, PKM-E[L-c (RGDxK)] 2Preparation (PKM is G 2Or G 3Or G 4Or PEG 4)
With Boc-PKM-OSu and E[L-c (RGDxK)] 2Be dissolved in 2mL DMF and H 2The mixed liquor of O (1:1=v:v) uses 0.1N NaOH to regulate pH value to 8.0-9.0, stirred overnight at room temperature.With the reactant liquor evaporated in vacuo, obtain thick product and it is dissolved in 2mL TFA, solution was at room temperature stirred 15 minutes; Product is collected the fraction of object through Zorbax C18 semi-preparative column HPLC separation and purification, merges to collect liquid and lyophilizing, obtains product and confirms as desired product PKM-E[L-c (RGDxK) through the ESI-MS mass spectral analysis] 2D, Chelator-PKM-E[L-c (RGDxK)] 2Preparation (Chelator is DOTA or DTPA or NOTA or TETA or derivatives thereof)
With Chelator and PKM-E[L-c (RGDxK)] 2Be dissolved among the 1mL DMF (dimethyl formamide), pH regulator arrived 8.5-9.0, stirred overnight at room temperature with DIEA (N, N-diisopropylethylamine); Product is collected the fraction of object through ZorbaxC18 semi-preparative column HPLC separation and purification, merges to collect liquid and lyophilizing;
E, Nuclide-Chelator-PKM-E[L-c (RGDxK)] 2Preparation (Nuclide is 111In or 90Y or 177Lu or 68Ga or 64Cu)
0.2mL is dissolved with Chelator-PKM-E[L-c (RGDxK)] 2NaOAc (pH=5.0) buffer solution of conjugate (concentration 0.2-0.5mg/mL) joins in the cillin bottle, add 10-50 μ L radionuclide (20-50mCi), 100 ℃ of heating in water bath cillin bottles, reacted 10-15 minute, reaction finishes back room temperature cooling 10 minutes, makes rgd peptide radiopharmaceutical Nuclide-Chelator-PKM-E[L-c (RGDxK)] 2
Described HPLC method is use LabAllianceHPLC system disposition Zorbax C18 semi-preparative column, gradient elution 36 minutes, and flow velocity 2.5mL/min, wherein mobile phase A is 25mM NH 4OAc, B are the second eyeball.The drip washing gradient is set at 90% A and 10% B when initial, 85% A and 15% B in the time of 5 minutes, 65% A and 35% B in the time of 30 minutes, 50% A and 50% B in the time of 32-36 minute.
Beneficial effect of the present invention:
1, in rgd peptide radiopharmaceutical of the present invention, at first with three glycine molecule (G 3) or four peg molecule (PEG 4) and rgd peptide monomer c (RGDfK)] 2Connect, and then with this dimerization, promptly synthetic E[G 3-c (RGDxK)] 2Or E[PEG 4-c (RGDxK)] 2, the distance between such two RGD blocks just is increased to 26 keys or 38 keys from 6 keys, makes between two RGD blocks in the dimer molecule apart from long enough so that it can be simultaneously and the adjacent integrin α of cell surface expression vβ 3Receptor combines, promptly with two valency forms and integrin α vβ 3In conjunction with, can further strengthen binding affinity and tumor like this to the picked-up of medicine, reach better diagnosis or therapeutic effect.
2, the present invention not only introduces G between two RGD blocks 3And PEG 4, simultaneously at the novel RGD cyclic peptide of rgd peptide molecule dimer E[L-c (RGDxK)] 2And introduce PKM between the bifunctional chelating agent, i.e. Chelator-PKM-E[L-c (RGDxK)] 2, with the further pharmacokinetic property that improves, particularly from the removing kinetics of nonneoplastic tissue.
3, utilize preparation method of the present invention, when passing through bifunctional chelating agent DOTA or DTPA or derivatives thereof labelling radionuclide 111During In, rgd peptide radiopharmaceutical of the present invention is used for integrin α vβ 3The single photon tomography diagnosis of positive tumor.When passing through bifunctional chelating agent DOTA or NOTA or derivatives thereof labelling radionuclide 68During Ga, rgd peptide radiopharmaceutical of the present invention is used for integrin α vβ 3The positron emission tomography (PET) diagnostic of positive tumor.When passing through bifunctional chelating agent DOTA or TETA or derivatives thereof labelling radionuclide 64During Cu, rgd peptide radiopharmaceutical of the present invention is used for integrin α vβ 3The positron emission tomography (PET) diagnostic of positive tumor.When passing through bifunctional chelating agent DOTA or DTPA or derivatives thereof labelling radionuclide 90Y or 177During Lu, rgd peptide radiopharmaceutical of the present invention is used for integrin α vβ 3The radiation targeted therapy of positive tumor.
The invention will be further described below in conjunction with drawings and Examples.
Description of drawings
Fig. 1 is RGD cyclic peptide dimer and integrin α before the structure of modification vβ 3The receptors bind sketch map;
Fig. 2 is RGD cyclic peptide dimer and integrin α behind the structure of modification vβ 3The receptors bind sketch map;
Fig. 3 be RGD cyclic peptide dimer and 111In tag structure sketch map;
Fig. 4 is different rgd peptide extracorporeal receptor competition binding analysis;
Fig. 5 is 111The different rgd peptides of In labelling are in the contrast of injection back different time in the glioma picked-up;
Fig. 6 is injection 111In-DOTA-3PEG 4The γ video picture figure of 24h glioma animal model behind the-dimer.
The specific embodiment
The material that is adopted in the embodiment of the invention: Dicyclcohexylcarbodiimide (DCC, N, N '-dicyclohexylcarbodiimide), N-hydroxysuccinimide (NHS, N-hydroxy-succinamide), N, N-Diisopropylethylamine (DIEA, N, N-diisopropylethylamine), N, N-Dimethylforn amide (DMF, N, dinethylformamide), Trifluoroacetic acid (TFA, trifluoroacetic acid) is available from U.S. Sigma-Aldrich company.DOTA (1,4,7,10-tetraazacyclododecane-N, N ', N ", N " '-tetraacetic acid, 1,4,7,10-tetraazacyclododecanand tetraacethyl), DTPA (diethylenetriaminepentaacetic acid, diethylene triamine pentacetic acid (DTPA)) and NOTA (1,4,7-triazacyclononane-N, N ', N "-triacetic acid; 1,4,7-7-triazacyclononane triacetic acid) available from U.S. Macrocyclics company.Cyclisation rgd peptide monomer c (RGDfK)] 2Available from U.S. Peptide International, Inc. company. 111The In nucleic is available from U.S. PerkinElmer company.
Embodiment 1:
Present embodiment with 111In-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2(be called for short 111In-DOTA-3PEG 4-dimer) rgd peptide radiopharmaceutical and preparation method thereof is an example.
111In-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2(be called for short 111In-DOTA-3PEG 4-dimer) polypeptide radiopharmaceutical comprises RGD cyclic peptide dimer, bifunctional chelating agent DOTA and radionuclide 111In.RGD cyclic peptide dimer is with bridging agent PEG 4Be connected with rgd peptide monomer c (RGDfK), be connected with PEG with two again 4Rgd peptide monomer PEG 4-c (RGDfK) dimerization and synthetic RGD cyclic peptide dimer, i.e. E[PEG 4-c (RGDfK)] 2, radionuclide 111In also is connected with pharmacokinetics decorating molecule PEG by the described RGD cyclic peptide of a bifunctional chelating agent DOTA labelling dimer between described RGD cyclic peptide dimer and the described bifunctional chelating agent 4, described rgd peptide radiopharmaceutical is 111In-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2Described rgd peptide radiopharmaceutical is the colourless transparent liquid injection.
This medicine is at first with four peg molecule (PEG 4, PEG=Polyethylene glycol) be connected with the RGD monomer, and then with the synthetic novel RGD cyclic peptide dimer E[L-c (RGDxK) of this dimerization] 2, make between two RGD blocks in the dimer molecule apart from long enough so that it can be simultaneously and the adjacent integrin α of cell surface expression vβ 3Receptor combines (referring to Fig. 2), promptly with two valency forms and integrin α vβ 3In conjunction with, with prior art RGD cyclic peptide dimer E[c (RGDxK)] 2Two RGD blocks be difficult to two simultaneously adjacent integrin α with cell surface vβ 3Receptors bind (referring to Fig. 1) is compared, novel RGD cyclic peptide dimer E[L-c (RGDxK)] 2Two RGD blocks (motif) can be simultaneously and the integrin α of cell surface vβ 3Combining has more important role, has further strengthened the picked-up to medicine of binding affinity and tumor, reaches better diagnosis and treatment effect.
This medicine by DOTA as bifunctional chelating agent with radionuclide 111The In labelling is to novel RGD cyclic peptide dimer molecule, and labeled drug is dense poly-to tumor locus by the targeting of rgd peptide in vivo, and the single photon tomography technology of utilizing nuclear medicine is to integrin α vβ 3Positive tumor carries out localization diagnosis,
111In-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2( 111In-DOTA-3PEG 4-dimer) preparation method is as follows:
Be equipped with Zorbax C18 semi-preparative column in advance, HPLC method one: use LabAlliance HPLC system, be equipped with Zorbax C18 semi-preparative column (9.4mm x 250mm, 100
Figure A200910077039D0011113642QIETU
Pore size), gradient elution 36 minutes, flow velocity 2.5mL/min, wherein mobile phase A is 25mM NH 4OAc (pH 5.0), B is an acetonitrile.The drip washing gradient is set at 90% A and 10% B when initial, 85% A and 15% B in the time of 5 minutes, 65% A and 35% B in the time of 30 minutes, 50% A and 50% B in the time of 32-36 minute.
PEG 4The preparation of-c (RGDfK):
PEG with Boc (t-Butyl carbamate, tertbutyloxycarbonyl) protection 4-OH is dissolved among the 1mL DMF (dimethyl formamide), add NHS (N-hydroxy-succinamide also is HOSu) (3.5mg, 0.03mmol) and DCC (dicyclohexylcarbodiimide) (6.2mg, 0.03mmol), stirring reaction is 2 hours under the room temperature.(26.3mg 0.02mmol) joins in the above reactant liquor, with DIEA (N, N-diisopropylethylamine) pH regulator is arrived 8.0-8.5, stirred overnight at room temperature with c (RGDfK).In reactant liquor, add 3mL 0.5M NH 4OAc buffer solution (pH=7.0) also filters, and filtrate is collected retention time and is about 14 minutes fraction through Zorbax C18 semi-preparative column (HPLC method one) separation and purification, merges and collects liquid and lyophilizing.Obtain product B oc-PEG 4The about 7.5mg of-c (RGDfK).The ESI-MS mass spectrometry results is m/z=1665 ([M+H] +), [C 75H 117N 20O 23] +Theoretical value is 1665.85.
With above-mentioned gained Boc-PEG 4(10mg 6mol) joins among the 3.0mL TFA (trifluoroacetic acid) room temperature reaction 30 minutes to-c (RGDfK).Revolve and boil off except that TFA, residue is dissolved in 2mL 0.5MNH 4OAc buffer solution (pH=7.0) through Zorbax C18 semi-preparative column (HPLC method one) separation and purification, is collected retention time and is about 14 minutes fraction, merges and collects liquid and lyophilizing.Obtain product P EG 4The about 7.0mg of-c (RGDfK).The ESI-MS mass spectrometry results is m/z=1565.2 ([M+H] +), [C 70H 109N 20O 21] +Theoretical value is 1565.80.
E[PEG 4-c (RGDfK)] 2Preparation:
With the glutamic acid (E) of Boc-protection (0.247g 1.0mmol) is dissolved in 5mL DMF, add NHS (0.253g, 2.2mmol) and DCC (0.453g, 2.2mmol), stirring at room 10 hours.Filter by-product DCU (1,3-Dicyclohexylurea), the filtrate evaporated in vacuo obtains crude product.Use 3mL CH 2Cl 2The dissolving crude product filters insoluble matter, and filtrate is concentrated into about 1mL.Slowly dropwise join in the 30mL ether, separate out white precipitate, vacuum drying obtains product 0.27g.Obtain the product warp 1H NMR nuclear-magnetism analysis of spectrum is confirmed as expection product B oc-E (OSu) 2
With above-mentioned gained Boc-E (OSu) 2(4.4mg 0.01mmol) is dissolved among the anhydrous 1mL DMF, adds PEG 4-c (RGDfK) (5.28mg, 0.03mmol).Use DIEA to regulate pH value to 8.0-9.0, stirred overnight at room temperature through Zorbax C18 semi-preparative column (HPLC method one) separation and purification, merges and collects liquid and lyophilizing, obtains the 15mg white powder.Confirm as expection product B oc-E[PEG through the ESI-MS mass spectral analysis 4-c (RGDfK)] 2The ESI-MS mass spectrometry results is m/z=1913.13 ([M+H] +), [C 86H 138N 21O 28] +Theoretical value is 1912.99.
Soak above-mentioned product B oc-E[PEG with anhydrous TFA 4-c (RGDfK)] 25 minutes, remove the Boc-blocking group.Thick product merges and collects liquid and lyophilizing through Zorbax C18 semi-preparative column (HPLC method one) separation and purification, obtains product and confirms as expection product E[PEG through the ESI-MS mass spectral analysis 4-c (RGDfK)] 2The ESI-MS mass spectrometry results is m/z=1813.0 ([M+H] +), [C 81H 130N 21O 26] +Theoretical value is 1812.99.
PEG 4-E[PEG 4-c (RGDfK)] 2Preparation:
With Boc-PEG 4-OSu (5.1mg, 11 μ mol) and E[PEG 4-c (RGDfK)] 2(5mg, 2.76 μ Lmol) are dissolved in 2mL DMF and H 2The mixed liquor of O (1:1=v:v) uses 0.1N NaOH to regulate pH value to 8.0-9.0, stirred overnight at room temperature.The reactant liquor evaporated in vacuo obtains thick product then, is dissolved in 2mL TFA, and solution was at room temperature stirred 15 minutes.Product is through Zorbax C18 semi-preparative column (HPLC method one) separation and purification, and the fraction when the collection retention time is 16.4 minutes merges and collects liquid and lyophilizing.Obtain desired product PEG 4-E[PEG 4-c (RGDfK)] 2About 2.4mg, purity is greater than 95%.The ESI-MS mass spectrometry results is m/z=2061.46 ([M+H] +), [C 92H 151N 22O 31] +Theoretical value is 2061.1.
DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2(be called for short DOTA-3PEG 4-dimer) preparation:
With DOTA-OSu (5.0mg ,～10.0 μ M) and PEG 4-E[PEG 4-c (RGDfk)] 2(10.30mg ,～5.0 μ M) are dissolved in the 1mL dry DMF, use DIEA to regulate pH value to 8.5-9.0, stirred overnight at room temperature; In reactant liquor, add 3mL0.5M NH 4OAc buffer solution (pH=7.0) also filters, and filtrate is through Zorbax C18 semi-preparative column HPLC (method one) separation and purification, and the fraction when the collection retention time is 22.5 minutes merges and collects liquid and lyophilizing, obtains product 4.0mg (productive rate is 33%).ESI-MS mass spectrometry results: m/z=2447.35 ([M+H] +), [C 108H 177N 26O 38] +Theoretical value is 2447.27.
111In-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2Preparation:
0.2mL is dissolved with DOTA-3PEG 4NaOAc (pH=5.0) buffer solution of-dimer (concentration 0.25mg/mL) joins in the cillin bottle, add 20 μ L radioisotope labeling liquid (20-50mCi), 100 ℃ of heating in water bath cillin bottles, reacted 10-15 minute, reaction finishes back room temperature cooling 10 minutes, makes rgd peptide radiopharmaceutical of the present invention 111In-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2( 111In-DOTA-3PEG 4-dimer).
In the rgd peptide radiopharmaceutical of the present invention, when bridging agent L is G 3, pharmacokinetics decorating molecule PKM is G 3The time, medicine of the present invention is 111In-DOTA-G 3-E[G 3-c (RGDfK)] 2( 111In-DOTA-3G 3-dimer).Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the rgd peptide radiopharmaceutical of the present invention, when bifunctional chelating agent was DTPA, medicine of the present invention can be 111In-DTPA-PEG 4-E[PEG 4-c (RGDfK)] 2( 111In-DTPA-3PEG 4-dimer) or 111In-DTPA-G 3-E[G 3-c (RGDfK)] 2( 111In-DTPA-3G 3-dimer).Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the present embodiment, rgd peptide radiopharmaceutical of the present invention is used bifunctional chelating agent DOTA or DTPA or derivatives thereof labelling radionuclide 111In.Rgd peptide radiopharmaceutical in the present embodiment is used for single photon tomography technology to integrin α vβ 3Positive tumor carries out localization diagnosis.
Referring to Fig. 3, Fig. 3 be RGD cyclic peptide dimer and 111In tag structure sketch map.
Rgd peptide radiopharmaceutical to the preparation of foundation the inventive method 111In-DOTA-3PEG 4-dimer sampling carrying out radioactivity HPLC analyzes (HPLC method two: use LabAlliance HPLC system, be equipped with radioactivity in thread detector and Zorbax C18 analytical column (4.6mm x 250mm, 300
Figure A200910077039D0011113642QIETU
Pore size), gradient elution 25 minutes, flow velocity 1.0mL/min, wherein mobile phase A is 25mM NH 4OAc (pH 5.0), B is an acetonitrile.The drip washing gradient is set at initial 90% A and 10% B during to 2 minutes, 85% A and 15% B in the time of 5 minutes, 80% A and 20% B in the time of 20 minutes, 90% A and 10% B in the time of 25 minutes), 111In-DOTA-3PEG 4The mark rate of-dimer〉95%, radiochemical purity behind Sep-Pak C18 column purification〉98%.
DOTA-3PEG 4-dimer and integrin α vβ 3Binding affinity is measured: high expressed integrin α vβ 3The U87MG human glioma cell as experiment sample, use 125I-c (RGDyK) is as integrin α vβ 3The bonded radioactive ligand of receptor-specific adopts competition in conjunction with measuring DOTA-3PEG 4The IC of-dimer 50Value (503nhibiting concentration), and establish c (RGDyK), DOTA-PEG 4-c (RGDfK) (DOTA-PEG 4-monomer), DTPA-Bz-PEG 4-E[PEG 4-c (RGDfK)] 2(DTPA-3PEG 4-dimer), DOTA-G 3-E[G 3-c (RGDfK)] 2(DOTA-3G 3-dimer), DOTA-E[c (RGDfK)] 2(DOTA-dimer) and DOTA-E{E[c (RGDfK)] 2} 2(DOTA-tetramer) be contrast.Experimental result shows, c (RGDyK), DOTA-PEG 4-monomer, DOTA-dimer, DOTA-3PEG 4-dimer, DTPA-3PEG 4-dimer, DOTA-3G 3-dimer and DOTA-tetramer competition 125I-c (RGDyK) and the bonded IC of U87MG cell 50Value is respectively 49.9 ± 5.5nM, 42.1 ± 3.5nM, and 8.0 ± 2.8nM, 1.3 ± 0.2nM, 1.3 ± 0.3nM, 1.1 ± 0.1nM and 1.4 ± 0.1nM (referring to Fig. 4) show DOTA-3PEG 4-dimer, DTPA-3PEG 4-dimer and DOTA-3G 3-dimer and integrin α vβ 3Affinity significantly better than its rgd peptide monomer and existing dimer, illustrate that improved RGD cyclic peptide dimerization physical ability is with two valency forms and integrin α vβ 3In conjunction with.
111In-DOTA-3PEG 4-dimer is in the tumor bearing nude mice bio distribution: lotus U87MG human glioma BALB/c nude mice is divided into some groups, 4 every group at random.Each group experiment nude mice respectively through tail vein injection 100 μ L (～74kBq) different 111The rgd peptide of In labelling was in back 0.5 hour of injection, 1.0 hours, 4.0 hour and extremely tested nude mice by the component other places in 24.0 hours, get blood and main organs, weigh and measure radiocounting, behind decay correction, calculate every gram and organize percentage injection dose rate (%ID/g).
In U87MG human glioma animal model, 111In-DOTA-3PEG 4-dimer, 111In-DOTA-3G 3-dimer reaches 111In-DTPA-3PEG 4The tumor uptake of-dimer apparently higher than 111In-DTPA-dimer (referring to Fig. 5).This proves absolutely 111In-DOTA-3PEG 4-dimer, 111In-DOTA-3G 3-dimer reaches 111In-DTPA-3PEG 4-dimer is with two valency forms and integrin α vβ 3In conjunction with, and 111In-DTPA-dimer is with unit price form and integrin α vβ 3In conjunction with.Referring to Fig. 6, Fig. 6 is the injection of lotus U87MG human glioma nude mice 111In-DOTA-3PEG 4The γ video picture figure (arrow is represented tumor locus among the figure) of 24h behind the-dimer.
Embodiment 2:
In the present embodiment, rgd peptide radiopharmaceutical of the present invention is used bifunctional chelating agent DOTA or TETA or derivatives thereof labelling radionuclide 64Cu is when bridging agent L is PEG 4, pharmacokinetics decorating molecule PKM is PEG 4The time, medicine of the present invention is 64Cu-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2( 64Cu-DOTA-3PEG 4-dimer) or 64Cu-TETA-PEG 4-E[PEG 4-c (RGDfK)] 2( 64Cu-TETA-3PEG 4-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
When bridging agent L is G 3, pharmacokinetics decorating molecule PKM is G 3The time, medicine of the present invention is 64Cu-DOTA-G 3-E[G 3-c (RGDfK)] 2( 64Cu-DOTA-3G 3-dimer) or 64Cu-TETA-G 3-E[G 3-c (RGDfK)] 2( 64Cu-TETA-3G 3-dimer), its preparation method is the same.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the present embodiment, rgd peptide radiopharmaceutical of the present invention is used bifunctional chelating agent DOTA or TETA or derivatives thereof labelling radionuclide 64Cu, the rgd peptide radiopharmaceutical in the present embodiment is used for integrin α vβ 3The positron emission tomography (PET) diagnostic of positive tumor.
Embodiment 3:
In the present embodiment, rgd peptide radiopharmaceutical of the present invention is used bifunctional chelating agent DOTA or NOTA or derivatives thereof labelling radionuclide 68Ga.When bridging agent L is PEG 4, pharmacokinetics decorating molecule PKM is PEG 4The time, medicine of the present invention is 68Ga-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2( 68Ga-DOTA-3PEG 4-dimer) or 68Ga-NOTA-PEG 4-E[PEG 4-c (RGDfK)] 2( 68Ga-NOTA-3PEG 4-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
When bridging agent L is G 3, pharmacokinetics decorating molecule PKM is G 3The time, medicine of the present invention is 68Ga-DOTA-G 3-E[G 3-c (RGDfK)] 2( 68Ga-DOTA-3G 3-dimer) or 68Ga-NOTA-G 3-E[G 3-c (RGDfK)] 2( 68Ga-NOTA-3G 3-dimer).Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the present embodiment, rgd peptide radiopharmaceutical of the present invention is used bifunctional chelating agent DOTA or NOTA or derivatives thereof labelling radionuclide 68Ga, the rgd peptide radiopharmaceutical in the present embodiment is used for integrin α vβ 3The positron emission tomography (PET) diagnostic of positive tumor.
Embodiment 4:
In the present embodiment, rgd peptide radiopharmaceutical of the present invention is used bifunctional chelating agent DOTA or DTPA or derivatives thereof labelling radionuclide 90Y.When bridging agent L is PEG 4, pharmacokinetics decorating molecule PKM is PEG 4The time, medicine of the present invention is 90Y-DTPA-PEG 4-E[PEG 4-c (RGDfK)] 2( 90Y-DTPA-3PEG 4-dimer) or 90Y-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2( 90Y-DOTA-3PEG 4-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
When bridging agent L is G 3, pharmacokinetics decorating molecule PKM is G 3The time, medicine of the present invention is 90Y-DTPA-G 3-E[G 3-c (RGDfK)] 2( 90Y-DTPA-3G 3-dimer) or 90Y-DOTA-G 3-E[G 3-c (RGDfK)] 2( 90Y-DOTA-3G 3-dimer), its preparation method is the same.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the present embodiment, rgd peptide radiopharmaceutical of the present invention is used bifunctional chelating agent DOTA or DTPA or derivatives thereof labelling radionuclide 90Y.Rgd peptide radiopharmaceutical in the present embodiment is used for integrin α vβ 3The radiation targeted therapy of positive tumor.
Embodiment 5:
In the present embodiment, rgd peptide radiopharmaceutical of the present invention is used bifunctional chelating agent DOTA or DTPA or derivatives thereof labelling radionuclide 177Lu.When bridging agent L is PEG 4, pharmacokinetics decorating molecule PKM is PEG 4The time, medicine of the present invention is 177Lu-DTPA-PEG 4-E[PEG 4-c (RGDfK)] 2( 177Lu-DTPA-3PEG 4-dimer) or 177Lu-DOTA-PEG 4-E[PEG 4-c (RGDfK)] 2( 177Lu-DOTA-3PEG 4-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
When bridging agent L is G 3, pharmacokinetics decorating molecule PKM is G 3The time, medicine of the present invention is 177Lu-DTPA-G 3-E[G 3-c (RGDfK)] 2( 177Lu-DTPA-3G 3-dimer) or 177Lu-DOTA-G 3-E[G 3-c (RGDfK)] 2( 177Lu-DOTA-3G 3-dimer), its preparation method is the same.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the present embodiment, rgd peptide radiopharmaceutical of the present invention is used bifunctional chelating agent DOTA or DTPA or derivatives thereof labelling radionuclide 177Lu.Rgd peptide radiopharmaceutical in the present embodiment is used for integrin α vβ 3The radiation targeted therapy of positive tumor.

Claims (9)

1, a kind of integrin α that is used for vβ 3The rgd peptide radiopharmaceutical of positive tumor, comprise rgd peptide, bifunctional chelating agent (Chelator) and radionuclide (Nuclide), it is characterized in that: described rgd peptide is a RGD cyclic peptide dimer, described RGD cyclic peptide dimer is that bridging agent L is connected with rgd peptide monomer c (RGDfK), again with two rgd peptide monomer L-c (RGDfK) dimerizations that are connected with bridging agent L and synthetic RGD cyclic peptide dimer E[L-c (RGDxK)] 2Described radionuclide is by the described RGD cyclic peptide of a bifunctional chelating agent labelling dimer, also be connected with pharmacokinetics decorating molecule PKM between described RGD cyclic peptide dimer and the described bifunctional chelating agent, described rgd peptide radiopharmaceutical is Nuclide-Chelator-PKM-E[L-c (RGDxK)] 2Described rgd peptide radiopharmaceutical is the colourless transparent liquid injection.
2, the integrin α that is used for according to claim 1 vβ 3The rgd peptide radiopharmaceutical of positive tumor is characterized in that: described bridging agent L is PEG 4Or G 3
3, the integrin α that is used for according to claim 1 vβ 3The rgd peptide radiopharmaceutical of positive tumor is characterized in that: described pharmacokinetics decorating molecule PKM is G 2Or G 3Or G 4Or PEG 4
4, the integrin α that is used for according to claim 1 vβ 3The rgd peptide radiopharmaceutical of positive tumor is characterized in that: described radionuclide is 111In, described radionuclide 111In is by the described RGD cyclic peptide of a kind of labelling dimer in bifunctional chelating agent DOTA and DTPA and the derivant thereof.
5, the integrin α that is used for according to claim 1 vβ 3The rgd peptide radiopharmaceutical of positive tumor is characterized in that: described radionuclide is 64Cu, described radionuclide 64Cu is by the described RGD cyclic peptide of a kind of labelling dimer in bifunctional chelating agent DOTA and TETA and the derivant thereof.
6, the integrin α that is used for according to claim 1 vβ 3The rgd peptide radiopharmaceutical of positive tumor is characterized in that: described radionuclide is 68Ga, described radionuclide 68Ga is by the described RGD cyclic peptide of a kind of labelling dimer in bifunctional chelating agent DOTA and NOTA and the derivant thereof.
7, the integrin α that is used for according to claim 1 vβ 3The rgd peptide radiopharmaceutical of positive tumor is characterized in that: described radionuclide is 90Y or 177Lu, described radionuclide 90Y or 177Lu is by the described RGD cyclic peptide of a kind of labelling dimer in bifunctional chelating agent DOTA and DTPA and the derivant thereof.
8, the described integrin α that is used for of a kind of claim 1 vβ 3The radiopharmaceutic preparation method of the rgd peptide of positive tumor is characterized in that: said method comprising the steps of:
(L is PEG in the preparation of a, L-c (RGDxK) 4Or G 3)
The bridging agent L of Boc (t-Butyl carbamate, tertbutyloxycarbonyl) protection is dissolved among the 1mL DMF (dimethyl formamide), adds NHS (N-hydroxy-succinamide also is HOSu) and DCC (dicyclohexylcarbodiimide), stirring reaction is 2 hours under the room temperature; Rgd peptide monomer c (RGDxK) is joined in the above-mentioned reactant liquor, pH regulator is arrived 8.0-8.5, stirred overnight at room temperature with DIEA (N, N-diisopropylethylamine); In reactant liquor, add 3mL0.5M NH 4OAc buffer solution (pH=7.0) also filters, and filtrate is collected the fraction of object through Zorbax C18 semi-preparative column HPLC separation and purification, merges and collects liquid and lyophilizing; Obtain product and confirm as expection product B oc-L-c (RGDxK) through the ESI-MS mass spectral analysis; Boc-L-c (RGDxK) is joined among the 3.0mL TFA (trifluoroacetic acid) room temperature reaction 30 minutes; Revolve and boil off except that TFA, residue is dissolved in 2mL0.5M NH 4OAc buffer solution (pH=7.0) through the separation and purification of Zorbax C18 semi-preparative column HPLC method, is collected the fraction of object, merges and collects liquid and lyophilizing; Obtain product and confirm as expection product L-c (RGDxK) through the ESI-MS mass spectral analysis;
B, E[L-c (RGDxK)] 2Preparation
The glutamic acid (E) of Boc protection is dissolved in 5mL DMF, adds NHS and DCC, stirring at room 10 hours; Filter by-product DCU (1,3-Dicyclohexylurea), the filtrate evaporated in vacuo obtains crude product; Use 3mL CH 2Cl 2The dissolving crude product filters insoluble matter, and filtrate is concentrated into about 1mL; Slowly dropwise join in the 30mL ether, separate out white precipitate, filtering also, vacuum drying obtains product; Obtain the product warp 1H NMR nuclear-magnetism analysis of spectrum is confirmed as expection product B oc-E (OSu) 2With Boc-E (OSu) 2Be dissolved among the anhydrous 1mL DMF, add L-c (RGDxK); Use DIEA to regulate pH value to 8.0-9.0, stirred overnight at room temperature through Zorbax C18 semi-preparative column HPLC separation and purification, merges and collects liquid and lyophilizing, obtains product and confirms as expection product B oc-E[L-c (RGDxK) through the ESI-MS mass spectral analysis] 2Soak Boc-E[L-c (RGDxK) with anhydrous TFA] 25 minutes, remove the Boc-blocking group; Thick product merges and collects liquid and lyophilizing through Zorbax C18 semi-preparative column HPLC separation and purification, obtains product and confirms as expection product E[L-c (RGDxK) through the ESI-MS mass spectral analysis] 2
C, PKM-E[L-c (RGDxK)] 2Preparation (PKM is G 2Or G 3Or G4 or PEG4)
With Boc-PKM-OSu and E[L-c (RGDxK)] 2Be dissolved in the mixed liquor (1:1=v:v) of 2mL DMF and H2O, use 0.1N NaOH to regulate pH value to 8.0-9.0, stirred overnight at room temperature; With the reactant liquor evaporated in vacuo, obtain thick product and it is dissolved in 2mL TFA, solution was at room temperature stirred 15 minutes; Product is collected the fraction of object through Zorbax C18 semi-preparative column HPLC separation and purification, merges to collect liquid and lyophilizing, obtains product and confirms as desired product PKM-E[L-c (RGDxK) through the ESI-MS mass spectral analysis] 2D, Chelator-PKM-E[L-c (RGDxK)] 2Preparation (Chelator is DOTA or DTPA or NOTA or TETA or derivatives thereof)
With Chelator and PKM-E[L-c (RGDxK)] 2Be dissolved among the 1mL DMF (dimethyl formamide), pH regulator arrived 8.5-9.0, stirred overnight at room temperature with DIEA (N, N-diisopropylethylamine); Product is collected the fraction of object through ZorbaxC18 semi-preparative column HPLC separation and purification, merges to collect liquid and lyophilizing;
E, Nuclide-Chelator-PKM-E[L-c (RGDxK)] 2Preparation (Nuclide is 111In or 90Y or 177Lu or 68Ga or 64Cu)
0.2mL is dissolved with Chelator-PKM-E[L-c (RGDxK)] 2NaOAc (pH=5.0) buffer solution of conjugate (concentration 0.2-0.5mg/mL) joins in the cillin bottle, add 10-50 μ L radionuclide (20-50mCi), 100 ℃ of heating in water bath cillin bottles, reacted 10-15 minute, reaction finishes back room temperature cooling 10 minutes, makes rgd peptide radiopharmaceutical Nuclide-Chelator-PKM-E[L-c (RGDxK)] 2
9, the integrin α that is used for according to claim 8 vβ 3The radiopharmaceutic preparation method of the rgd peptide of positive tumor, it is characterized in that: described HPLC method is for using LabAlliance HPLC system disposition Zorbax C18 semi-preparative column, gradient elution 36 minutes, flow velocity 2.5mL/min, wherein mobile phase A is 25mM NH 4OAc, B are the second eyeball; The drip washing gradient is set at 90%A and 10%B when initial, 85%A and 15%B in the time of 5 minutes, 65%A and 35%B in the time of 30 minutes, 50%A and 50%B in the time of 32-36 minute.
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