CN106581700B - A kind of novel polypeptide radiopharmaceutical for targeting HER2 and its preparation method and application - Google Patents
A kind of novel polypeptide radiopharmaceutical for targeting HER2 and its preparation method and application Download PDFInfo
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- CN106581700B CN106581700B CN201611095338.5A CN201611095338A CN106581700B CN 106581700 B CN106581700 B CN 106581700B CN 201611095338 A CN201611095338 A CN 201611095338A CN 106581700 B CN106581700 B CN 106581700B
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 58
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 57
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 57
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 title claims abstract description 47
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 title claims abstract description 47
- 230000008685 targeting Effects 0.000 title claims abstract description 32
- 239000012217 radiopharmaceutical Substances 0.000 title claims abstract description 31
- 229940121896 radiopharmaceutical Drugs 0.000 title claims abstract description 31
- 230000002799 radiopharmaceutical effect Effects 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 239000002738 chelating agent Substances 0.000 claims abstract description 9
- 230000001588 bifunctional effect Effects 0.000 claims abstract description 7
- 238000002347 injection Methods 0.000 claims abstract description 5
- 239000007924 injection Substances 0.000 claims abstract description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- 206010006187 Breast cancer Diseases 0.000 claims description 11
- 208000026310 Breast neoplasm Diseases 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- 239000001384 succinic acid Substances 0.000 claims description 10
- -1 trihydroxy methyl Chemical group 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 108010077895 Sarcosine Proteins 0.000 claims description 9
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 9
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 5
- 239000008236 heating water Substances 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- VYFPSYVVFFFYBF-UHFFFAOYSA-N sodium;triphenylphosphane Chemical compound [Na].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VYFPSYVVFFFYBF-UHFFFAOYSA-N 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 238000003745 diagnosis Methods 0.000 claims description 3
- 230000004807 localization Effects 0.000 claims description 3
- 230000002285 radioactive effect Effects 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 229960000575 trastuzumab Drugs 0.000 description 7
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 229940022353 herceptin Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 3
- 239000007997 Tricine buffer Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- MYAJTCUQMQREFZ-UHFFFAOYSA-K tppts Chemical compound [Na+].[Na+].[Na+].[O-]S(=O)(=O)C1=CC=CC(P(C=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=C(C=CC=2)S([O-])(=O)=O)=C1 MYAJTCUQMQREFZ-UHFFFAOYSA-K 0.000 description 3
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000005075 mammary gland Anatomy 0.000 description 2
- 238000011242 molecular targeted therapy Methods 0.000 description 2
- 230000000149 penetrating effect Effects 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 2
- NAQWICRLNQSPPW-UHFFFAOYSA-N 1,2,3,4-tetrachloronaphthalene Chemical compound C1=CC=CC2=C(Cl)C(Cl)=C(Cl)C(Cl)=C21 NAQWICRLNQSPPW-UHFFFAOYSA-N 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011337 individualized treatment Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000012831 peritoneal equilibrium test Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000012636 positron electron tomography Methods 0.000 description 1
- 238000012877 positron emission topography Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/025—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus inorganic Tc complexes or compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
Abstract
The present invention provides a kind of novel polypeptide radiopharmaceutical for targeting HER2 and its preparation method and application, the novel polypeptide radiopharmaceutical of the targeting HER2 includes HYLF8 polypeptides and radionuclide99mTc, the HYLF8 polypeptides are to be connected polypeptide YLFFVFER with bifunctional chelating agent HYNIC, i.e. HYNIC YLFFVFER；The radionuclide99mTc marks the HYLF8 polypeptides to get to the novel polypeptide radiopharmaceutical of the targeting HER2 by bifunctional chelating agent HYNIC, i.e.,99mTc HYLF8, the novel polypeptide radiopharmaceutical of the targeting HER2 is colourless transparent liquid injection.
Description
Technical field
The present invention relates to diagnosing tumor radiopharmaceutical, more particularly to a kind of novel polypeptide radiopharmaceutical for targeting HER2
And its preparation method and application.
Background technology
In worldwide, breast cancer still comes first of women's kinds of tumor, and the death rate is located at second.Mesh
Before, the methods for clinical diagnosis of breast cancer routine includes mammary X-ray photography, color ultrasound and MRI.These Imaging Methods and breast tissue
Biopsy is compared, have the advantages that it is noninvasive, but be also faced with accuracy rate it is low, lack specificity, molecular level information can not be provided
The shortcomings of.As the important mode of molecular imaging, PET and SPECT are clinically widely used.They the characteristics of
It is high sensitivity, and with accurate quantitative analysis and tumor-related molecules horizontal information can be provided.At present, clinically 25% ~ 30%
All there are the height expression of HER2 albumen for patients with breast cancer cell.The high expression of HER2 is often implied with high transfer wind
Danger, Tumor Differentiation difference and prognosis are bad.As what HER2 was studied gos deep into, become mammary gland for the molecular targeted therapy of HER2
The important directions of cancer Therapy study.Herceptin（Trastuzumab, trastuzumab）It is that first, the whole world goes through to be applied to face
The specific humanized monoclonal antibodies of HER2 of bed.Trastuzumab energy specific effects are in the HER2 on breast cancer cell surface
Receptor, and immunocyte is induced to kill tumour, it is smaller to the killing of normal cell, there is high-affinity and targeting, be mammary gland
The representative drugs of cancer molecular targeted therapy.However, not all patient has response to the treatment of Trastuzumab,
Only the breast cancer patients of fraction can benefit from treatment.More seriously, most patient with breast cancer eventually exists
Generate drug resistance in Trastuzumab therapeutic processes, and the somewhat expensive of Trastuzumab immunization therapies, cycle are long.Therefore, build
Vertical new breast cancer HER2 targeting nucleus medical image methods for screening patient, accurately monitoring curative effect, reasonably exactly
It arranges therapeutic scheme, prognostic evaluation is effectively performed finally to realize that individualized treatment is of great significance.
The content of the invention
Object of the present invention is to provide a kind of novel polypeptide radiopharmaceutical for targeting HER2, which passes through double work(
Can chelating agent by radionuclide99mTc is tagged on HYLF8 peptide molecules, the target that labeled drug passes through HYLF8 polypeptides in vivo
Gather tumor locus to effect is dense, using the single photon tomography technology of nuclear medicine, imaging is carried out to HER2 positive tumors and is examined
It is disconnected.
The purpose of the present invention is what is be achieved through the following technical solutions：
A kind of novel polypeptide radiopharmaceutical for targeting HER2, including HYLF8 polypeptides and radionuclide99mTc, it is described
HYLF8 polypeptides are to be connected polypeptide YLFFVFER with bifunctional chelating agent HYNIC, i.e. HYNIC-YLFFVFER；The radioactivity
Nucleic99mTc marks the HYLF8 polypeptides to be put to get the novel polypeptide to the targeting HER2 by bifunctional chelating agent HYNIC
Penetrating property drug, i.e.,99mTc-HYLF8, the novel polypeptide radiopharmaceutical of the targeting HER2 is colourless transparent liquid injection.
The preparation method of the novel polypeptide radiopharmaceutical of the targeting HER2, comprises the following steps：
A, the preparation of HYNIC-YLFFVFER
SBz-HYNIC and Fmoc-YLFFVFER polypeptides are dissolved in DMF, are adjusted with DIEA (n,N-diisopropylethylamine)
PH value is stirred overnight at room temperature to 8.5-9.0；Adding in piperidines makes final concentration of 20%, reacts at room temperature 10 minutes, obtained product warp
YMC-Pack ODS-A semi-preparative columns HPLC is isolated and purified, and collects the fraction of object, is merged collection liquid and is freezed, and is obtained described
HYLF8 linear polypeptides, i.e. HYNIC-YLFFVFER；
b、99mThe preparation of Tc-HYLF8
1）Prepare the mixed of sodium trisulfonate containing triphenylphosphine, trihydroxy methyl glycine, disodium succinate, succinic acid and HYLF8
500 μ L of liquid are closed in 10 mL cillin bottles, add in Na of the radioactive activity in 10 ~ 50 mCi of 1.0-1.5 mL99mTcO4It is molten
Liquid, 100 DEG C of heating water bath cillin bottles react 20 ~ 25 minutes, treat that room temperature cools down 10 minutes after reaction, is made the targeting
The novel polypeptide radiopharmaceutical of HER2, i.e.,99mTc-HYLF8；
Further, sodium trisulfonate containing triphenylphosphine, trihydroxy methyl glycine, disodium succinate, succinic acid described in step b
In the mixed liquor of HYLF8, the content of each substance is：
5.0 mg of triphenylphosphine sodium trisulfonate
6.5 mg of trihydroxy methyl glycine
38.5 mg of disodium succinate
12.7 mg of succinic acid
HYLF8 20 μg。
Further, HPLC methods described in step b are to be equipped with YMC-Pack using 1260 HPLC systems of Agilent
ODS-A semi-preparative columns, gradient elution 35 minutes, wherein 4 mL/min of flow velocity, mobile phase A are H2O, B are acetonitrile, elute gradient
It is set as 100% A at 0-5 minutes, 50% A and 50% B at 15 minutes, 30% A and 70% B at 25 minutes, 50% A at 30 minutes
With 50% B, 100% A at 35 minutes.
The application of the novel polypeptide radiopharmaceutical of the targeting HER2, the novel polypeptide radioactivity of the targeting HER2
Drug can be used for the radiopharmaceutical for preparing HER2 positive tumor localization diagnosises.
Further, the HER2 positive tumors include breast cancer, cancer of pancreas, the carcinoma of the rectum, stomach cancer.
The present invention having the beneficial effect that compared with prior art：
1st, use HYNIC in the present invention as bifunctional chelating agent, at the same use tricine (trihydroxy methyl glycine) and
TPPTS (trisodium triphenylphosphine- 3,3', 3''-trisulfonate, triphenylphosphine sodium trisulfonate)
As synergy modes so that "99mTc-HYNIC cores " have more good internal external stability；
2nd, the HYLF8 polypeptides for targeting HER2 have good HER2 Targeting Performances, can effectively tell different tumours
The HER2 expressions of cell.It is worth noting that, HYLF8 is different from the HER2 binding sites of Herceptin so that it has
There is the situation of change of HER2 in monitoring Herceptin therapeutic process in real time, and the shadow of excessive Herceptin will not be subject to
It rings.This can effectively instruct the treatment of Herceptin, play a key effect for the accurate medication of patient with breast cancer；
3rd, the novel polypeptide radiopharmaceutical of targeting HER2 of the present invention, can be applied to HER2 positive tumor patients'
Localization diagnosis and monitoring and therapeutic evaluation to receiving anticancer drug Trastuzumab treatment patients.
Description of the drawings
Fig. 1 for HYLF8 and its99mTc tag structure schematic diagrames；
Fig. 2 is99mInternal distribution results of the Tc-HYLF8 in MDA-MB-453 breast cancer BALB/c nude mice models；
Fig. 3 is injection99mThe SPECT imaging figures of MDA-MB-453 cancers of pancreas BALB/c nude mice models after Tc-HYLF8.
Specific embodiment
Material employed in the embodiment of the present invention：succinic acid（Succinic acid）、disodium succinate
hexahydrate （Disodium succinate）、trisodium triphenylpheosphine-3,3',3''-trisulfonate
（TPPTS, triphenylphosphine sodium trisulfonate）、N,N-Dimethylform amide（DMF, n,N-Dimethylformamide）、tricine
（Trihydroxy methyl glycine）It is purchased from Sigma-Aldrich.YLFFVFER polypeptide monomers are purchased from China CSBio
Ltd. company.Na99mTcO4Eluent is purchased from Beijing Atom High Tech Co., Ltd..
The present embodiment is to target the novel polypeptide radiopharmaceutical of HER2, i.e.,99mTc-HYLF8 polypeptide radiopharmaceuticals and its
Exemplified by preparation method.
The novel polypeptide radiopharmaceutical of the targeting HER2, including HYLF8 polypeptides and radionuclide99mTc.It is described to put
Penetrating property nucleic99mTc marks the HYLF8 polypeptides by difunctional chelation group HYNIC, and the HYLF8 linear polypeptides are will be more
P277 LFFVFER is connected with bifunctional chelating agent HYNIC, i.e. HYNIC-YLFFVFER, described99mTc-HYLF8 polypeptide radioactivity medicines
Object is colourless transparent liquid injection.
The preparation method of the novel polypeptide radiopharmaceutical of the targeting HER2 is as follows：
A. the preparation of YLFFVFER-HYNIC：SBz-HYNIC and Fmoc-YLFFVFER polypeptides are dissolved in DMF, are used
DIEA adjusts pH value to 8.5-9.0, is stirred overnight at room temperature；Adding in piperidines makes final concentration of 20%, reacts at room temperature 10 minutes.Product
It is isolated and purified through YMC-Pack ODS-A semi-preparative columns HPLC, collects the fraction of object, merge collection liquid and freezed.
b. 99mThe preparation of Tc-HYLF8：Sodium trisulfonate containing triphenylphosphine (TPPTS) 5.0 mg is prepared, trihydroxy methyl is sweet
Propylhomoserin（tricine）The mixed liquor 500 of the HYLF8 of 6.5 mg, 38.5 mg of disodium succinate, 12.7 mg of succinic acid and 20 μ g
μ L add in the Na of 1.0-1.5 mL in 10 mL cillin bottles99mTcO4Solution（10~50 mCi）, 100 °C of heating water bath XiLin
Bottle reaction 20 ~ 25 minutes treats that room temperature cools down 10 minutes after reaction, is made the novel polypeptide radiopharmaceutical of targeting HER2.
Radioactivity is carried out to the HYLF8 polypeptide radiopharmaceuticals 99mTc-HYLF8 samplings prepared according to the method for the present invention
HPLC is analyzed（Using 1260 HPLC systems of Agilent, C18 points of radioactivity on-line checking device and YMC-Pack ODS-A are equipped with
Analyse column（4.6mm × 250mm, 300pore size）, gradient elution 35 minutes, 1.0 mL/min of flow velocity.Wherein mobile phase A is
H2O, B are acetonitrile.Elution gradient is set as 100% A at 0-5 minutes, 50% A and 50% B at 15 minutes, 30% A at 25 minutes
With 70% B, 50% A and 50% B at 30 minutes, 100% A at 35 minutes.
Claims (4)
1. a kind of novel polypeptide radiopharmaceutical for targeting HER2 is used to prepare the radioactivity medicine of HER2 positive tumor localization diagnosises
The application of object, including HYLF8 polypeptides and radionuclide99mTc, which is characterized in that the HYLF8 polypeptides are by polypeptide
YLFFVFER is connected with bifunctional chelating agent HYNIC, i.e. HYNIC-YLFFVFER；The radionuclide99mTc passes through difunctional
Chelating agent HYNIC marks the HYLF8 polypeptides to get to the novel polypeptide radiopharmaceutical of the targeting HER2, i.e.,99mTc-
HYLF8, the novel polypeptide radiopharmaceutical of the targeting HER2 is colourless transparent liquid injection；
The method for preparing the novel polypeptide radiopharmaceutical of the targeting HER2 comprises the following steps：
A, SBz-HYNIC and Fmoc-YLFFVFER polypeptides are dissolved in DMF by the preparation of HYNIC-YLFFVFER, are adjusted with DIEA
PH value is stirred overnight at room temperature to 8.5-9.0；Adding in piperidines makes final concentration of 20%, reacts at room temperature 10 minutes, obtained product warp
YMC-Pack ODS-A semi-preparative columns HPLC is isolated and purified, and collects the fraction of object, is merged collection liquid and is freezed, and is obtained described
HYLF8 linear polypeptides, i.e. HYNIC-YLFFVFER；
b、99mThe preparation of Tc-HYLF8
1）Prepare the mixed liquor of sodium trisulfonate containing triphenylphosphine, trihydroxy methyl glycine, disodium succinate, succinic acid and HYLF8
500 μ L add in Na of the radioactive activity in 10 ~ 50 mCi of 1.0-1.5 mL in 10 mL cillin bottles99mTcO4Solution,
100 DEG C of heating water bath cillin bottles react 20 ~ 25 minutes, treat that room temperature cools down 10 minutes after reaction, is made the targeting
The novel polypeptide radiopharmaceutical of HER2, i.e.,99mTc-HYLF8。
2. a kind of preparation method of the novel polypeptide radiopharmaceutical of targeting HER2 as described in claim 1, which is characterized in that
It the described method comprises the following steps：
A, SBz-HYNIC and Fmoc-YLFFVFER polypeptides are dissolved in DMF by the preparation of HYNIC-YLFFVFER, are adjusted with DIEA
PH value is stirred overnight at room temperature to 8.5-9.0；Adding in piperidines makes final concentration of 20%, reacts at room temperature 10 minutes, obtained product warp
YMC-Pack ODS-A semi-preparative columns HPLC is isolated and purified, and collects the fraction of object, is merged collection liquid and is freezed, and is obtained described
HYLF8 linear polypeptides, i.e. HYNIC-YLFFVFER；
b、99mThe preparation of Tc-HYLF8
1）Prepare the mixed liquor of sodium trisulfonate containing triphenylphosphine, trihydroxy methyl glycine, disodium succinate, succinic acid and HYLF8
500 μ L add in Na of the radioactive activity in 10 ~ 50 mCi of 1.0-1.5 mL in 10 mL cillin bottles99mTcO4Solution,
100 DEG C of heating water bath cillin bottles react 20 ~ 25 minutes, treat that room temperature cools down 10 minutes after reaction, is made the targeting
The novel polypeptide radiopharmaceutical of HER2, i.e.,99mTc-HYLF8；
The sodium trisulfonate containing triphenylphosphine, trihydroxy methyl glycine, disodium succinate, succinic acid and HYLF8 mixed liquor in,
The content of each substance is：
5.0 mg of triphenylphosphine sodium trisulfonate
6.5 mg of trihydroxy methyl glycine
38.5 mg of disodium succinate
12.7 mg of succinic acid
HYLF8 20 μg。
3. the preparation method of the novel polypeptide radiopharmaceutical of targeting HER2 according to claim 2, which is characterized in that step
HPLC methods described in rapid b are to be equipped with YMC-Pack ODS-A semi-preparative columns, gradient elution using 1260 HPLC systems of Agilent
35 minutes, 4 mL/min of flow velocity, wherein mobile phase A were H2O, B are acetonitrile, and elution gradient is set as 100% A at 0-5 minutes,
50% A and 50% B at 15 minutes, 30% A and 70% B at 25 minutes, 50% A and 50% B at 30 minutes, 100% at 35 minutes
A。
4. the application of the novel polypeptide radiopharmaceutical of targeting HER2 according to claim 1, which is characterized in that described
HER2 positive tumors include breast cancer, cancer of pancreas, the carcinoma of the rectum, stomach cancer.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611095338.5A CN106581700B (en) | 2016-12-02 | 2016-12-02 | A kind of novel polypeptide radiopharmaceutical for targeting HER2 and its preparation method and application |
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| CN106581700B true CN106581700B (en) | 2018-05-18 |
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|---|---|---|---|---|
| CN109045313B (en) * | 2018-09-11 | 2020-02-18 | 北京大学 | D-type polypeptide radiopharmaceutical targeting HER2 and preparation method thereof |
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| CN112358531B (en) * | 2020-11-09 | 2022-05-27 | 国家纳米科学中心 | Polypeptide targeting HER2 protein and application thereof |
| CN114456227B (en) * | 2022-01-19 | 2023-03-21 | 北京师范大学 | Technetium-99 m labeled D-proline-containing glycine polypeptide modified FAPI derivative, and preparation method and application thereof |
| CN117430670A (en) * | 2022-07-20 | 2024-01-23 | 中国科学院上海药物研究所 | HER2 targeting peptide molecule and application thereof |
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