CN106478820A - A kind of liver cancer PET diagnosis tracer and preparation method thereof and purposes - Google Patents

A kind of liver cancer PET diagnosis tracer and preparation method thereof and purposes Download PDF

Info

Publication number
CN106478820A
CN106478820A CN201610885725.2A CN201610885725A CN106478820A CN 106478820 A CN106478820 A CN 106478820A CN 201610885725 A CN201610885725 A CN 201610885725A CN 106478820 A CN106478820 A CN 106478820A
Authority
CN
China
Prior art keywords
heavy chain
single domain
chain antibody
mark
domain heavy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201610885725.2A
Other languages
Chinese (zh)
Inventor
方鹏
颜成龙
虞善友
张姣
李新平
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Degree (nanjing) Biotechnology Co Ltd
Original Assignee
Degree (nanjing) Biotechnology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Degree (nanjing) Biotechnology Co Ltd filed Critical Degree (nanjing) Biotechnology Co Ltd
Priority to CN201610885725.2A priority Critical patent/CN106478820A/en
Publication of CN106478820A publication Critical patent/CN106478820A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/303—Liver or Pancreas
    • 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
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A61K51/1057—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from liver or pancreas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Oncology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cell Biology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The invention belongs to radiopharmaceutical and the field of nuclear medicine, are related to a kind of liver cancer PET diagnosis tracer and preparation method thereof and purposes.The present invention's18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark, structural formula is18The alpaca single domain heavy chain antibody of the anti-CD105 of F.Zoopery shows, is somebody's turn to do18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark, on the one hand, tumour is higher to its uptake values, and tumor imaging sensitivity is higher, and on the other hand, liver is relatively low to its uptake values, and the toxic and side effect to liver is less；This shows which can diagnose tracer as PET, diagnose tracer especially as liver cancer PET.

Description

A kind of liver cancer PET diagnosis tracer and preparation method thereof and purposes
Technical field
The invention belongs to radiopharmaceutical and the field of nuclear medicine, and in particular to a kind of liver cancer PET diagnosis tracer and its system Preparation Method and purposes.
Background technology
Positron emission computerized tomography (PET) is used as 21 century biomedical research and the sophisticated technology of clinical diagnosis, quilt Referred to as " live body biochemical imaging " technology, can from physiology noninvasive, quantitative, dynamically in observer's body in vitro and Biochemical changes, See clearly activity of the labeled drug in normal person or in patient body.Compared with SPECT, PET has high resolution and can quantitative analysis The advantages of.18F has positive electron efficiency, low positive electron energy (0.64 million electro-volt) and the relatively short physics for being close to 100% Half-life (t1/2=109.7min) the features such as, it is preferable PET imaging nucleic.
Liver cancer is the malignant tumour of liver, can be divided into primary carcinoma of liver and two big class of secondary carcinoma of liver；Primary hepatic is disliked Property tumour originates from epithelium or the mesenchymal tissue of liver, and the former is referred to as primary carcinoma of liver, is occurred frequently, the very harmful evil of China Property tumour；The latter is referred to as sarcoma, more rare compared with primary carcinoma of liver；Secondary cases claims metastatic hepatic carcinoma, means whole body The malignant tumour of multiple organs origin is invaded to liver, be typically more common in stomach, biliary tract, pancreas, Colon and rectum, ovary, uterus, lung, The hepatic metastases of the organ malignant tumours such as mammary gland.
At present, the diagnosis of liver cancer depend on liver cancer serum mark (serum alpha-fetoprotein AFP), blood zymetology and The iconographies such as CT/MRI detect that liver cancer serum mark AFP is the standard of function assessment diagnosis, but which is in polytype liver cancer sun Property rate is relatively low, particularly primary carcinoma of liver, and its positive rate is only 8%；CT/MRI imaging methods are only capable of diagnosing moderate or advanced liver cancer, Low to early liver cancer diagnosis efficiency；Primary carcinoma of liver, the sensitiveness only 50% or so of PET diagnosis, liver cancer stove is absorbed18F-FDG Degree relevant with the size of the degree that tumor tissue cell breaks up, the doubling time of tumour and tumour, low differentiation liver cancer intake18F-FDG degree is higher, and differentiated and middle differentiation are absorbed18F-FDG degree is relatively low, and normal liver tissue intake18F-FDG is relatively High.Therefore, clinically still not widely used at present18F-FDG PET carries out the diagnosis of liver cancer.
CD105 (also known as endoglin) is the glycoprotein of endothelial cell endoglin expression, is transforming growth factor β One of composition of (transform growth factor, TGF-β) receptor complex, but cell surface can be independently present in, CD105 adjusts the signal transmission of endothelium interstitial by the signal transduction of participation TGF-β acceptor, participates in Angiogenesiss, in tumour blood Play a significant role in pipe generating process.TGF-β is the polypeptide cytokines of angiogenesispromoting effect, adjusts cell propagation, swells Knurl growth, cell migration and extracellular matrix are formed.Hepatocarcinoma patient biological tissue is dissected the result of biopsy and is shown, primary carcinoma of liver The positive rate of patient's biological tissue CD105 expression is 100%, and cancer beside organism's positive rate is 40.5%, normal structure SABC Dye-free.Therefore, CD105 can be used as the important symbol of the malignant tumours such as liver cancer.
The variable region (variable domains of the HcAb, VHH) of heavy chain antibody, also referred to as single domain antibody (single domain antibody, sdAb), relative molecular mass are 15000, and only the 1/10 of conventional antibody, is at present may be used With the smallest molecule fragment with complete antibody function for obtaining, its antigen binding domain is only by 3 hypervariable regions (H1-H3) of VHH Composition, spatially defines the antigen binding domains different from conventional antibody typical structure, and the average length of H3 therein is than often Rule antibody is long, spatially can be in prominent finger.Therefore, heavy chain antibody be able to cannot be close in conjunction with some conventional antibodies Epitope (such as：Active sites in zymoprotein crack)；Additionally, which is also good, steady with easily expression, solubility Qualitative strong, the advantages of immunogenicity is weak, penetrability is good.
At present, have no18The single domain heavy chain antibody of the anti-CD105 of F mark diagnoses the report of tracer as PET.
Content of the invention
For this purpose, the present invention provides one kind18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark, and then its preparation side is provided Method and purposes.
For solving above-mentioned technical problem, the present invention is achieved through the following technical solutions：
The present invention provides a kind of18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark, its structural formula is：18F- resists The alpaca single domain heavy chain antibody of CD105.
The present invention also provides one kind18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark,
Reaction equation is as follows：
The preparation method is comprised the following steps：
S05：Take the alpaca single domain heavy chain antibody of anti-CD105 with18F-SFB is dissolved in solvent, is mixed, 60～70 React at DEG C；Cooling, during reactant liquor is added to the centrifuge tube for filling ether, centrifugation, abandon supernatant；And add ether to wash again Wash and supernatant is abandoned, the ether in the centrifuge tube is dried up, the precipitation in pipe is18The alpaca heavy chain of the anti-CD105 of F mark Single domain antibody；
The solvent is selected from water, acetonitrile, carbonate buffer solution, phosphate buffer and citrate buffer at least A kind of.
Preferably, the present invention is above-mentioned18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark,
The alpaca single domain heavy chain antibody of the anti-CD105 with described18The mol ratio of F-SFB is：1.0：(1.0～2.0).
It is further preferred that the present invention is above-mentioned18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark, institute State in step S05, the reaction time is 20～40min, the rotating speed of centrifugation is 12000-15000rpm.
It is further preferred that the present invention is above-mentioned18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark,
After the step of mixing, also include the step of pH value is adjusted to 9～10 using buffer solution；
At least one of the buffer solution in carbonate buffer solution, phosphate buffer and citrate buffer.
It is further preferred that the present invention is above-mentioned18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark, institute State18F-SFB is prepared by the following method and forms：
S01：Pass through18O (p, n)18F reaction generates carrier-free18F-, and be enriched on QMA post, with containing K2CO3/K2,2,2 Acetonitrile solution will18F-It is eluted in the first reaction tube, is passed through nitrogen heating and solution is evaporated；To in first reaction tube Acetonitrile is added, and nitrogen heating is passed through, solution is evaporated, the first reaction tube of cooling is to 35-45 DEG C；
S02：The acetonitrile solution containing SFB precursor, control temperature 110-120 DEG C reaction is added in first reaction tube 500-600s, and intermittent solution is mixed with nitrogen stream；Hydrolyze then to NaOH, 85-95 DEG C of reaction is added in reaction tube 300-400s, and intermittent solution is mixed with nitrogen stream；After hydrolysis, with the mixed solution of HCl and acetonitrile and alkali, obtain Arrive18F-FBA reactant liquor；
S03：Described in obtaining in step S0218F-FBA reactant liquor crosses a C18 post；First is dry with 90 DEG C of nitrogen streams C18 post, and with anhydrous acetonitrile by C18 post18F-FBA is eluted in the second reaction tube, is passed through in second reaction tube Nitrogen simultaneously heats eliminating water；The aqueous solution of tetrapropylammonium hydroxide TBOH is subsequently adding, is led to nitrogen and heats and react described second Liquid in pipe is evaporated, and cools down second reaction tube to 35-45 DEG C；
S04：Sealing reaction 300s at the acetonitrile solution containing TSTU, 85-95 DEG C is added in second reaction tube；Again HCl acidifying is added, the reactant liquor for obtaining is crossed the 2nd C18 post；The 2nd C18 post is dried up again with 85-95 DEG C of nitrogen stream；Washed with acetonitrile The 2nd C18 post is taken off, is obtained18F-SFB reactant liquor.
It is further preferred that the present invention is above-mentioned18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark,
In step S02, for the first time described with nitrogen stream mixed solution the step of be specially：At interval of 200s with nitrogen Reactant liquor is mixed 1 time by stream, each 5s；The step of described in second with nitrogen stream mixed solution, is specially：At interval of 100s with Solution is mixed 1 time by nitrogen stream, each 5s.
It is further preferred that the present invention is above-mentioned18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark,
In step S03, the concentration of the TBOH is 1mol/L.
It is further preferred that the present invention is above-mentioned18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark,
In step S04, in the acetonitrile solution containing TSTU, the concentration of TSTU is 12～15mg/mL.
The present invention also provides what above-mentioned preparation method was prepared18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark.
The present invention also provides above-mentioned18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark is preparing PET diagnosis tracer In application.
Preferably, the above-mentioned application of the present invention, the application are the application in liver cancer PET diagnosis tracer is prepared.
The present invention also provides a kind of PET diagnosis tracer, and which is included described in claim 1 or 1018It is anti-that F is marked The alpaca single domain heavy chain antibody of CD105.
Preferably, the above-mentioned PET of the present invention diagnoses tracer, and the PET diagnosis tracer diagnoses tracer for liver cancer PET.
Compared with prior art, the technique scheme of the present invention has advantages below：
(1) present invention18F mark anti-CD105 alpaca single domain heavy chain antibody, on the one hand, tumour to its uptake values relatively Height, tumor imaging sensitivity are higher, and on the other hand, liver is relatively low to its uptake values, and the toxic and side effect to liver is less；This table Bright, which can diagnose tracer as PET, diagnose tracer especially as liver cancer PET；
(2) present invention pass through by the alpaca single domain heavy chain antibody of anti-CD105 with18F-SFB is dissolved in carbonate buffer solution At 60～70 DEG C, reaction can be prepared18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark；The preparation method is not only Cost is relatively low, easy to operate, quick, and mark rate is higher, marked product radiochemical purity is higher, is conducive to being prepared into Arrive18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark diagnoses tracer clinically popularization and application as PET.
Description of the drawings
In order that present disclosure is more likely to be clearly understood, the specific embodiment below according to the present invention is simultaneously combined Accompanying drawing, the present invention is further detailed explanation, wherein：
Fig. 1 is the structural representation of PET-MF-2V-IT-I type fluorine multifunctional synthesis module in embodiment 4；
Fig. 2 is in experimental example 119The HPLC figure of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark；
Fig. 3 is in experimental example 118The HPLC figure of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark；
Fig. 4 is in experimental example 218HPLC after the alpaca single domain heavy chain antibody of the anti-CD105 of F mark places 3h schemes；
Fig. 5 is in experimental example 218HPLC after the alpaca single domain heavy chain antibody of the anti-CD105 of F mark places 4h schemes；
Fig. 6 is in experimental example 318The microPET imaging figure of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark, tumour Position is as shown by arrows；
Fig. 7 is tumour, liver, kidney and muscle pair in experimental example 318The alpaca single domain heavy chain antibody of the anti-CD105 of F mark Quantitative uptake values, ROIs represents with average %ID/g ± SD.
Specific embodiment
In following examples of the present invention and experimental example,18F-SFB is referred to：N- succinimide -4-18F- fluorobenzoate, All of reagent and solvent are commercially available product, and the concentration of concrete reagent can be configured according to the method for prior art.
Embodiment 1
The present embodiment18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark comprises the steps：
S01：Pass through18O (p, n)18F reaction generates carrier-free18F-, and be enriched on QMA post, with containing K2CO3/K2,2,2 Acetonitrile solution will18F-The first reaction tube is eluted to, nitrogen heating is passed through, solution is evaporated；Second is added in the reaction tube Nitrile 2mL, is passed through nitrogen heating, solution is evaporated, and the first reaction tube of cooling is to 40 DEG C；
S02：The acetonitrile solution containing SFB precursor is added in first reaction tube, and 116 DEG C of reaction 600s, per 200s Solution is mixed 1 time with nitrogen stream, each 5s；The NaOH of 0.5mL0.5mol/L, 90 DEG C of reaction hydrolysis are added in reaction tube Solution is mixed 1 time, each 5s by 300s per 100s nitrogen stream；Mixed with HCl the and 1.5mL acetonitrile of 7.5mL 0.1mol/L Close in solution and alkali, obtain18F-FBA reactant liquor；
S03：Described in obtaining in step S0218F-FBA reactant liquor crosses a C18 post；First is dry with 90 DEG C of nitrogen streams C18 post, is eluted to the 18F-FBA on a C18 post in the second reaction tube with 2mL anhydrous acetonitrile, is passed through nitrogen simultaneously in pipe Heating, azeotropic, eliminating water；The aqueous solution of the tetrapropylammonium hydroxide TBOH of 40uL1mol/L is subsequently adding, is led to nitrogen and heats, will The second reaction liquid in pipe is evaporated, and cools down second reaction tube to 40 DEG C；
S04：The acetonitrile solution containing TSTU of 1mL 13mg/mL is added in second reaction tube, is sealed at 90 DEG C Reaction 300s；The HCl acidifying of 5mL 0.1mol/L is added, the reactant liquor for obtaining is crossed the 2nd C18 post；Again with 90 DEG C of nitrogen streams Dry up the 2nd C18 post；The 2nd C18 post is eluted with 2mL acetonitrile, obtain18F-SFB reactant liquor；
S05：Take the alpaca single domain heavy chain antibody of anti-CD105 with18(the two mol ratio is F-SFB：1.0：1.2) second is dissolved in In nitrile, mixing, pH value being adjusted to 9.6 using carbonate buffer solution, 30min is reacted at 65 DEG C；Cooling, by reactant liquor plus Enter to fill in the centrifuge tube of 4mL ether, rock uniform, be centrifuged 5 minutes under 12000rpm rotating speed, outwell supernatant；To institute State in centrifuge tube and add 2mL ether again, after rocking washing, supernatant liquor is outwelled, dried up in the centrifuge tube with the hair-dryer of heat Ether, the precipitation in pipe is18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark.
Embodiment 2
The present embodiment18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark comprises the steps：
S01：Pass through18O (p, n)18F reaction generates carrier-free18F-, and be enriched on QMA post, with containing K2CO3/K2,2,2 Acetonitrile solution will18F-The first reaction tube is eluted to, nitrogen heating is passed through, solution is evaporated；Second is added in the reaction tube Nitrile, is passed through nitrogen heating, solution is evaporated, and the first reaction tube of cooling is to 35 DEG C；
S02：The acetonitrile solution containing SFB precursor is added in first reaction tube, and 110 DEG C of reaction 600s, per 200s Solution is mixed 1 time with nitrogen stream, each 5s；The NaOH of 0.25mL1mol/L, 85 DEG C of reaction hydrolysis are added in reaction tube Solution is mixed 1 time, each 5s by 300s per 100s nitrogen stream；Mixed with HCl the and 1.5mL acetonitrile of 7.5mL 0.1mol/L Close in solution and alkali, obtain 18F-FBA reactant liquor；
S03：Described in obtaining in step S0218F-FBA reactant liquor crosses a C18 post；First is dry with 85 DEG C of nitrogen streams C18 post, with 2mL anhydrous acetonitrile by the 18F on a C18 post-- FBA is eluted in the second reaction tube, is passed through nitrogen simultaneously in pipe Heating, azeotropic, eliminating water；The aqueous solution of the tetrapropylammonium hydroxide TBOH of 45uL1mol/L is subsequently adding, is led to nitrogen and heats, will The second reaction liquid in pipe is evaporated, and cools down second reaction tube to 35 DEG C；
S04：The acetonitrile solution of the TSTU of 12mg/mL is added in second reaction tube, sealing reaction 300s at 85 DEG C； The HCl of 5mL 0.1mol/L is added, the reactant liquor for obtaining is crossed the 2nd C18 post；The 2nd C18 is dried up again with 85 DEG C of nitrogen streams Post；The 2nd C18 post is eluted with 2mL acetonitrile, obtain18F-SFB reactant liquor；
S05：Take the alpaca single domain heavy chain antibody of anti-CD105 with18(the two mol ratio is F-SFB：1.0：1.0) second is dissolved in In nitrile, mixing, pH value being adjusted to 9 using phosphate buffer buffer solution, 40min is reacted at 60 DEG C；Cooling, will reaction Liquid is added in the centrifuge tube for filling 4mL ether, is rocked uniformly, is centrifuged 5 minutes, abandons supernatant under 13000rpm rotating speed；To institute State in centrifuge tube and add 2mL ether again, after rocking washing, supernatant liquor is outwelled, dried up in the centrifuge tube with the hair-dryer of heat Ether, the precipitation in pipe is18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark.
Embodiment 3
The present embodiment18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark comprises the steps：
S01：Pass through18O (p, n)18F reaction generates carrier-free18F-, and be enriched on QMA post, with containing K2CO3/K2,2,2 Acetonitrile solution will18F-The first reaction tube is eluted to, nitrogen heating is passed through, solution is evaporated；Second is added in the reaction tube Nitrile, is passed through nitrogen heating, solution is evaporated, and the first reaction tube of cooling is to 45 DEG C；
S02：The acetonitrile solution containing SFB precursor is added in first reaction tube, and 120 DEG C of reaction 600s, per 200s Solution is mixed 1 time with nitrogen stream, each 5s；The NaOH of 0.5mL0.5mol/L, 95 DEG C of reaction hydrolysis are added in reaction tube Solution is mixed 1 time, each 5s by 300s per 100s nitrogen stream；Mixed with HCl the and 1.5mL acetonitrile of 2.5mL 0.3mol/L Close in solution and alkali, obtain 18F-FBA reactant liquor；
S03：Described in obtaining in step S0218F-- FBA reactant liquor crosses a C18 post；The is dry with 95 DEG C of nitrogen streams One C18 post, with 2mL anhydrous acetonitrile by the 18F on a C18 post-- FBA is eluted in the second reaction tube, is passed through nitrogen in pipe And heat, azeotropic, eliminating water；The aqueous solution of the tetrapropylammonium hydroxide TBOH of 50uL1mol/L is subsequently adding, is led to nitrogen and heats, Described second reaction liquid in pipe is evaporated, and second reaction tube is cooled down to 45 DEG C；
S04：The acetonitrile solution of the TSTU of 0.9mL 15mg/mL is added in second reaction tube, is sealed anti-at 95 DEG C Answer 300s；The HCl of 5mL 0.1mol/L is added, the reactant liquor for obtaining is crossed the 2nd C18 post；Is dried up again with 95 DEG C of nitrogen streams Two C18 posts；The 2nd C18 post is eluted with 2mL acetonitrile, obtain18F-SFB reactant liquor；
S05：Take the alpaca single domain heavy chain antibody of anti-CD105 with18(the two mol ratio is F-SFB：1.0：2.0) second is dissolved in In nitrile, mixing, pH value being adjusted to 10 using citrate buffer, 20min is reacted at 70 DEG C；Cooling, by reactant liquor Add in the centrifuge tube for filling 4mL ether, rock uniformly, be centrifuged 3 minutes under 15000rpm rotating speed, outwell supernatant；To 2mL ether is added again in the centrifuge tube, after rocking washing, supernatant liquor is outwelled, the centrifuge tube is dried up with the hair-dryer of heat In ether, the precipitation in pipe is18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark.
Embodiment 4
The present embodiment resists the sheep of CD105 by PET-MF-2V-IT-I type fluorine multifunctional synthesis module as shown in Figure 1 Hunchbacked single domain heavy chain antibody is carried out18F is marked, and concrete preparation method is comprised the following steps：
(1) QAM post activation：NaHCO with 10mL (0.5M)3Solution rinses QAM post, then is rinsed with 20mL water, then blows Dry；A post activates (C18 post)：First rinsed with 10mL acetonitrile, rinsed with HCl the and 2.5mL acetonitrile of 7.5mL (0.1M) afterwards, then blow Dry；B post activates (C18 post)：First rinsed with 10mL methyl alcohol, then rinsed with 20mL water, dry up；
(2) 1.5mL is added to contain K in B1 reaction tube2CO3/K2,2,2Acetonitrile solution, in B2 reaction tube add 2.0mL super dry Dry acetonitrile solution, adds 10mg SFB precursor and 1mL acetonitrile in B3 reaction tube, add 0.5mL's (0.5M) in B4 reaction tube NaOH solution, adds HCl the and 1.5mL acetonitrile of 7.5mL (0.1M) in B5 reaction tube, add 2.5mL acetonitrile molten in B6 reaction tube Liquid, adds the acetonitrile solution of 12mg TSTU and 1mL ultra dry in B7 reaction tube, add the HCl solution of 0.1M in B8 reaction tube 2mL acetonitrile is added in 5mL, B9 reaction tube；
(3) target is passed：By18O (p, n)18The carrier-free that F reaction is generated18F (232mCi) is enriched on QMA post；
(4) drip washing：Start wash-out, six-way valve V1 is opened, uses 1mL K2CO3/K2,2,2Acetonitrile solution will18F-Elute into In RV1 reaction tube, QMA is remained18F-(5mCi)；
(5) dry：After 5 minutes, V9, V8 is opened successively, 116 DEG C of evaporation drying eliminating waters, after 3 minutes, V5 is opened, add The acetonitrile solution of 2.0mL ultra dry, 116 DEG C of evaporation redrying eliminating waters；
(6) necleophilic reaction：After the completion of drying, P1 cooling is opened, V3 is opened, 10mg SFB precursor and 1mL acetonitrile is added, is opened Close and close V3 afterwards for several times, V8 air-blowing stirring is opened, closes V8, V9；Confined reaction 10min at 90 DEG C, per minute open V9, V8 ventilation 5s after close V8, V9, close H1, stop heating, open P1 cooling；The NaOH solution that V9, V4 add 0.5mL (0.5M) is opened, V4 is closed, opens V8 air-blowing number Second, close V8, V9；Confined reaction 5min at 90 DEG C, per minute open V9, V8 ventilation 5s after close V8, V9；H1 is closed, is stopped heating, opens P1 Cooling；HCL the and 1.5mL acetonitrile that V9, V5 add 7.5mL (0.1M) is opened, V5 is closed, opens the V8 air-blowing several seconds；
(7) shift：After first step reaction terminates, V10, V7, V8, V3 is closed, first C18 post is reached, activity is 63.7mCi；Close V3, V8, V7, V10；V9, V4, plus acetonitrile 3mL to No. 1 reaction tube is opened, is opened and closes V4, V9 afterwards for several times, V14 is opened, V16, V7, V8, V4, are eluted to No. 2 reaction tubes,
(8) substitution reaction：A total of 45.6mCi enters No. 2 reaction tubes, and No. 2 reaction tubes are not being passed18F-Before The aqueous solution of the 40 μ L TBOH of 1moL/L is added, V6, V8, V7, V16, V14 is closed, V14, V16, V21 is opened, 116 DEG C are arranged, opens H2 Heat drying, closes H2, stops heating, opens P2 and be cooled to 48 DEG C, open V14, V11 and add N, N- tetramethylurea tetrafluoroborate TSTU (12mg, 0.75mL), switch close V11 for several times afterwards, open V16, V21 air-blowing, close V21, V16, V14.90 DEG C are arranged, opens H2, heating 5 Minute, per minute open V14, V16, V21 ventilation 5s after close V21, V16, V14, close H2, stop heating, open P2 and be cooled to 48 DEG C, open V14, V12 add the HCL solution 5mL of 0.1M, close V21, V16, V14, open V17, V15, V16 after opening V14, V16, V21 air-blowing, V12 is transferred to No. 2 C18, obtains 32.4mCi, closes V12, V16, V15, V17, opens V14, V13, plus 2mL acetonitrile, after switching for several times V13, V14 is closed, opens V15, V16, V13 wash-out, output aggregate：28.7mCi；
(9) carbonate solution of the alpaca single domain heavy chain antibody of the anti-CD105 of 300 μ L1mg/mL is taken, adds 50 μ L18F- In SFB acetonitrile solution, 65 DEG C are reacted 30 minutes, are cooled down 1 minute；Reactant liquor is added in the centrifuge tube for filling 4mL ether, rock Uniformly, it is centrifuged 5 minutes under 13000rpm rotating speed, supernatant is outwelled；The washing of 2mL ether is added in centrifuge tube, is rocked Washing, then outwells upper strata organic liquor, and the hair-dryer of the organic solvent heat in pipe is dried up, and the precipitation in pipe is18F mark The alpaca single domain heavy chain antibody of anti-CD105.
Embodiment 5
The preparation method of the alpaca single domain heavy chain antibody of anti-CD105, with reference to following document：Cell selection and Characterization of a novel human endothelial cell specific nanobody, Molecular Immunology, 2009,46,1814-1823.
Experimental example 1Radio-chemical purity is tested
1st, experiment purpose
Embodiment 1 is studied with HPLC18The radio-chemical purity of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark.
2nd, experimental technique
With (2) 250 × 4.6mm of Agilent 5TC-C18 as chromatographic column, with the aqueous solution containing 0.1%TFA as mobile phase A, with the acetonitrile solution containing 0.1%TFA as Mobile phase B, carry out gradient elution according to following procedure：0-1min, A：B is 90%：10%；1-14min, A：B is 90%：10% → 50%：50%；14min, A：B is 50%：50%；14-17min, A：B For 50%：50% → 0%：100%；17-20min, A：B is 0%：100%；20-25min, A：B is 0%：100% → 90%： 10%；25min, A：B is 90%：10%；Detection wavelength：254nm；Flow velocity：1mL/min.
3rd, experimental result
Specific experiment result is respectively as shown in Figures 2 and 3.
As shown in Figure 2,19The retention time of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark is 11.13min, by Fig. 3 Understand,18The retention time of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark is 11.10min, and the error of the two is 0.27%.From the figure 3, it may be seen that18The radio-chemical purity of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark is 97.44%.
Additionally, through calculating,18The specific radioactivity of alpaca single domain heavy chain antibody of the anti-CD105 of F mark is 1.651Ci/ μm of ol or 61.09GBq/ μm of ol, activity concentration are 370MBq/mL.
4th, experiment conclusion
Embodiment 118The radio-chemical purity of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark is higher, up to 97.44%, reach zooperal requirement.This shows, the present invention's18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark Requirement of experiment can be met completely.
Experimental example 2Vitro stability is tested
1st, experiment purpose
Embodiment 1 is studied with HPLC18The vitro stability of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark.
2nd, experimental technique
By embodiment 118The alpaca single domain heavy chain antibody of the anti-CD105 of F mark, divides according to the experimental technique of experimental example 1 Radio-chemical purity its normal temperature under place 3h after and 4h after is not determined.
3rd, experimental result
Specific experiment result is respectively as shown in Figure 4 and Figure 5.
As shown in Figure 4, embodiment 118After 3h being placed under the alpaca single domain heavy chain antibody normal temperature of the anti-CD105 of F mark Radio-chemical purity is 97.31%；As shown in Figure 5, embodiment 118The alpaca single domain heavy chain antibody of the anti-CD105 of F mark It is 97.33% to place the radio-chemical purity after 4h under normal temperature.
4th, experiment conclusion
Embodiment 118The radio chemistry after 4h is placed under the alpaca single domain heavy chain antibody normal temperature of the anti-CD105 of F mark Purity change is less, finds no defluorinate phenomenon.This shows, the present invention's18The alpaca single domain heavy chain of the anti-CD105 of F mark resists The vitro stability that places in 4h under body normal temperature is preferable.
Experimental example 3MicroPET imaging experiment
1st, experiment purpose
Embodiment 1 is verified and is analyzed by zoopery18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark MicroPET imaging results.
2nd, experimental technique
(1) mouse is gone to bed fixation：Head by the mice with tumor (liver cancer is modeled by way of subcutaneous vaccination) of pre- fiber crops Be placed on scanning bed so as to alignment anesthesia outlet, then the head of the mice with tumor and body are straightened, four limbs separate, use medical adhesive Its four limbs is fixed by band, has recorded the pendulum position of mouse；
(2) tail vein passage is built：With the gauze wrapped mousetail for being impregnated with warm water, after the angioplerosis of mice with tumor, Prick into the insulin needle containing water for injection that builds used by passage；
(3) needle exchange, injection：Take the marked product in embodiments of the invention 118The alpaca heavy chain list of the anti-CD105 of F mark Domain antibodies, by the insulin needle containing water for injection for setting up tail vein passage change into containing18The alpaca weight of the anti-CD105 of F mark The insulin needle of chain single domain antibody, according to the dosage per only 100 μ Ci, is injected in mouse body；
(4) radium-shine, positioning is opened, and is scanned：Positioned after radium-shine unlatching, the whole body to mice with tumor is swept Retouch, many experiments image is obtained, image reconstruction is carried out using sequential 2 D subset expectation maximization (two-dimentional OSEM) algorithm, is passed through PMOD software is analyzed delineating region of interest (ROI), and acquisition starts complete to the mouse of each transverse section scan from the superiors Body scanning figure.Obtain from multiple ROI average pixel values radioactive activity (adding up) in tumour, liver, kidney and muscle and MBq/mL is converted into, income value obtains %ID/g (it is assumed that tissue density is 1g/mL) divided by injection dosage.
3rd, experimental result
Specific experiment result is respectively as shown in Figure 6 and Figure 7.
From Fig. 6 and Fig. 7, after injecting 60min, tumour is to embodiment 118The alpaca heavy chain list of the anti-CD105 of F mark The uptake values of domain antibodies are 14.32 ± 3.21%ID/g, organize far above muscle etc.；From Fig. 6 and Fig. 7,30min is injected Afterwards, in addition to tumour, embodiment 118The alpaca single domain heavy chain antibody of the anti-CD105 of F mark is highly dense poly- in kidney, then soon Speed is excluded.
4th, experiment conclusion
Embodiment 118The alpaca single domain heavy chain antibody of the anti-CD105 of F mark, on the one hand, tumour is higher to its uptake values, Tumor imaging sensitivity is higher, and on the other hand, liver is relatively low to its uptake values, and the toxic and side effect to liver is less.
Obviously, above-described embodiment is only intended to clearly illustrate example, and the not restriction to embodiment.Right For those of ordinary skill in the art, can also make on the basis of the above description other multi-forms change or Change.There is no need to be exhaustive to all of embodiment.And the obvious change thus extended out or Change among still in the protection domain of the invention.

Claims (10)

1. a kind of18The alpaca single domain heavy chain antibody of the anti-CD105 of F mark, it is characterised in that its structural formula is：18The anti-CD105 of F- Alpaca single domain heavy chain antibody.
2. a kind of18The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark, it is characterised in that the preparation method bag Include following steps：
S05：Take the alpaca single domain heavy chain antibody of anti-CD105 with18F-SFB is dissolved in solvent, is mixed, at 60～70 DEG C Reaction；Cooling, during reactant liquor is added to the centrifuge tube for filling ether, centrifugation, abandon supernatant；And add ether to wash again, And supernatant is abandoned, and the ether in the centrifuge tube is dried up, the precipitation in pipe is18The alpaca single domain heavy chain of the anti-CD105 of F mark Antibody；
The solvent in water, acetonitrile, carbonate buffer solution, phosphate buffer and citrate buffer at least one Kind.
3. according to claim 218The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark, its feature exist In,
The alpaca single domain heavy chain antibody of the anti-CD105 with described18The mol ratio of F-SFB is 1.0：(1.0～2.0).
4. according to Claims 2 or 318The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark, which is special Levy and be, in step S05, the reaction time is 20～40min, the rotating speed of centrifugation is 12000-15000rpm.
5. according to any one of claim 2-418The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark, Characterized in that,
After the step of mixing, also include the step of pH value is adjusted to 9～10 using buffer solution；
At least one of the buffer solution in carbonate buffer solution, phosphate buffer and citrate buffer.
6. according to any one of claim 2-518The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark, Characterized in that, described18F-SFB is prepared by the following method and forms：
S01：Pass through18O (p, n)18F reaction generates carrier-free18F-, and be enriched on QMA post, with containing K2CO3/K2,2,2Second Nitrile solution will18F-It is eluted in the first reaction tube, is passed through nitrogen heating and solution is evaporated；Add in first reaction tube Acetonitrile, and nitrogen heating is passed through, solution is evaporated, the first reaction tube of cooling is to 35-45 DEG C；
S02：The acetonitrile solution containing SFB precursor, control temperature 110-120 DEG C reaction 500- is added in first reaction tube 600s, and intermittent solution is mixed with nitrogen stream；Then to NaOH, 85-95 DEG C of reaction is added in reaction tube hydrolyze 300- 400s, and intermittent solution is mixed with nitrogen stream；After hydrolysis, with the mixed solution of HCl and acetonitrile and alkali, obtain18F- FBA reactant liquor；
S03：Described in obtaining in step S0218F-FBA reactant liquor crosses a C18 post；A C18 is dry with 90 DEG C of nitrogen streams Post, and with anhydrous acetonitrile by C18 post18F-FBA is eluted in the second reaction tube, is passed through nitrogen in second reaction tube And heat eliminating water；The aqueous solution of tetrapropylammonium hydroxide TBOH is subsequently adding, is led to nitrogen and heats in second reaction tube Liquid is evaporated, and cools down second reaction tube to 35-45 DEG C；
S04：Sealing reaction 300s at the acetonitrile solution containing TSTU, 85-95 DEG C is added in second reaction tube；Add HCl is acidified, and the reactant liquor for obtaining is crossed the 2nd C18 post；The 2nd C18 post is dried up again with 85-95 DEG C of nitrogen stream；With acetonitrile wash-out the Two C18 posts, obtain18F-SFB reactant liquor.
7. according to any one of claim 2-618The preparation method of the alpaca single domain heavy chain antibody of the anti-CD105 of F mark, Characterized in that,
In step S02, for the first time described with nitrogen stream mixed solution the step of be specially：Will with nitrogen stream at interval of 200s Reactant liquor mixes 1 time, each 5s；The step of described in second with nitrogen stream mixed solution, is specially：At interval of 100s with nitrogen Solution is mixed 1 time by stream, each 5s；
In step S03, the concentration of the TBOH is 1mol/L；
In step S04, in the acetonitrile solution containing TSTU, the concentration of TSTU is 12～15mg/mL.
8. the preparation method described in any one of claim 2-7 is prepared18The alpaca single domain heavy chain of the anti-CD105 of F mark Antibody.
9. described in claim 1 or 818The alpaca single domain heavy chain antibody of the anti-CD105 of F mark is preparing PET diagnosis tracer In application.
10. a kind of PET diagnoses tracer, it is characterised in which is included described in claim 1 or 818The anti-CD105's of F mark Alpaca single domain heavy chain antibody.
CN201610885725.2A 2016-10-10 2016-10-10 A kind of liver cancer PET diagnosis tracer and preparation method thereof and purposes Pending CN106478820A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610885725.2A CN106478820A (en) 2016-10-10 2016-10-10 A kind of liver cancer PET diagnosis tracer and preparation method thereof and purposes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610885725.2A CN106478820A (en) 2016-10-10 2016-10-10 A kind of liver cancer PET diagnosis tracer and preparation method thereof and purposes

Publications (1)

Publication Number Publication Date
CN106478820A true CN106478820A (en) 2017-03-08

Family

ID=58270533

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610885725.2A Pending CN106478820A (en) 2016-10-10 2016-10-10 A kind of liver cancer PET diagnosis tracer and preparation method thereof and purposes

Country Status (1)

Country Link
CN (1) CN106478820A (en)

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101564541A (en) * 2009-05-19 2009-10-28 山东省肿瘤医院 Developing agent adaptable to positron emission computed tomography
CN101574532A (en) * 2009-06-15 2009-11-11 山东省肿瘤医院 Targeted Claudin-4 developer without influence on permeability between epithelial cells
CN102660551A (en) * 2012-02-09 2012-09-12 陈志南 VHH (variable domain of heavy chain of heavy-chain antibody) antibody gene derived from anti-CyPA (CyclophilinA) animal of family Camelidae, encoded polypeptide, and application thereof
CN102867559A (en) * 2011-07-08 2013-01-09 复旦大学附属肿瘤医院 Automated synthesizer of <18>F-marked PET (positron emission tomograph)/CT (computerized tomograph) molecular image probe
CN103030689A (en) * 2012-12-27 2013-04-10 无锡江原安迪科分子核医学研究发展有限公司 CART polypeptide compound, and preparation method and application of compound
CN103041412A (en) * 2013-01-29 2013-04-17 江苏省原子医学研究所 PET (Positron Emission Tomography) tracer with FSHR (Follicle-stimulating Hormone Receptor) targeting as well as preparation method and application thereof
CN103495188A (en) * 2013-09-29 2014-01-08 无锡江原安迪科分子核医学研究发展有限公司 Medical polymer material with radioactive nuclide marker, and preparation method as well as application thereof
CN103665152A (en) * 2013-12-02 2014-03-26 山西农业大学 Canine parvovirus single-domain antibody, and preparation method and application thereof
CN103833829A (en) * 2014-01-07 2014-06-04 江苏省原子医学研究所 Radioactive <18>F-labeled imaging drug <18>F-AL-NOTA-IF7 targeting Anxa1 in tumor blood vessels and preparation method thereof
WO2015073746A2 (en) * 2013-11-13 2015-05-21 Whitehead Institute For Biomedical Research 18f labeling of proteins using sortases
CN104684580A (en) * 2012-09-05 2015-06-03 特雷康制药公司 Antibody formulations and uses thereof
CN104725473A (en) * 2014-09-11 2015-06-24 厦门大学附属第一医院 [<18>F] AlF marked positron emission tomography (PET) polypeptide probe and preparation method thereof
CN105085617A (en) * 2014-08-20 2015-11-25 江苏省原子医学研究所 Compound for nanometer PET developer and its preparation method and use
CN103384824B (en) * 2010-12-06 2016-02-03 Thd股份公司 Method for cancer diagnostics and uses thereof
CN105884867A (en) * 2016-03-14 2016-08-24 江苏省原子医学研究所 18 F-labeling affinity type compound and preparation method and application thereof

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101564541A (en) * 2009-05-19 2009-10-28 山东省肿瘤医院 Developing agent adaptable to positron emission computed tomography
CN101574532A (en) * 2009-06-15 2009-11-11 山东省肿瘤医院 Targeted Claudin-4 developer without influence on permeability between epithelial cells
CN103384824B (en) * 2010-12-06 2016-02-03 Thd股份公司 Method for cancer diagnostics and uses thereof
CN102867559A (en) * 2011-07-08 2013-01-09 复旦大学附属肿瘤医院 Automated synthesizer of <18>F-marked PET (positron emission tomograph)/CT (computerized tomograph) molecular image probe
CN102660551A (en) * 2012-02-09 2012-09-12 陈志南 VHH (variable domain of heavy chain of heavy-chain antibody) antibody gene derived from anti-CyPA (CyclophilinA) animal of family Camelidae, encoded polypeptide, and application thereof
CN104684580A (en) * 2012-09-05 2015-06-03 特雷康制药公司 Antibody formulations and uses thereof
CN103030689A (en) * 2012-12-27 2013-04-10 无锡江原安迪科分子核医学研究发展有限公司 CART polypeptide compound, and preparation method and application of compound
CN103041412A (en) * 2013-01-29 2013-04-17 江苏省原子医学研究所 PET (Positron Emission Tomography) tracer with FSHR (Follicle-stimulating Hormone Receptor) targeting as well as preparation method and application thereof
CN103495188A (en) * 2013-09-29 2014-01-08 无锡江原安迪科分子核医学研究发展有限公司 Medical polymer material with radioactive nuclide marker, and preparation method as well as application thereof
WO2015073746A2 (en) * 2013-11-13 2015-05-21 Whitehead Institute For Biomedical Research 18f labeling of proteins using sortases
CN103665152A (en) * 2013-12-02 2014-03-26 山西农业大学 Canine parvovirus single-domain antibody, and preparation method and application thereof
CN103833829A (en) * 2014-01-07 2014-06-04 江苏省原子医学研究所 Radioactive <18>F-labeled imaging drug <18>F-AL-NOTA-IF7 targeting Anxa1 in tumor blood vessels and preparation method thereof
CN105085617A (en) * 2014-08-20 2015-11-25 江苏省原子医学研究所 Compound for nanometer PET developer and its preparation method and use
CN104725473A (en) * 2014-09-11 2015-06-24 厦门大学附属第一医院 [<18>F] AlF marked positron emission tomography (PET) polypeptide probe and preparation method thereof
CN105884867A (en) * 2016-03-14 2016-08-24 江苏省原子医学研究所 18 F-labeling affinity type compound and preparation method and application thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
YIN ZHANG 等: "ImmunoPET and near-infrared fluorescence imaging of CD105 expression using a monoclonal antibody dual-labeled with 89Zr and IRDye 800CW", 《AM J TRANSL RES》 *
YIN ZHANG 等: "PET Imaging of CD105/Endoglin Expression with a 61/64Cu-Labeled Fab Antibody Fragment", 《EUR J NUCL MED MOL IMAGING》 *
于建宪 等: "肝癌组织中CD105与Nestin表达的比较", 《齐鲁医学杂志》 *
曹永新 等: "肝癌患者肝组织中CD105的表达及临床意义", 《实用医学杂志》 *
苏幼红 等: "骆驼来源单域抗体在免疫治疗中的研究进展", 《生物技术通报》 *

Similar Documents

Publication Publication Date Title
Hong et al. Positron emission tomography imaging of CD105 expression with 89 Zr-Df-TRC105
Evans et al. A bioorthogonal 68 Ga-labelling strategy for rapid in vivo imaging
Hong et al. Positron emission tomography imaging of CD105 expression during tumor angiogenesis
CN107412794B (en) Double target spot imaging molecular probes and its preparation method and application
Zhang et al. ImmunoPET and near-infrared fluorescence imaging of CD105 expression using a monoclonal antibody dual-labeled with 89Zr and IRDye 800CW
CN103041412B (en) PET (Positron Emission Tomography) tracer with FSHR (Follicle-stimulating Hormone Receptor) targeting as well as preparation method and application thereof
CN107501393B (en) Method and kit for synthesizing 18F-labeled amino acid polypeptide drug
CN104725473B (en) A kind of [18F] AlF marks PET polypeptide probes and preparation method thereof
CN106967152A (en) Compound that a kind of fluorine 18 is marked and preparation method and application
CN103242255A (en) Evans blue complex as well as preparation method and application thereof
CN113648434A (en) PET molecular probe targeting PD-L1 and preparation method and application thereof
Oroujeni et al. The Use of a Non-Conventional Long-Lived Gallium Radioisotope 66Ga Improves Imaging Contrast of EGFR Expression in Malignant Tumours Using DFO-ZEGFR: 2377 Affibody Molecule
CN108434469A (en) A kind of HER2 affinities body68Ga markers and preparation method thereof, application
CN110339375A (en) A kind of rk polypeptide radiopharmaceutical and preparation method thereof targeting HER2
CN110172084A (en) 68Ga marks NODAGA modification c-Met molecular probe and preparation and application
CN106478820A (en) A kind of liver cancer PET diagnosis tracer and preparation method thereof and purposes
CN107629016A (en) Azo-Blue complex and its preparation method and application
Qiu et al. A pretargeted imaging strategy for EGFR-positive colorectal carcinoma via modulation of Tz-radioligand pharmacokinetics
CN103495188A (en) Medical polymer material with radioactive nuclide marker, and preparation method as well as application thereof
CN115286693A (en) Tumor targeting peptide aiming at carcinoembryonic antigen related cell adhesion molecule CEACAM6 and application thereof
CN106492237B (en) A kind of isoDGR polypeptide radiopharmaceuticals and its preparation method and application
CN105884867B (en) 18The affinity body class compound and the preparation method and application thereof of F label
van Dijk et al. Perfusion of tumor-bearing kidneys as a model for scintigraphic screening of monoclonal antibodies
CN104645362A (en) Preparation process of positron imaging agent 18F-5-floro-N-(2-(diethylamino) ethyl) pyridinecarboxamide
Reiner et al. Harnessing the bioorthogonal inverse electron demand Diels-Alder cycloaddition for pretargeted PET imaging

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20170308

WD01 Invention patent application deemed withdrawn after publication