CN110183533A - Radioiodide, preparation method and the application for the trastuzumab of resistance to former times - Google Patents
Radioiodide, preparation method and the application for the trastuzumab of resistance to former times Download PDFInfo
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- CN110183533A CN110183533A CN201910406995.4A CN201910406995A CN110183533A CN 110183533 A CN110183533 A CN 110183533A CN 201910406995 A CN201910406995 A CN 201910406995A CN 110183533 A CN110183533 A CN 110183533A
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- trastuzumab
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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Abstract
The invention discloses a kind of radioiodide of trastuzumab of resistance to former times, preparation method and applications.The radioiodide of the trastuzumab of resistance to former times, which refers to be covalently attached on the trastuzumab of resistance to former times molecule, to be had125I、131I、4‑125Iodo- benzamido or 4-131Iodo- benzamido.It can be used for preparing single photon emission computerized tomography tumor developer or anti-tumor drug.
Description
Technical field
The present invention relates to a kind of radioiodide of trastuzumab of resistance to former times, preparation method and applications.
Background technique
EGF-R ELISA (EGFR) is played the part of in Several Kinds of Malignancy occurrence and development key player, in mammary gland
A variety of human malignants such as cancer, lung cancer, head and neck scale carcinoma, glioblastoma, bladder cancer, colon cancer, oophoroma and prostate cancer are swollen
Find that EGFR is overexpressed and/or is mutated (Hwangbo W, Lee JH, Ahn S, et al.EGFR gene in tumor
amplification and protein expression in invasive ductal carcinoma of the
breast[J].Korean J Pathol,2013,47(2):107-115.Kalman B,Szep E,Garzuly F,et
al.Epidermal growth factor receptor as a therapeutic target in glioblastoma
[J].Neuromolecular Med,2013,15(2):420-434.Naik DS,Sharma S,Ray A,et
al.Epidermal growth factor receptor expression in urinary bladder cancer[J]
.Indian J Urol,2011,27(2):208-214.Abd EI ALL HS,Mishriky AM,Mohamed
FA.Epidermal growth factor receptor in colorectal carcinoma:correlation with
clinico-pathological prognostic factors[J].Colorectal Dis,2008,10(2):170-
178.Lee ES,Lee Y,Suh D,et al.Detection of HER-2 and EGFR gene amplification
using chromogenic in-situ hybridization technique in ovarian tumors[J].Appl
Immunohistochem Mol Morphol,2010,18(1):69-74.).EGFR is the one of tyrosine kinase receptor family
Member can star as EGFR and ligand binding activation and cause proliferation, differentiation or the signal system repaired.Many experiments have all been demonstrate,proved
Real EGFR is overexpressed and the correlation between tumour growth, angiogenesis, invasion, transfer and Apoptosis inhibitor.Clinical trial
It has proven to EGFR overexpression and implies that tumor invasiveness increases, chemicotherapy is resisted, prognosis is poor and life cycle is shorter；In addition, big
Amount experimental result shows that EGFR mutation has a significant effect to the reaction of chemotherapy and targeted therapy；Additionally, due to which EGFR is located at cell
Surface makes promising target (the Gazdar AF.Activating and resistance of molecular targeted therapy
mutations of EGFR in non-small cell lung cancer:role in clinical response to
EGFR tyrosine kinase inhibitors[J].Oncogene,2009,28:S24-S31.Chung CH,Ely K,
McGavran L,et al.Increased epidermal growth factor receptor gene copy number
is associated with poor prognosis in head and neck squamous cell carcinomas
[J].J Clin Oncol,2006,24(25):4170-4176.Spano JP,Lagorce C,Atlan D,et
al.Impact of EGFR expression on colorectal cancer patient prognosis and
survival[J].Ann Oncol,2005,16(1):102-108.)。
In recent years, it studies extensively, quickly grows by the molecular targeted agents of target spot of EGFR, there are many drugs through FDA
Approval is applied to clinic.However, using EGFR as the molecular targeted agents of target spot although achieving breakthrough on clinical efficacy,
It allows patient using EGFR molecular targeted agents indiscriminately, the total effective rate for the treatment of can be made relatively low.Homologous tumour may
Overexpression may not also express EGFR, and the tumor patient for only over-expressing EGFR could be benefited；For not expressing EGFR
Patient, not only result in over-treatment, and therefore patient cannot may receive other more suitable treatment methods again.It is right
Patient be layered and Classification Management, and picking out the benefited patient of most probable is that antineoplastic target treats successful necessary condition.
In addition, the therapeutic response of tumour, there are property complicated and changeable, such as same tumour there may be reaction reactionless to treatment, press down
Or start treatment when have reaction and it is reactionless over time.Therefore, distinguishing in time has reaction and unresponsive tumour simultaneously
Early monitoring is carried out to therapeutic response, patient's integrality is fully assessed, formulation for individual's therapeutic scheme and
Implementation is of great significance.
The nuclear medicine image of targeting EGFR can be noninvasive, real-time, repeated multiple times offer tumour EGFR expression and
Mutation status is realized to the curative effect early stage accurate detection of EGFR targeted drug and prognosis evaluation, and also by means of nuclear medicine image
The antibody drug for reaching tumor locus can be quantified, to promote cancer individuation EGFR targeted therapy.Although radiation
Property isotope labeling EGFR tyrosine kinase micromolecular inhibitor (EGFR-TKI) class probe have a more research report, but such
Probe (Lu XM, Wang C, Li X, et al.Synthesis and preliminary evaluation of F-18-
icotinib for EGFR-targeted PET imaging of lung cancer[J].Bioorg Med Chem,
2019,27:545-551.Memon AA, Weber B, Winterdahl M, et al.PET imaging of patients
with non-small cell lung cancer employing an EGF receptor targeting drug as
tracer[J].Br J Cancer,2011,105(12):1850-1855.Petrulli JR,Sullivan JM,Zheng M-
Q,et al.Quantitative analysis of C-11-Erlotinib PET demonstrates specific
binding for activating mutations of the EGFR kinase domain[J].Neoplasia,2013,
15 (12): 1347-1353.) in the organs such as liver, kidney and gastrointestinal tract non-specific uptake with higher, radioactivity concentration is higher,
Cause tumour/non-tumour of imaging relatively low, and some probes (Su H, Seimbille Y, Ferl GZ, et
al.Evaluation of[18F]gefitinib as a molecular imaging probe for the
assessment of the epidermal growth factor receptor status in malignant tumors
[J].Eur J Nucl Med Mol Imaging,2008,35(6):1089-1099.Slobbe P,Windhorst AD,
Stigter-van Walsum M,et al.Development of F-18afatinib as new TKI-PET tracer
For EGFR positive tumors [J] .Nucl Med Biol, 2014,41 (9): 749-757.) intake in tumour
With the expression and non-correlation of EGFR.Monoclonal antibody because directly competitively being combined with EGFR with endogenic ligand,
So it is better than micromolecular inhibitor in terms of specificity, while antibody drug also has good pharmacokinetic properties, because
This such probe great potential.
Necitumumab (i.e. the trastuzumab of resistance to former times) is a kind of non-small cell lung cancer targeted therapy list of Li Lai company research and development
Clonal antibody drug.It is a kind of recombination human source lgG1 monoclonal antibody, passes through the table in conjunction with human endogenous Ligand Competition
Skin growth factor receptor (EGFR) extracellular ligand binding domain blocks the activation of EGFR tyrosine kinase, and new vessels is inhibited to be formed
And endothelial cell proliferation, it induces cell apoptosis, inhibits tumor cell proliferation, transfer and invasion, reach the work for inhibiting tumour growth
With.2015, U.S.'s food and Drug Administration (FDA) had been approved by necitumumab (Portrazza) for shifting
The treatment of property squama type non-small cell lung cancer (NSCLC) patient.(Greillier,L.；Tomasini,P.；Barlesi,F.,
Necitumumab for non-small cell lung cancer.Expert Opinion on Biological
Therapy 2015,15(8),1.Dienstmann,R.；Tabernero,J.,Necitumumab,a fully human
IgG1mAb directed against the EGFR for the potential treatment of
cancer.Current Opinion in Investigational Drugs 2010,11(12),1434-41)。
Currently without the report that the trastuzumab of resistance to former times is used to radioiodination.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of completely new radioiodide of trastuzumab of resistance to former times,
Preparation method and application can be used as single photon emission computerized tomography (i.e. SPECT) tumor developer.
The present invention provides the radioiodide of trastuzumab of resistance to former times (i.e. Necitumumab) a kind of, structure is
Y1-Y2, wherein Y1 is the trastuzumab of resistance to former times, and Y2 is125I、131I、Or
In some embodiments, the specific activity of the radioiodide is 21~60 μ Ci/ μ g, such as 21 μ
Ci/ μ g, 45 μ Ci/ μ g or 60 μ Ci/ μ g.
In some embodiments, when Y2 is125When I, the specific activity of the radioiodide is 45~60 μ Ci/
μ g, such as 45 μ Ci/ μ g or 60 μ Ci/ μ g.
In some embodiments, when Y2 is125I or131When I, the radioiodide is iodogen labelling method
Obtained.
In some embodiments, when Y2 is125I or131When I, the radioiodide is iodogen labelling method
Obtained, specific activity is 45~60 μ Ci/ μ g (such as 45 μ Ci/ μ g or 60 μ Ci/ μ g).
In some embodiments, when Y2 isWhen, the specific activity of the radioiodide
For 21 μ Ci/ μ g.
In some embodiments, when Y2 isWhen, the radioiodide is by resistance to former times
Trastuzumab and compound BMade from reaction；When Y2 isWhen, it is described
Radioiodide is by the trastuzumab of resistance to former times and compound CMade from reaction.
In some embodiments, when Y2 isWhen, the specific activity of the radioiodide
It is by the trastuzumab of resistance to former times and compound B for 21 μ Ci/ μ gMade from reaction.
In some embodiments, the radioiodide is to be prepared as follows made from method:
When Y2 is125I or131When I, the preparation method include the following steps: in a solvent, by the trastuzumab of resistance to former times with
Na125I or Na131I carries out electrophilic substitution reaction in the presence of iodogen, obtains the radioiodide；
When Y2 isOrWhen, the preparation method includes the following steps:
In solvent, by the trastuzumab of resistance to former times withOrAmidation process is carried out,
Obtain the radioiodide.
In the electrophilic substitution reaction, the solvent can for this field the type react Conventional solvents, such as water and/
Or PBS buffer solution (such as " the PBS buffer solution of pH 8.0,0.01mol/L " or " the PBS buffering of pH 7.4,0.01mol/L
Solution ").In some embodiments, the solvent is " the PBS buffer solution of pH 7.4,0.01mol/L ".
In the electrophilic substitution reaction, the dosage that the dosage of the solvent can be conventional for the reaction of this field the type,
Such as concentration of the trastuzumab of resistance to former times in the solvent be 0.1~10mg/mL (such as 1~5mg/mL, such as 1~
2mg/mL)。
In the electrophilic substitution reaction, the dosage of the iodogen can be the use of this field the type reaction routine
Amount, such as the mass ratio of the iodogen and the trastuzumab of resistance to former times is 0.5:1~2:1 (such as 0.5:1~1:1).
In the electrophilic substitution reaction, the Na125I or Na131The dosage of I can be conventional for the reaction of this field the type
Dosage, such as: every 1 μ g trastuzumab of resistance to former times, Na125I or Na131The dosage of I be 0.03~0.1mCi (such as 0.03~
0.05mCi)。
In the electrophilic substitution reaction, the reaction temperature that reaction temperature can be conventional for the reaction of this field the type, example
Such as 10~40 DEG C (such as 20~35 DEG C).
In the electrophilic substitution reaction, the reaction time that the reaction time can be conventional for the reaction of this field the type, example
Such as 5~90min (such as 10~60min, such as 30~50min).
The electrophilic substitution reaction can further include post-processing step, and the post-processing step can be this
The conventional post-processing step of field the type reaction, such as: after the reaction was completed, through PD-10 column purification, obtain product.?
In some embodiments, the post-processing be may include steps of: after the reaction was completed, reaction solution is splined on PD-10 column,
The PBS buffer solution of 0.01mol/L pH=7.4 elutes, and obtains product.
In the amidation process, the solvent can react Conventional solvents, such as water, PBS for this field the type
Buffer solution (such as " the PBS buffer solution of pH 8.0,0.01mol/L " or " PBS of pH 7.4,0.01mol/L buffering is molten
Liquid ") and one of DMSO or a variety of.When the solvent is the mixed solution of DMSO and PBS buffer solution, DMSO and PBS
The volume ratio of buffer solution can be 1:4~1:6, such as 1:5.
In the amidation process, the dosage that the dosage of the solvent can be conventional for the reaction of this field the type, example
If concentration of the trastuzumab of resistance to former times in the solvent is 0.1~10mg/mL (such as 1~5mg/mL, such as 1~2mg/
mL)。
It is described in the amidation processOrDosage can
Think the conventional dosage of this field the type reaction, such as: every 1 μ g trastuzumab of resistance to former times,OrDosage be 0.03~0.1mCi (such as 0.03~0.05mCi).
In the amidation process, the reaction temperature that reaction temperature can be conventional for the reaction of this field the type, such as
10~40 DEG C (such as 20~35 DEG C).
In the amidation process, the reaction time that the reaction time can be conventional for the reaction of this field the type, such as 5
~90min (such as 10~60min, such as 30~60min).
The amidation process can further include post-processing step, and the post-processing step can be ability
The conventional post-processing step of domain the type reaction, such as: after the reaction was completed, through PD-10 column purification, obtain product.One
In a little embodiments, the post-processing be may include steps of: after the reaction was completed, reaction solution is splined on PD-10 column,
The PBS buffer solution of 0.01mol/L pH=7.4 elutes, and obtains product.
The present invention also provides a kind of preparation method of the radioiodide of trastuzumab of resistance to former times, the radioiodine
The structure of marker is Y1-Y2, and wherein Y1 is the trastuzumab of resistance to former times, and Y2 is125I、131I、Or
When Y2 is125I or131When I, the preparation method include the following steps: in a solvent, by the trastuzumab of resistance to former times with
Na125I or Na131I carries out electrophilic substitution reaction in the presence of iodogen, obtains the radioiodide；
When Y2 isOrWhen, the preparation method include the following steps: by
The trastuzumab of resistance to former times withOrAmidation process is carried out, is obtained described
Radioiodide.
In the preparation method of radioiodide as described above, the electrophilic substitution reaction and amidation process
Reaction condition can be as described above.
The present invention also provides what a kind of preparation method of radioiodide as described above was prepared to put
Penetrating property iodine label.
The present invention also provides a kind of radioiodide application in preparations of anti-tumor drugs as described above.
The present invention also provides a kind of radioiodide application in preparation of anti-tumor drugs as described above,
Described in radioiodide in Y2 be131I or
The present invention also provides a kind of radioiodides as described above to prepare single photon emission computed tomography
The application of (i.e. SPECT) tumor developer is imaged.
The present invention also provides a kind of radioiodides as described above to prepare single photon emission computed tomography
The application of (i.e. SPECT) tumor developer is imaged, wherein Y2 is in the radioiodide125I or
Compound B and compound C is known compound, and (Zhang P, Zhuang can be prepared by document
RQ,Guo ZD,Su XH,Chen XY,Zhang XZ.A Highly Efficient Copper-Mediated
Radioiodination Approach Using Aryl Boronic Acids.Chemistry-A European
Journal 2016；22(47):16782-16785).
Iodogen reagent described herein refers to following compound:
Iodogen labelling method is known to those skilled in the art, can specifically refer to following document: Li Nan, Li Peiyong,
The progress [J] of radioiodine indirect labelling antibody method, international Radiation Medicine Journal of Nuclear Medicine, volume 32 of in September, 2008
5th phase, 260-263 pages.
The present invention is used to indicate in the structure " Y1-Y2 " of radioiodide that "-" to indicate between Y1 segment and Y2 segment
To be covalently attached, " Y1-Y2 " indicates to be covalently attached one or more Y2 segments in per molecule Y1 segment.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
Unless otherwise specified, the reagents and materials used in the present invention are commercially available.PD-10 column of the present invention, filler
For Sephadex G-25.
The positive effect of the present invention is that a kind of radioiodide of completely new trastuzumab of resistance to former times is provided,
It can be used for preparing single photon emission computerized tomography (i.e. SPECT) tumor developer or anti-tumor drug.
Detailed description of the invention
Fig. 1 is the marked product A-1 of embodiment 2 that studies in effect example 1 37 DEG C when being incubated for 96h in PBS
Radio-TLC detects spectrogram.
Fig. 2 is the marked product A-1 of embodiment 2 that studies in effect example 2 in mice serum when 37 DEG C of incubation 96h
Radio-TLC detect spectrogram.
Fig. 3 is the marked product A-1 for the embodiment 2 studied in effect example 6 when being injected into lotus A549 tumor mouse for 24 hours
SPECT image figure.
Fig. 4 is the marked product A-1 for the embodiment 2 studied in effect example 6 when being injected into lotus A549 tumor mouse for 24 hours
SPECT/CT fusion imaging figure.
Fig. 5 is that the marked product A-1 for the embodiment 2 studied in effect example 7 is being injected into lotus HCC827 tumor mouse for 24 hours
When SPECT image figure.
Fig. 6 is that the marked product A-1 for the embodiment 2 studied in effect example 7 is being injected into lotus HCC827 tumor mouse for 24 hours
When SPECT/CT fusion imaging figure.
Fig. 7 is the marked product A-1 for the embodiment 2 studied in effect example 8 when being injected into lotus VX2 tumor mouse for 24 hours
SPECT image figure.
Fig. 8 is the marked product A-1 for the embodiment 2 studied in effect example 8 when being injected into lotus VX2 tumor mouse for 24 hours
SPECT/CT fusion imaging figure.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
In following embodiment, PD-10 column is purchased from GE Products, and prepackage filler is Sephadex G-25.
In the examples below, room temperature refers to 20~35 DEG C.
Embodiment 1: the synthesis of marked product A-1
The 1mg/mL trastuzumab of resistance to former times of 50 μ L is added in the reactor of the iodogen reagent containing 50 μ g, and (solvent is
PBS, pH=7.4,0.01mol/L) and 2.5mCi [125I]-NaI, reacts 30min at room temperature.After the reaction was completed, it is taken with liquid-transfering gun
Reaction solution terminates reaction out.Obtained marked product A-1, with the measurement of radio thin layer's chromatogram scanner, (solvent is positive
Butanol: pyridine: water: acetic acid=3:2:0.6:0.4), for mark rate up to 95%, specific activity is about 45 μ Ci/ μ g.
Embodiment 2: the synthesis of marked product A-1
The 2mg/mL trastuzumab of resistance to former times of 30 μ L is added in the reactor of the iodogen reagent containing 30 μ g, and (solvent is
PBS, pH=7.4,0.01mol/L) and 2.0mCi [125I]-NaI, reacts 50min at room temperature.After the reaction was completed, it is taken with liquid-transfering gun
Reaction solution terminates reaction out.
Marked product PD-10 column separating purification.1mL PBS (pH=7.4,0.01mol/ are added in the reaction solution of taking-up
L), the reaction solution after dilution is transferred on PD-10 desalting column, is slowly eluted with 5mL PBS (pH=7.4,0.01mol/L)
PD-10 column is in charge of reception to leacheate with centrifuge tube, merges the receiving liquid containing marked product A-1.Gained marked product A-1
Radiochemical purity be greater than 99%, specific activity is about 60 μ Ci/ μ g.
Embodiment 3: the synthesis of marked product A-2
The trastuzumab of the resistance to former times (solvent of the 1mg/mL of 50 μ L is added in the reactor of the iodogen reagent containing 50 μ g
For PBS, pH=7.4,0.01mol/L) and 2mCi [131I]-NaI, reacts 30min at room temperature.After the reaction was completed, it is taken with liquid-transfering gun
Reaction solution terminates reaction out.Obtain marked product A-2, mark rate is up to 95%.
Embodiment 4: the synthesis of marked product A-3
In the reactor of the 10 μ L DMSO solutions containing compound B (2mCi), the trastuzumab of resistance to former times of 50 μ L is added
PBS (pH 7.4, the 0.01mol/L) solution of (2mg/mL) reacts at room temperature 1h.After the reaction was completed, marked product A-3 is obtained, is marked
Note rate is up to 98%.
Embodiment 5: the synthesis of marked product A-4
In the reactor of the 10 μ LDMSO solution containing compound C (1.5mCi), the trastuzumab of resistance to former times of 50 μ L is added
PBS (pH 8.0, the 0.01mol/L) solution of (1mg/mL) reacts at room temperature 1h.After the reaction was completed, marked product A-4 is obtained, is marked
Note rate is up to 95%.
Embodiment 6: the synthesis of marked product A-3
In the reactor of the 10 μ L DMSO solutions containing compound B (2.5mCi), the trastuzumab of resistance to former times of 50 μ L is added
PBS (pH 8.0, the 0.01mol/L) solution of (2mg/mL), 30 DEG C of reaction 1h.After the reaction was completed, the mark of marked product A-3 is obtained
Note rate is up to 95%.
Marked product PD-10 column separating purification.1mL PBS (pH=7.4,0.01mol/ are added in the reaction solution of taking-up
L), the reaction solution after dilution is transferred on PD-10 desalting column, is slowly eluted with 5mL PBS (pH=7.4,0.01mol/L)
PD-10 column is in charge of reception to leacheate with centrifuge tube, merges the receiving liquid containing marked product A-3.Marked product A-3's puts
Chemical purity is penetrated greater than 99%, specific activity is about 21 μ Ci/ μ g.
Effect example 1
Stability test of the marked product A-1 of embodiment 2 in PBS: the 50 μ L of marked product A-1 of Example 2
(about 20 μ Ci), is placed in 0.5mL PBS (PH=7.4,0.01mol/L), is placed at 37 DEG C, oscillation incubation 2 hours, 6 hours,
After 12 hours, 24 hours, 36 hours, 48 hours, 72 hours and 96 hours, its radiochemical purity is measured with Radio-TLC, with
Observe its vitro stability.Radio-TLC analysis as the result is shown this embodiment labeled compound be incubated for 96 hours after still
There is 85% or more A-1 to keep stablizing, de- iodine does not occur, shows that it has good stability in PBS.Radio-TLC detection
Spectrogram is as shown in Figure 1.
Effect example 2
Stability test of the marked product A-1 of embodiment 2 in serum: the 50 μ L of marked product A-1 of Example 2
(about 20 μ Ci), is placed in 0.5mL mice serum, is placed at 37 DEG C, oscillation incubation 2 hours, 6 hours, 12 hours, 24 hours, 36
Hour, 48 hours, 72 hours and after 96 hours, its radiochemical purity is measured with Radio-TLC, to observe its stabilization in vitro
Property.The labeled compound that Radio-TLC analyzes this embodiment as the result is shown still has 80% A-1 to keep after being incubated for 96 hours
Stablize, de- iodine does not occur, shows that it has preferable stability in clear.It is as shown in Figure 2 that Radio-TLC detects spectrogram.
Effect example 3
The measurement of the lipophilicity (Log P) of the marked product A-1 of embodiment 2: the lipophilicity of labeled compound is in n-octyl alcohol
It is measured with the system of water-soluble buffer solution (PBS) composition.This index is the absorption measured drug in vivo, divides
Cloth, metabolism and a key factor of elimination.Log P is the lipid of compound, can reflect a compound parent
The power of lipid.Its survey calculation formula are as follows:
Log P=Log (compound is counted in γ counting/compound of n-octyl alcohol layer in the γ of water layer)
The 2 marked product A-1 of embodiment of 5 μ L is taken (to contain 600 μ L n-octyl alcohols and 595 μ L PBS (pH in 2mL dactylethrae
=7.4,0.01mol/L), it is sealed, at room temperature after sufficient vortex 5min, high speed centrifugation 3min, until biphase equilibrium.Use liquid relief
Device respectively samples 100 μ L from organic phase and water phase and is placed in two V counter tubes, is measured and is counted with gamma counter.It is flat according to 6 times
Row experiment, calculates P=-0.32 ± 0.03 Log (n=6).Lipophilicity data shows, labeled compound has certain hydrophilic
Property, it is easy to remove by kidney.
Effect example 4
The Cell binding specificity of the marked product A-1 of embodiment 2 measures: by the HCC827 of specific expressed EGFR and
A549 cell is inoculated in 24 porocyte culture plates with the cell density in every hole 100,000, and being incubated overnight keeps its attachment adherent, wherein
One group is experimental group, and another group is control group.Cell all adherent growths of every disk are determined before same day experiment, to determine that cell is grown
Well.Culture medium is sucked out, is rinsed cell 2 times with PBS (pH=7.4,0.01mol/L), 1mL culture medium is added.The every hole of experimental group
It is added in 2 marked product A-1 of embodiment (hole~0.6MBq/), the every hole addition 2 marked product A-1 of embodiment of control group (~
The hole 0.6MBq/) and the 35 μ g trastuzumabs of resistance to former times, it is cultivated 1 hour at 37 DEG C.After incubation time, draw culture solution in from
It in heart pipe, then with the cold PBS (pH=7.4,0.01mol/L) of 500 μ L rinses each hole, then PBS is sucked out in centrifuge tube,
Repetition is washed 3 times.1M NaOH 1mL is added, 37 DEG C digest 5 minutes.Gently blow and beat, it, later will be thin to ensure that cell is laid completely
Born of the same parents are sucked out, and are placed in corresponding V counter tube.500 μ L PBS (pH=7.4,0.01mol/L) are recycled to rinse each later
PBS suction is placed in front and filled in the corresponding test tube of cell suspending liquid by hole, repeats this movement twice with by this cell
Sufficiently collect.By all test tubes γ-counter measurement count, test data is analyzed.By calculating putting for million cellular uptakes
Penetrating property counts the ratio between the total radiocounting of Zhan (every million cell of %ID) to determine that marked product A-1 is thin to non-small cell lung cancer
The binding ability of born of the same parents.
Cell binding experiments show after marked product A-1 and HCC827 cell and A549 cell are incubated for 1 hour jointly,
The probe intake of probe every million cell in HCC827 cell and A549 cell is respectively 19.53 than (%ID every million cells)
± 1.97% and 14.24 ± 1.20%.And when the trastuzumab of resistance to former times is added as being incubated for after blocking agent with A-1, probe exists
Million cellular uptakes are than being respectively 1.64 ± 0.28% and 2.03 ± 0.53%, A-1 and thin in HCC827 cell and A549 cell
The binding ability of born of the same parents is significantly blocked.To prove marked product A-1 to the non-small cell lung cancer cell of EGFR overexpression
With good compatibility and targeting, can specificity in conjunction with EGFR.
Effect example 5
The marked product A-1 of embodiment 2 divides in vivo healthy nude mice (concrete model that BALB/c-nu please supplement nude mice)
Cloth: by the marked product A-1 solution of the embodiment 2 of about 30 μ Ci of 200 μ L through in tail vein injection to nude mouse, and after injection
Different time points (3h, 12h, for 24 hours, 48h and 72h, n=4) it is put to death by disconnected neck and is dissected immediately.Acquire interested internal organs or
Tissue, weighs the quality of sample, and measure its radiocounting with gamma counter.After carrying out decay correction, each tissue is calculated
The radioactive uptake rate (%ID/g) of sample.Internal distribution situation is as shown in table 1 below.
Table 1: the internal distribution situation of the marked product A-1 of embodiment 2
After internal distribution results show the marked product A-1 3h of tail vein injection embodiment 2, in blood, kidney, lung etc.
In have higher radioactive uptake rate.But with the extension of time after injection, radioactive uptake rate is gradually decreased, marked product
Removing of the A-1 in normal tissue and organ is very fast.Probe does not generate specificity in most of non-target tissues and organ and takes the photograph
It taking, probe overall performance goes out lower background absorption and non-target absorbs, this is conducive to the imaging effect for improving tumour SPECT-CT,
Optimize picture quality.
Effect example 6
Application of the marked product A-1 of embodiment 2 in the SPECT/CT imaging of lotus non-small cell lung cancer A549 tumor mouse:
The A-1 of 200 μ L (about 10MBq) of lotus A549 tumour tail vein injection.Tumor mouse is fixed by intraperitoneal injection anaesthetized with pentobarbital
SPECT/CT scanning imagery is carried out after anesthetized mice.First CT scan tumor mouse positioning, then carries out SPECT scanning imagery.Scanning
The PET imaging figure of striograph when for 24 hours such as Fig. 3 and SPECT/CT blending image (is as shown in Figure 4 tumour position at arrow in figure
It sets).It can be seen from the figure that most of non-target tissues and organ do not generate specific intake to marked product A-1, background is inhaled
It receives and non-target absorption is lower, the radioactive uptake of tumor locus is high-visible.A-1 compared to111In-Cetuximab, lung are taken the photograph
Take it is lower, can be to avoid false positive results (Huhtala, the T. during diagnosis；Laakkonen,P.；Sallinen,H.；S.；A.In vivo SPECT/CT imaging of human orthotopic
ovarian carcinoma xenografts with In-labeled monoclonal
antibodies.Nucl.Med.Biol.2010,37(8),957-964.)。
Effect example 7
The marked product A-1 of embodiment 2 answering in the SPECT/CT imaging of lotus non-small cell lung cancer HCC827 tumor mouse
With: the A-1 of 200 μ L (about 10MBq) of lotus HCC827 tumour tail vein injection.Tumor mouse passes through intraperitoneal injection amobarbital fiber crops
It is liquor-saturated, SPECT/CT scanning imagery is carried out after fixed anesthetized mice.Then first CT scan tumor mouse positioning carries out SPECT and is scanned into
Picture.The PET imaging of striograph when scanning for 24 hours is schemed
Knub position).It can be seen from the figure that most of non-target tissues and organ do not generate specific intake to marked product A-1,
The radioactive uptake of tumor locus is high-visible.
Effect example 8
Application of the marked product A-1 of embodiment 2 in the SPECT/CT imaging of lotus VX2 rabbit liver squamous carcinoma tumor mouse: lotus VX2
Tumour tail vein injection 200 μ L, the marked product A-1 of the embodiment 2 of about 10MBq.Tumor mouse passes through penta bar of ratio of intraperitoneal injection
Appropriate anesthesia carries out SPECT/CT scanning imagery after fixing anesthetized mice.Then first CT scan tumor mouse positioning carries out SPECT and sweeps
Retouch imaging.Scanning for 24 hours when striograph SPECT imaging figure such as Fig. 7 and SPECT/CT blending image (arrow in figure as shown in Figure 8
It is knub position at head).It can be seen from the figure that most of non-target tissues and organ do not generate specific intake to A-1, swell
The radioactive uptake at tumor position is high-visible.
Claims (10)
1. a kind of radioiodide for the trastuzumab of resistance to former times, it is characterised in that: its structure is Y1-Y2, and wherein Y1 is resistance to former times
Trastuzumab, Y2 are125I、131I、
2. radioiodide as described in claim 1, it is characterised in that: its specific activity is 21~60 μ Ci/ μ g, such as
21 μ Ci/ μ g, 45 μ Ci/ μ g or 60 μ Ci/ μ g.
3. radioiodide as described in claim 1, it is characterised in that: when Y2 is125When I, the radioidination
The specific activity for remembering object is 45~60 μ Ci/ μ g, such as 45 μ Ci/ μ g or 60 μ Ci/ μ g；
And/or when Y2 isWhen, the specific activity of the radioiodide is 21 μ Ci/ μ g.
4. radioiodide as claimed in any one of claims 1-3, it is characterised in that: when Y2 is125I or131When I,
The radioiodide is obtained by iodogen labelling method；
And/or when Y2 isWhen, the radioiodide is by the trastuzumab of resistance to former times and chemical combination
Object BMade from reaction；When Y2 isWhen, the radioiodide
It is by the trastuzumab of resistance to former times and compound CMade from reaction.
5. radioiodide as claimed in any one of claims 1-3, it is characterised in that: the radioiodination
Object is to be prepared as follows made from method:
When Y2 is125I or131When I, the preparation method includes the following steps: in a solvent, by the trastuzumab of resistance to former times and Na125I
Or Na131I carries out electrophilic substitution reaction in the presence of iodogen, obtains the radioiodide；
When Y2 isWhen, the preparation method includes the following steps: in solvent
In, by the trastuzumab of resistance to former times withAmidation process is carried out, is obtained
The radioiodide.
6. radioiodide as described in claim 5, it is characterised in that: described in the electrophilic substitution reaction
Solvent be water and/or PBS buffer solution；
And/or in the electrophilic substitution reaction, concentration of the trastuzumab of resistance to former times in the solvent is 0.1~10mg/
mL；
And/or the mass ratio of iodogen described in the electrophilic substitution reaction and the trastuzumab of resistance to former times is 0.5:1~2:1；
And/or in the electrophilic substitution reaction, every 1 μ g trastuzumab of resistance to former times, Na125I or Na131The dosage of I be 0.03~
0.1mCi；
And/or in the electrophilic substitution reaction, reaction temperature is 10~40 DEG C；
And/or in the electrophilic substitution reaction, the reaction time is 5~90min；
And/or the electrophilic substitution reaction still further comprises post-processing step: after the reaction was completed, through PD-10 column purification,
Obtain product；
And/or in the amidation process, the solvent is one of water, PBS buffer solution and DMSO or a variety of；
And/or in the amidation process, concentration of the trastuzumab of resistance to former times in the solvent is 0.1~10mg/
mL；
And/or in the amidation process, every 1 μ g trastuzumab of resistance to former times, Dosage be 0.03~0.1mCi；
And/or in the amidation process, reaction temperature is 10~40 DEG C；
And/or in the amidation process, the reaction time is 5~90min；
And/or the amidation process still further comprises post-processing step: after the reaction was completed, through PD-10 column purification, obtaining
To product.
7. radioiodide as described in claim 6, it is characterised in that: described in the electrophilic substitution reaction
Solvent is water and/or PBS buffer solution, wherein the PBS buffer solution is " the PBS buffer solution of pH8.0,0.01mol/L "
Or " the PBS buffer solution of pH7.4,0.01mol/L "；
And/or in the electrophilic substitution reaction, concentration of the trastuzumab of resistance to former times in the solvent is 1~5mg/mL,
Such as 1~2mg/mL；
And/or in the electrophilic substitution reaction, the mass ratio of the iodogen and the trastuzumab of resistance to former times is 0.5:1~1:1；
And/or in the electrophilic substitution reaction, every 1 μ g trastuzumab of resistance to former times, Na125I or Na131The dosage of I be 0.03~
0.05mCi；
And/or in the electrophilic substitution reaction, reaction temperature is 20~35 DEG C；
And/or in the electrophilic substitution reaction, the reaction time is 10~60min, such as 30~50min；
And/or post-processing step is still further comprised in the electrophilic substitution reaction: after the reaction was completed, by reaction solution loading
It is eluted in the PBS buffer solution of PD-10 column, 0.01mol/L pH=7.4, obtains product；
And/or in the amidation process, the solvent is one of water, PBS buffer solution and DMSO or a variety of, institute
PBS buffer solution is stated as " the PBS buffer solution of pH8.0,0.01mol/L " or " the PBS buffering of pH7.4,0.01mol/L are molten
Liquid "；When the solvent is the mixed solution of DMSO and PBS buffer solution, the volume ratio of DMSO and PBS buffer solution can be
1:4~1:6, such as 1:5；
And/or concentration of the trastuzumab of resistance to former times described in the amidation process in the solvent is 1~5mg/mL, example
Such as 1~2mg/mL；
And/or in the amidation process, every 1 μ g trastuzumab of resistance to former times, Dosage be 0.03~0.05mCi；
And/or in the amidation process, reaction temperature is 20~35 DEG C；
And/or in the amidation process, the reaction time is 10~60min, such as 30~60min；
And/or the amidation process still further comprises post-processing step: after the reaction was completed, reaction solution being splined on PD-
10 columns, the PBS buffer solution elution of 0.01mol/L pH=7.4, obtain product.
8. a kind of preparation method of the radioiodide for the trastuzumab of resistance to former times, it is characterised in that: described to put
The structure of penetrating property iodine label is Y1-Y2, and wherein Y1 is the trastuzumab of resistance to former times, and Y2 is125I、131I、
When Y2 is125I or131When I, the preparation method includes the following steps: in a solvent, by the trastuzumab of resistance to former times and Na125I
Or Na131I carries out electrophilic substitution reaction in the presence of iodogen, obtains the radioiodide；
When Y2 isWhen, the preparation method included the following steps: resistance to former times
Trastuzumab withAmidation process is carried out, described put is obtained
Penetrating property iodine label；
The reaction condition of the electrophilic substitution reaction and/or amidation process is as described in any one of claim 5-7.
9. a kind of radioiodide for the trastuzumab of resistance to former times that preparation method as claimed in claim 8 is prepared.
10. a kind of radioiodide as described in any one of claim 1-7,9 answering in the preparation of antitumor drugs
With or prepare the application of single photon emission computerized tomography tumor developer；
In application in preparation of anti-tumor drugs, Y2 is preferably in the radioiodide131I, or
In the application for preparing single photon emission computerized tomography tumor developer, Y2 in the radioiodide
Preferably125I or
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