CN101485891A - Radioactive nuclide marked RGD polypeptide medicament and preparation method thereof - Google Patents

Radioactive nuclide marked RGD polypeptide medicament and preparation method thereof Download PDF

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CN101485891A
CN101485891A CNA2009100777283A CN200910077728A CN101485891A CN 101485891 A CN101485891 A CN 101485891A CN A2009100777283 A CNA2009100777283 A CN A2009100777283A CN 200910077728 A CN200910077728 A CN 200910077728A CN 101485891 A CN101485891 A CN 101485891A
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rgdxk
rgd
product
pkm
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王凡
史继云
贾兵
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Peking University
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Peking University
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Abstract

The invention relates to a radionuclide-marked RGD polypeptide medicine and a preparation method thereof. The medicine comprises RGD polypeptide, a bifunctional Chelator and radioactive Nuclide, wherein the RGD polypeptide is RGD cyclic peptide dimer, namely E(L-c(RGDxK))2, which is synthesized by connecting a connecting agent L and an RGD polypeptide monomer and dimerizing two RGD polypeptide monomers connected with the connecting agent L; the radioactive Nuclide marks the RGD cyclic peptide dimer through the bifunctional Chelator; and a pharmacokinetic modified molecule PKM is also connected between the RGD cyclic peptide dimer and the bifunctional Chelator. The radionuclide-marked RGD polypeptide medicine is Nuclide-Chelator-PKM-E(L-c(RGDxK))2, and is a colorless and transparent liquid injection solution. The radionuclide-marked RGD polypeptide medicine is used for diagnosing and treating integrin alpha v beta 3 positive tumor.

Description

Rgd peptide medicine of radioisotope labeling 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 medicine of the radioisotope labeling of positive tumor diagnosis and treatment 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 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 radiopharmaceutical of positive tumor diagnosis and treatment is to reach better diagnosis and treatment effect.
Summary of the invention
The object of the present invention is to provide rgd peptide medicine of a kind of radioisotope labeling 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 this dimerization, 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 diagnosis and treatment effect.This medicine passes through MAG 2(S-Acetyl-Mercaptocacetyl-glycyl-glycine, thioacetyl-glycine-glycine) or N 2S 2Or N 3Bifunctional chelating agents such as S are with radionuclide 99mTc or 188The Re 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, 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 MAG 2Or N 2S 2Or N 3Bifunctional chelating agent labelling radionuclides such as S 99mDuring Tc, the rgd peptide medicine of radioisotope labeling of the present invention is used for the α to integrin vβ 3Positive tumor carries out the diagnosis of single photon tomography.When passing through MAG 2Or N 2S 2Or N 3Bifunctional chelating agent labelling radionuclides such as S 188During Re, the rgd peptide medicine of radioisotope labeling 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 rgd peptide medicine of radioisotope labeling, 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 the rgd peptide monomer, again with two rgd peptide monomer dimerizations that are connected with bridging agent L and synthetic RGD cyclic peptide dimer, i.e. E[L-c (RGDxK)] 2, described radionuclide also is connected with pharmacokinetics decorating molecule PKM by the described RGD cyclic peptide of a bifunctional chelating agent labelling dimer between described RGD cyclic peptide dimer and the described bifunctional chelating agent; The rgd peptide medicine of described radioisotope labeling is Nuclide-Chelator-PKM-E[L-c (RGDxK)] 2, the rgd peptide medicine of described radioisotope labeling is the colourless transparent liquid injection.
Described radionuclide is 99mTc.
Described radionuclide is 188Re.
Described bridging agent L is PEG 4Or G 3
Described pharmacokinetics decorating molecule PKM is G 2Or G 3Or G 4Or PEG 4
Described bifunctional chelating agent is MAG 2Or N 2S 2Or N 3S.
A kind of preparation method of rgd peptide medicine of radioisotope labeling said method comprising the steps of: the preparation (L=PEG of a, L-c (RGDxK) 4Or G 3)
With Boc (t-Butyl carbamate, tertbutyloxycarbonyl) Bao Hu bridging agent L is dissolved among the 1 mL DMF (dimethyl formamide), add NHS (N-hydroxy-succinamide also is HOSu) and DCC (dicyclohexylcarbodiimide), stirring reaction is 2 hours under the room temperature; 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 3 mL 0.5MNH 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 3.0 mL TFA (trifluoroacetic acid) room temperature reaction 30 minutes; Revolve and boil off except that TFA, residue is dissolved in 2mL 0.5 M 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=G 2Or G 3Or G 4Or PEG 4)
With Boe-PKM-OSu and E[L-c (RGDxK)] 2Be dissolved in 2mL DMF and H 2The mixed liquor of O (1:1=v:v) uses 0.1 N 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=MAG 2Or N 2S 2Or N 3S)
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= 99mTc or 188Re)
Configuration 1mL contains the 40mg glucoheptose, 25-50 μ g Chelator-PKM-E[L-c (RGDxK)] 2Conjugate and 50 μ g SnCl 2PB (pH=7.4) buffer solution in the 10mL cillin bottle, add 10-50 μ L radionuclide then 99mTc or 188Re (20-50mCi), 100 ℃ of heating in water bath cillin bottles reacted 20-25 minute, reaction finishes back room temperature cooling 10 minutes, makes the rgd peptide medicine Nuclide-Chelator-PKM-E[L-c (RGDxK) of radioisotope labeling] 2
Described HPLC method is use LabAlliance HPLC 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, at the rgd peptide medicine of radioisotope labeling of the present invention, at first with three glycine molecule (G 3) or four peg molecule (PEG 4) be connected with the rgd peptide monomer, 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 and treatment effect.
2, the present invention not only introduces G between two RGD blocks 3And PEG 4, between rgd peptide molecule and bifunctional chelating agent, introduce pharmacokinetics decorating molecule PKM, i.e. Chelator-PKM-E[L-c (RGDxK) simultaneously] 2, with the further pharmacokinetic property that improves, particularly from the removing kinetics of nonneoplastic tissue.
3, use MAG among the present invention 2Or N 2S 2Or N 3Chemical compounds such as S are as bifunctional chelating agent, the labelling radionuclide 99mTc is used for the single photon tomography, the labelling radionuclide 188Re is used for the radiation targeted therapy of 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 99mTc tag structure sketch map;
Fig. 4 is different rgd peptide extracorporeal receptor competition binding analysis;
Fig. 5 is 99mThe different rgd peptides of Tc labelling are in the contrast of injection back different time in the glioma picked-up;
Fig. 6 is injection 99mTc-MAG 2-3PEG 4The γ video picture figure of 30min 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-Dimethylform amide (DMF, N, dinethylformamide), Trifluoroacetic acid (TFA, trifluoroacetic acid), MAG 2(S-Acetyl-Mercaptocacetyl-glycyl-glycine, thioacetyl-glycine-glycine), N 2S 2, N 3S is available from U.S. Sigma-Aldrich company.Cyclisation rgd peptide monomer c (RGDfK)] 2Available from U.S. PeptideInternational, Inc. company.Na 99mTcO 4Eluent is available from Beijing Atom High Tech Co., Ltd.. 188The Re nucleic is available from U.S. PerkinElmer company.
Embodiment 1:
Present embodiment is with radionuclide 99mThe rgd peptide medicine of Tc labelling 99mTc-MAG 2-PEG 4-E[PEG 4-c (RGDfK)] 2(be called for short 99mTc-MAG 2-3PEG 4-be example dimer) and preparation method thereof.
99mTc-MAG 2-PEG 4-E[PEG 4-c (RGDfK)] 2In, 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 dimerization and synthetic RGD cyclic peptide dimer, i.e. E[PEG 4-c (RGDfK)] 2, radionuclide 99mTc is by a bifunctional chelating agent MAG 2The described RGD cyclic peptide of labelling dimer also is connected with pharmacokinetics decorating molecule PEG between described RGD cyclic peptide dimer and the described bifunctional chelating agent 4, the rgd peptide medicine of described radioisotope labeling 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 passes through MAG 2As bifunctional chelating agent with radionuclide 99mThe Tc 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.
99mTc-MAG 2-PEG 4-E[PEG 4-c (RGDfK)] 2Preparation 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 A200910077728D0010094846QIETU
Pore size), gradient elution 36 minutes, flow velocity 2.5mL/min, wherein mobile phase A is 25mM NH 4OAc (pH5.0), B are 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): with the PEG of 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 3 mL 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 0.5 M NH 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 1 mL 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 mol) 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.
MAG 2-PEG 4-E[PEG 4-c (RGDfK)] 2(be called for short MAG 2-3PEG 4-dimer) preparation: with MAG 2-OSu (4mg, 9.7 μ mol) and PEG 4-E[PEG 4-c (RGDfk)] 2(5mg, 2.43 μ mol) are dissolved in 2mL DMF (dimethyl formamide) and H 2The mixed liquor of O (1:1=v:v) arrives 8.5-9.0, stirred overnight at room temperature with DIEA (N, N-diisopropylethylamine) with pH regulator; Reactant liquor is through Zorbax C18 semi-preparative column HPLC (method one) separation and purification, and the fraction when the collection retention time is 19.5 minutes merges and collects liquid and lyophilizing, obtains product 4.0mg (productive rate is 33%).ESI-MS mass spectrometry results: m/z=1176.95 ([M+2H] +/ 2), [C 105H 164N 24O 35S] 2+/ 2 theoretical values are 1177.
99mTc-MAG 2-PEG 4-E[PEG 4-c (RGDfK)] 2( 99mTc-MAG 2-3PEG 4-dimer) preparation: configuration 1mL contains the 40mg glucoheptose, 25-50 μ g MAG 2-PKM-E[L-c (RGDxK)] 2Conjugate and 50 μ gSnCl 2PB (pH=7.4) buffer solution in the 10mL cillin bottle, add 10-50 μ L radionuclide then 99mTc (20-50mCi), 100 ℃ of heating in water bath cillin bottles reacted 20-25 minute, and reaction finishes back room temperature cooling 10 minutes, makes the rgd peptide medicine of radioisotope labeling 99mTc-MAG 2-PEG 4-E[PEG 4-c (RGDfK)] 2( 99mTc-MAG 2-3PEG 4-dimer).
In the rgd peptide medicine of radioisotope labeling 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 99mTc-MAG 2-G 3-E[G 3-c (RGDfK)] 2( 99mTc-MAG 2-3G 3-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the rgd peptide medicine of radioisotope labeling of the present invention, when bifunctional chelating agent is N 2S 2The time, medicine of the present invention can be 99mTc-N 2S 2-PEG 4-E[PEG 4-c (RGDfK)] 2( 99mTc-N 2S 2-3PEG 4-dimer) or 99mTc-N 2S 2-G 3-E[G 3-c (RGDfK)] 2( 99mTc-N 2S 2-3G 3-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the rgd peptide medicine of radioisotope labeling of the present invention, when bifunctional chelating agent is N 3During S, medicine of the present invention can be 99mTc-N 3S-PEG 4-E[PEG 4-c (RGDfK)] 2( 99mTc-N 3S-3PEG 4-dimer) or 99mTc-N 3S-G 3-E[G 3-c (RGDfK)] 2( 99mTc-N 3S-3G 3-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
Referring to Fig. 3, Fig. 3 be RGD cyclic peptide dimer and 99mTc tag structure sketch map.
Rgd peptide medicine to the radioisotope labeling of foundation the inventive method preparation 99mTc-MAG 2-3PEG 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 (4.6mmx 250mm, 300
Figure A200910077728D0010094846QIETU
Pore size), gradient elution 30 minutes, flow velocity 1.0mL/min, wherein mobile phase A is 25mM NH 4OAc (pH5.0), B are 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, and 80% A and 20% B in the time of 15 minutes, 50% A and 50% B in the time of 20-25 minute, 26-30 get back to baseline gradient 90% A and 10% B drip washing), 99mTc-MAG 2-3PEG 4The mark rate of-dimer〉95%, radiochemical purity behind Sep-Pak C18 column purification〉98%.
MAG 2-3PEG 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 MAG 2-3PEG 4The IC of-dimer 50Value (503nhibiting concentration), and establish c (RGDyK), MAG 2-PEG 4-c (RGDfK) (MAG 2-PEG 4-monomer), MAG 2-G 3-E[G 3-c (RGDfK)] 2(MAG 2-3G 3-dimer), HYNIC-PEG 4-E[PEG 4-c (RGDfK)] 2(HYNIC-3PEG 4-dimer) and PEG 4-E[PEG 4-c (RGDfK)] 2(3PEG 4-dimer) for contrasting.Experimental result shows, c (RGDyK), MAG 2-PEG 4-monomer, HYNIC-3PEG 4-dimer, MAG 2-3PEG 4-dimer, MAG 2-3G 3-dimer and 3PEG 4-dimer competition 125I-c (RGDyK) and the bonded IC of U87MG cell 50Value is respectively 50.6 ± 5.5 nM, 23.5 ± 3.5nM, and 4.1 ± 2.8 nM, 3.9 ± 1.2 nM, 3.7 ± 1.3 nM and 4.6 ± 2.1 nM (as shown in Figure 4) show MAG 2-3PEG 4-dimer, MAG 2-3G 3-dimer and integrin α vβ 3Affinity significantly better than its rgd peptide monomer and existing dimer (7.5 ± 2.3nM), illustrate that improved RGD cyclic peptide dimerization physical ability is with two valency forms and integrin α vβ 3In conjunction with.
99mTc-MAG2-3PEG4-dime 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 99mThe rgd peptide of Tc labelling, in back 0.5 hour of injection, nude mice was extremely tested by the component other places in 1.0 hours and 2.0 hours, gets blood and main organs, weighed and measured radiocounting, and the every gram of calculating is organized percentage injection dose rate (%ID/g) behind decay correction.In U87MG human glioma animal model, tumor is right 99mTc-MAG2-3PEG4-dimer and 99mTc-MAG2-3G 3The picked-up of-dimer is right apparently higher than tumor 99mThe picked-up of Tc-HYNIC-dimer (Fig. 5), injection back 1h tumor is right 99mTc-MAG2-3PEG4-dimer and 99mTc-MAG2-3G 3The picked-up of-dimer is that tumor is right 99mThe twice of Tc-HYNIC-dimer picked-up, this is consistent with extracorporeal receptor affinity experimental result, proves absolutely 99mTc-MAG 2-3PEG 4-dimer, 99mTc-MAG 2-3G 3-dimer is with two valency forms and integrin α vβ 3In conjunction with, and 99mTc-HYNIC-dimer is with unit price form and integrin α vβ 3In conjunction with.Fig. 6 is the injection of lotus U87MG human glioma nude mice 99mTc-MAG 2-3PEG 4The γ video picture figure of 30min behind the-dimer, injection back 30min tumor is high-visible, and body radioactivity background lower (labeled drug is mainly through renal excretion) except that kidney is more conducive to the localization diagnosis of tumor.
Embodiment 2:
Present embodiment is with radionuclide 188The rgd peptide medicine of Re labelling 188Re-MAG 2-PEG 4-E[PEG 4-c (RGDfK)] 2(be called for short 188Re-MAG 2-3PEG 4-dimer) be example.
188Re-MAG 2-PEG 4-E[PEG 4-c (RGDfK)] 2In, 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 dimerization and synthetic RGD cyclic peptide dimer, i.e. E[PEG 4-c (RGDfK)] 2, radionuclide 188Re is by a bifunctional chelating agent MAG 2The described RGD cyclic peptide of labelling dimer also is connected with pharmacokinetics decorating molecule PEG between described RGD cyclic peptide dimer and the described bifunctional chelating agent 4, the rgd peptide medicine of described radioisotope labeling is the colourless transparent liquid injection.
The rgd peptide medicine of the radioisotope labeling of present embodiment is 188Re-MAG 2-PEG 4-E[PEG 4-c (RGDfK)] 2, this medicine is by bifunctional chelating agent MAG 2With radionuclide 188The Re 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.The rgd peptide medicine of the radioisotope labeling in the present embodiment is used for integrin α vβ 3The radiation targeted therapy of positive tumor.
The rgd peptide process for preparing medicine of the radioisotope labeling of present embodiment is with embodiment 1.
In the rgd peptide medicine of radioisotope labeling 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 188Re-MAG 2-G 3-E[G 3-c (RGDfK)] 2( 188Re-MAG 2-3G 3-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the rgd peptide medicine of radioisotope labeling of the present invention, when bifunctional chelating agent is N 2S 2The time, medicine of the present invention can be 188Re-N 2S 2-PEG 4-E[PEG 4-c (RGDfK)] 2( 188Re-N 2S 2-3PEG 4-dimer) or 188Re-N 2S 2-G 3-E[G 3-c (RGDfK)] 2( 188Re-N 2S 2-3G 3-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4
In the rgd peptide medicine of radioisotope labeling of the present invention, when bifunctional chelating agent is N 3During S, medicine of the present invention can be 188Re-N 3S-PEG 4-E[PEG 4-c (RGDfK)] 2( 188Re-N 3S-3PEG 4-dimer) or 188Re-N 3S-G 3-E[G 3-c (RGDfK)] 2( 188Re-N 3S-3G 3-dimer), its preparation method is with embodiment 1.Pharmacokinetics decorating molecule PKM also can be G 2Or G 4

Claims (8)

1, a kind of rgd peptide medicine of radioisotope labeling, 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 the rgd peptide monomer, again with two rgd peptide monomer dimerizations that are connected with bridging agent L and synthetic RGD cyclic peptide dimer, i.e. E[L-c (RGDxK)] 2, described radionuclide also is connected with pharmacokinetics decorating molecule PKM by the described RGD cyclic peptide of a bifunctional chelating agent labelling dimer between described RGD cyclic peptide dimer and the described bifunctional chelating agent; The rgd peptide medicine of described radioisotope labeling is Nuclide-Chelator-PKM-E[L-c (RGDxK)] 2, the rgd peptide medicine of described radioisotope labeling is the colourless transparent liquid injection.
2, the rgd peptide medicine of radioisotope labeling according to claim 1, it is characterized in that: described radionuclide is 99mTc.
3, the rgd peptide medicine of radioisotope labeling according to claim 1, it is characterized in that: described radionuclide is 188Re.
4, according to the rgd peptide medicine of claim 2 or 3 described radioisotope labelings, it is characterized in that: described bridging agent L is PEG 4Or G 3
5, according to the rgd peptide medicine of claim 2 or 3 described radioisotope labelings, it is characterized in that: described pharmacokinetics decorating molecule PKM is G 2Or G 3Or G 4Or PEG 4
6, according to the rgd peptide medicine of claim 2 or 3 described radioisotope labelings, it is characterized in that: described bifunctional chelating agent is MAG 2Or N 2S 2Or N 3S.
7, the preparation method of the rgd peptide medicine of the described radioisotope labeling of a kind of claim 1 is characterized in that: said method comprising the steps of:
Preparation (the L=PEG 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; 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 3mL 0.5M 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 3.0mLTFA (trifluoroacetic acid) room temperature reaction 30 minutes; Revolve and boil off except that TFA, residue is dissolved in 2mL 0.5MNH 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=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] 2
D, Chelator-PKM-E[L-c (RGDxK)] 2Preparation (Chelator=MAG 2Or N 2S 2Or N 3S)
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= 99mTc or 188Re)
Configuration 1mL contains the 40mg glucoheptose, 25-50 μ g Chelator-PKM-E[L-c (RGDxK)] 2Conjugate and 50 μ g SnCl 2PB (pH=7.4) buffer solution in the 10mL cillin bottle, add 10-50 μ L radionuclide Nuclide (20-50mCi) then, 100 ℃ of heating in water bath cillin bottles, reacted 20-25 minute, reaction finishes back room temperature cooling 10 minutes, makes the rgd peptide medicine Nuclide-Chelator-PKM-E[L-c (RGDxK) of radioisotope labeling] 2
8, the preparation method of the rgd peptide medicine of radioisotope labeling according to claim 7, 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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