CN111084889A - Preparation method of nuclide molecular probe targeting CD4 receptor and application of nuclide molecular probe as heart transplantation rejection developer - Google Patents
Preparation method of nuclide molecular probe targeting CD4 receptor and application of nuclide molecular probe as heart transplantation rejection developer Download PDFInfo
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- CN111084889A CN111084889A CN202010040264.5A CN202010040264A CN111084889A CN 111084889 A CN111084889 A CN 111084889A CN 202010040264 A CN202010040264 A CN 202010040264A CN 111084889 A CN111084889 A CN 111084889A
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- 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
- A61K51/1027—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 receptors, cell-surface antigens or cell-surface determinants
Abstract
The invention relates to a preparation method of a nuclide molecular probe targeting a CD4 receptor and application of the nuclide molecular probe as a heart transplantation rejection developer; mixing the leukocyte differentiation antigen 4 monoclonal antibody with a 6-hydrazino nicotinoyl succinimide ester hydrochloride solution, extracting and reacting to obtain a 6-hydrazino nicotinamide-leukocyte differentiation antigen 4 monoclonal antibody, mixing the 6-hydrazino nicotinamide-leukocyte differentiation antigen 4 monoclonal antibody with N-tris (hydroxymethyl) methylglycine, stannous chloride and technetium, and carrying out oscillation reaction; the beneficial effects are that: has higher marking rate and radiochemical purity and good affinity to CD4+ T lymphocytes; the imaging agent for transplant rejection reaction has the characteristics of high sensitivity and high specificity, and can realize the early diagnosis of acute rejection reaction.
Description
Technical Field
The invention belongs to the technical field of radiochemistry and clinical nuclear medicine, and particularly relates to a preparation method and application of a nuclide molecular probe targeting a CD4 (leukocyte differentiation antigen 4) receptor.
Background
Heart Transplantation (HT) is an effective means of treating end-stage heart disease. Despite the increasing immunosuppressive effects, the incidence of Acute Rejection (AR) is as high as 40%, with a mortality rate of 12%, the most common complication and major cause of death after heart transplantation. Therefore, the method has extremely important effects on early diagnosis and monitoring of AR after HT operation.
However, there is no highly specific non-invasive detection technique clinically available at present. Transjugular Endocardial Myocardial Biopsy (EMB) is the "gold standard" for diagnosing AR after HT operation, and plays an important role in diagnosing whether rejection reaction exists after heart transplantation, evaluating immunosuppressive treatment effect, monitoring myocardial lesion after transplantation and the like.
However, EMB is an invasive technique, and may cause serious complications in clinical applications, such as myocardial perforation, pericardial tamponade, infection, thrombosis, etc.; in addition, the rejection pathological manifestations of transplanted hearts are mostly focus-type lesions, missed diagnosis exists when local materials are taken from the right ventricle, accurate judgment of the disease conditions is seriously influenced, and in clinical practice, EMB is usually carried out under the conditions that rejection has already occurred and the cardiac function is reduced, and early diagnosis is difficult, so that the optimal treatment time is delayed; at the same time, the high cost of EMB also reduces patient compliance with continuous monitoring, limiting the opportunity for optimization and treatment of immunosuppressive therapy. In addition, conventional imaging examinations are not sensitive to acute rejection.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of a nuclide molecular probe targeting a CD4 receptor and application of the nuclide molecular probe as a heart transplantation rejection developer, and mainly solves the problems of invasiveness, low diagnostic sensitivity, poor specificity, insufficient image resolution and the like in the prior art.
In order to solve the problems, the invention adopts the following technical scheme:
a method for preparing a nuclide molecular probe targeting a CD4 receptor,
A. mixing the 4 monoclonal antibody of the leucocyte differentiation antigen with the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution,
B. extracting the 6-hydrazinonicotinamide-leukocyte differentiation antigen 4 monoclonal antibody obtained by the reaction,
C. mixing 6-hydrazino nicotinamide-leucocyte differentiation antigen 4 monoclonal antibody with N-tri (hydroxymethyl) methylglycine, stannous chloride and technetium,
D. the reaction was shaken.
In one embodiment, the leukocyte differentiation antigen 4 monoclonal antibody is pretreated before step A: antibody purification was performed by desalting column.
One way, the pretreatment of the leukocyte differentiation antigen 4 monoclonal antibody before the step A comprises the following specific steps:
putting the desalting column into a centrifuge tube, centrifuging, discarding the storage solution,
adding a modified buffer solution to adjust the pH value to 8, centrifuging,
and putting the desalting column into a new centrifugal tube, adding the leukocyte differentiation antigen 4 monoclonal antibody into the desalting column, centrifuging, and collecting the purified leukocyte differentiation antigen 4 monoclonal antibody.
In one mode of the method, the first step is that,
in step B, an excess of the reactant 6-hydrazino nicotinoyl succinimide ester hydrochloride is added.
In one mode of the method, the first step is that,
purifying the 6-hydrazinonicotinamide-leukocyte differentiation antigen 4 monoclonal antibody by desalting column centrifugation.
In one mode of the method, the first step is that,
mixing the leukocyte differentiation antigen 4 monoclonal antibody with 6-hydrazino nicotinoyl succinimide ester hydrochloride solution, and oscillating at 4-5 ℃ for lucifugal reaction.
One way, in step A, 6-hydrazino nicotinoyl succinimide ester hydrochloride is dissolved in dimethyl sulfoxide to form 6-hydrazino nicotinoyl succinimide ester hydrochloride solution,
the concentration of the 6-hydrazino nicotinoyl succinimide ester hydrochloric acid in the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution is 10-20 mg/ml;
the molar ratio of the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution to the antibody is (10-30): 1.
in one mode, the step D is specifically carried out for 30-60min by shaking in the dark.
In one mode, in step C,
the concentration of the N-tris (hydroxymethyl) methylglycine is 100-120mg/ml,
the concentration of the stannous chloride is 7-10mg/ml,
the technetium radiation dose was 740-1110 MBq.
Use of a nuclear molecular probe targeting the CD4 receptor as an imaging agent for heart transplant rejection.
The invention has the beneficial effects that:
1. has higher marking rate and radiochemical purity and good affinity to CD4+ T lymphocytes;
2. the imaging agent for transplant rejection reaction has the characteristics of high sensitivity and high specificity, and can realize the early diagnosis of acute rejection reaction.
Drawings
FIG. 1 is a schematic diagram of a preparation process of the present invention;
FIG. 2 is a graph of the stability of probes in PBS (phosphate buffered saline) and FBS (fetal bovine serum) at various time points;
FIG. 3 is a comparative table showing the results of cell uptake experiments;
FIG. 4 shows the SPECT imaging result of the heart transplantation model mouse;
FIG. 5 is a graph showing the biodistribution of the product of the present invention in heart transplantation model mice;
fig. 6 is a graph showing HE staining and immunohistochemistry results for myocardial tissue.
Detailed Description
Example 1
Zeba desalting column (Thermo scientific, usa) treated CD4 mab:
1. removing the bottom plug and the top cover of the desalting column, putting into a 1.5mL centrifuge tube, centrifuging at 1500 Xg for 1min, and discarding the storage solution;
2. adding 300. mu.L of 1 × modifying buffer (modified buffer, Solulink, USA), centrifuging at 1500 × g for 1min, and repeating for three times;
3. placing the desalting column in a new centrifuge tube, adding CD4 monoclonal antibody (150ug, 1nmol) into the center of the resin, centrifuging at 1500 Xg for 2min, and collecting the sample;
B.99mtc-labeled CD4 (leukocyte differentiation antigen 4) mab:
1. weighing SHNH, dissolving in anhydrous DMSO (dimethyl sulfoxide) (10ug/μ L), mixing with 4 μ L (140nmol) of the treated antibody, and placing on a shaker for reaction at 4 deg.C in dark overnight;
2. removing excessive unreacted SHNH (6-hydrazino nicotinoyl succinimide ester hydrochloride) from the reaction product by a Zeba desalting column;
① removing bottom plug and top cover of desalting column, placing into 1.5ml centrifuge tube, centrifuging at 1500 × g for 1min, and discarding the storage solution;
② adding 1 Xconugating buffer (conjugate buffer containing sodium phosphate and EDTA) 300. mu.L, 1500 Xg centrifugation for 1min, repeating three times;
loading reacted HYNIC (6-hydrazinonicotinamide) -monoclonal antibody, centrifuging at 1500 Xg for 2min, and removing excessive HYNIC.
The treated HYNIC-mab was added to 100. mu.L of LTricine (N-tris (hydroxymethyl) methylglycine) (100mg/ml), 4. mu.L of stannous chloride (SnCl2, 7mg/ml), 500. mu.L99mTc (technetium) (800MBq), mixing completely, shaking reacting for 30min at room temperature in dark to prepare99mTc-HYNIC-mAbCD4。
As described above99mTc-HYNIC-mAbCD4The performance studies of (a) were as follows:
A. rapid thin layer chromatography (ITLC) assay for labeling rate:
adding 500 μ L of PBS into the developing cylinder, spotting the product on the chromatographic paper for several times about 1cm away from the edge, developing the chromatographic paper in a developing agent, naturally drying after the chromatography is finished, and scanning with a radio-chromatography instrument to see the labeling rate of the label. The labeling rate of the targeting probe is 73.31 + -0.95%.
Pd-10 column purification of product, ITLC assay radiochemical purification:
(1) removing the PD-10 column bottom plug to completely drain the liquid in the column, and discarding the storage liquid;
(2) balancing: the column was filled with PBS and the liquid was drained. Repeating the steps for 4 times, and discarding effluent liquid;
(3) sample adding: the product was applied to a PD-10 column and, after the sample had completely entered the column and no liquid was drained, it was made up to 2.5ml with PBS. Discarding the effluent when the PBS completely flows through the column and no liquid flows out;
(4) and (3) elution: the effluent was connected with 1.5ml of EP tubing and 500ul PBS was added each time. 16 tubes were connected in total and the radioactivity of each tube was measured. Collecting the liquid of the 1 st radiation peak, namely the purified labeled product; the probe has greater than 95% radiochemical purity as determined by ITLC.
C. In vitro stability of the assay probe:
the purified product is placed in PBS and serum, and subjected to ITLC (ionization and purification) determination radiochemical purification at different time points (1, 3, 6 and 12h) to obtain the stability of the PBS and the serum, so as to predict the stability of the PBS and the serum in vivo. The experimental result shows that the radiochemical purity of the probe is more than 85 percent after the probe is placed in PBS and serum at 37 ℃ for 12 hours, which indicates that the in vitro stability of the probe is good.
FIG. 2 stability of probes in PBS and FBS at different time points.
D. Determination of the affinity of the probes for binding to CD4+ T cells in vitro:
CD4+ T lymphocytes were obtained from lymph nodes of mature SD rats and macrophage NR8383 was obtained from Wuhan Protech. Verification of the specificity of the targeting probes in vitro by cellular uptake, CD4+ T lymphocytes (experimental group) and macrophages (control group) were added99mTc-HYNIC-mAbCD4And (3) incubating for a proper time, performing in-vitro cell uptake experiments and cell blocking experiments, and evaluating the binding affinity and specificity of the probe to the CD4 molecule in vitro.
The method comprises the following specific steps: the extracted CD4+ T lymphocytes and macrophages are inoculated on a 24-well plate (7 multiplied by 105 cells/well), the complete culture medium is discarded during the experiment, the plate is washed once by serum-free 1640 culture medium, excessive unlabelled CD4 monoclonal antibody is added into a blocking group, 0.1mL labeled probe (about 7.4kBq) is added into each well of an experimental group, a blocking group and a control group after 30min, and then the plate is placed into an incubator at 37 ℃ for incubation. After 1, 3, 6h, respectively, radioactivity counts in the supernatant and in the cells were determined with a gamma counter, respectively. The experimental results show that compared with the experimental group, the control group has far lower intake than the experimental group, and the probe has higher in vitro binding affinity. Successful blocking was achieved when excess unlabeled antibody was added, indicating better in vitro specificity of the probe.
FIG. 3 results of cellular uptake experiments.
Spect imaging and biodistribution:
the allografting group model is transplanted into a Lewis rat body from the heart of a BN rat, the homologous grafting group model is transplanted into the Lewis rat body from the heart of the Lewis rat body, and the normal group model adopts the non-transplanted Lewis rat body. SPECT imaging: SPECT imaging is carried out 5 days after modeling, and three groups of rats are respectively injected by tail vein99mTc-HYNIC-mAbCD4After (37MBq), SPECT imaging was performed 1, 3, 6, 12, 24h after injection, respectively. The result shows that the transplantation heart of the allograft group is absorbed, and the homologous transplantation and normal mice do not have acute rejection reaction, so that the transplantation heart has no radioactive concentration, and the probe is mainly concentrated in the liver and spleen, thereby showing that the target probe has good specificity.
FIG. 4 SPECT imaging results of heart transplantation model mouse. a allograft group, b syngeneic transplantation group, c normal group (L ═ liver, Ht ═ transplantation heart, S ═ spleen);
biodistribution: three groups of rats are injected via tail vein99mTc-HYNIC-mAbCD4(18.5MBq), sacrifice was performed 6h after injection. The in-situ heart, transplanted heart, liver, spleen, lung, kidney and other tissues and organs are taken, weighed after being wiped clean, corresponding radioactivity counting is measured by an automatic well type gamma counter, the percent injection dose ratio (% ID/g) of each gram weight of each tissue after attenuation correction is calculated, and the pharmacokinetics of the molecular probe in vivo is inspected. The number of rats in each group was 5, and the results of the biodistribution experiment are shown in FIG. 5,99mTc-HYNIC-mAbCD4biodistribution results in heart transplant model mice (x. + -. SD,% ID/g) Note: ALL as allograft group, ISO as syngeneic transplantation group, NOR as normal group;
as can be seen,99mTc-HYNIC-mAbCD4the uptake of the target probe in the heart of the allograft mouse is higher 6h after injection, while the uptake in the heart of the syngeneic transplantation mouse and the normal mouse is lower, and the uptake value of the target probe in the heart of the allograft mouse is about 10 times of that of the orthogeneic transplantation mouse and is obviously higher than that of the syngeneic transplantation mouse and the normal mouse. The result shows that the compound can be used as a novel acute rejection contrast agent.
F. Ex vivo histology confirmed CD4 expression:
in order to further verify the imaging specificity, tissues such as an in-situ heart, a transplanted heart and the like of three groups of rats are taken, HE staining, immunohistochemistry and the like of isolated tissues are performed to verify the expression of CD4, and the result is analyzed by using Image J software;
FIG. 6 HE staining and immunohistochemistry of myocardial tissue.
HE staining revealed significant inflammatory cell infiltration and cardiomyocyte destruction in the transplanted hearts of the xenograft rats. Immunohistochemistry results showed that the transplanted heart of the allograft group rats had CD4 expression, and the other two groups did not; results the SPCET visualization results were again verified.
Example 2
A. Mixing the leukocyte differentiation antigen 4 monoclonal antibody with 6-hydrazino nicotinoyl succinimide ester hydrochloride solution, and oscillating at 4 ℃ for lucifugal reaction;
6-hydrazino nicotinoyl succinimide ester hydrochloride is dissolved in dimethyl sulfoxide solution to form 6-hydrazino nicotinoyl succinimide ester hydrochloride solution,
the concentration of the 6-hydrazino nicotinoyl succinimide ester hydrochloric acid in the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution is 10 mg/ml;
the molar ratio of the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution to the leukocyte differentiation antigen 4 monoclonal antibody is 10: 1;
B. extracting the 6-hydrazinonicotinamide-leukocyte differentiation antigen 4 monoclonal antibody obtained by the reaction,
C. mixing 6-hydrazino nicotinamide-leucocyte differentiation antigen 4 monoclonal antibody with N-tri (hydroxymethyl) methylglycine, stannous chloride and technetium,
the concentration of the N-tris (hydroxymethyl) methylglycine is 100mg/ml,
the concentration of the stannous chloride is 7mg/ml,
the technetium radiation dose is 740MBq,
D. the reaction was shaken at room temperature in the dark for 30 min.
Example 3
A. Mixing the leukocyte differentiation antigen 4 monoclonal antibody with a 6-hydrazino nicotinoyl succinimide ester hydrochloride solution, and oscillating at 5 ℃ for light-shielding reaction;
6-hydrazino nicotinoyl succinimide ester hydrochloride is dissolved in dimethyl sulfoxide solution to form 6-hydrazino nicotinoyl succinimide ester hydrochloride solution,
the concentration of the 6-hydrazino nicotinoyl succinimide ester hydrochloric acid in the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution is 20 mg/ml;
the molar ratio of the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution to the leukocyte differentiation antigen 4 monoclonal antibody is 30: 1;
B. extracting the 6-hydrazinonicotinamide-leukocyte differentiation antigen 4 monoclonal antibody obtained by the reaction,
C. mixing 6-hydrazino nicotinamide-leucocyte differentiation antigen 4 monoclonal antibody with N-tri (hydroxymethyl) methylglycine, stannous chloride and technetium,
the concentration of N-tris (hydroxymethyl) methylglycine is 120mg/ml,
the concentration of the stannous chloride is 10mg/ml,
the technetium radiation dose is 1110MBq,
D. the reaction was stirred at room temperature for 60min in the dark.
Example 4
A. Mixing the leukocyte differentiation antigen 4 monoclonal antibody with 6-hydrazino nicotinoyl succinimide ester hydrochloride solution, and oscillating at 4.5 ℃ for light-shielding reaction;
6-hydrazino nicotinoyl succinimide ester hydrochloride is dissolved in dimethyl sulfoxide solution to form 6-hydrazino nicotinoyl succinimide ester hydrochloride solution,
the concentration of the 6-hydrazino nicotinoyl succinimide ester acid in the 6-hydrazino nicotinoyl succinimide ester acid salt solution is 15 mg/ml;
the molar ratio of the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution to the leukocyte differentiation antigen 4 monoclonal antibody is 15: 1;
B. extracting the 6-hydrazinonicotinamide-leukocyte differentiation antigen 4 monoclonal antibody obtained by the reaction,
C. mixing 6-hydrazino nicotinamide-leucocyte differentiation antigen 4 monoclonal antibody with N-tri (hydroxymethyl) methylglycine, stannous chloride and technetium,
the concentration of the N-tris (hydroxymethyl) methylglycine is 110mg/ml,
the concentration of the stannous chloride is 8mg/ml,
the technetium radiation dose is 900MBq,
D. the reaction was stirred at room temperature with light for 50 min.
It will be apparent to those skilled in the art that various modifications may be made to the above embodiments without departing from the general spirit and concept of the invention. All falling within the scope of protection of the present invention. The protection scheme of the invention is subject to the appended claims.
Claims (10)
1. A preparation method of a nuclide molecular probe targeting a CD4 receptor is characterized by comprising the following steps:
A. mixing the 4 monoclonal antibody of the leucocyte differentiation antigen with the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution,
B. extracting the 6-hydrazinonicotinamide-leukocyte differentiation antigen 4 monoclonal antibody obtained by the reaction,
C. mixing 6-hydrazino nicotinamide-leucocyte differentiation antigen 4 monoclonal antibody with N-tri (hydroxymethyl) methylglycine, stannous chloride and technetium,
D. the reaction was shaken.
2. The method for preparing the nuclide molecular probe for targeting a CD4 receptor as claimed in claim 1, wherein the method comprises the following steps:
pretreating a leukocyte differentiation antigen 4 monoclonal antibody before the step A: antibody purification was performed by desalting column.
3. The method for preparing the nuclide molecular probe for targeting a CD4 receptor as claimed in claim 2, wherein the method comprises the following steps:
the pretreatment of the leukocyte differentiation antigen 4 monoclonal antibody before the step A comprises the following specific steps:
putting the desalting column into a centrifuge tube, centrifuging, discarding the storage solution,
adding a modified buffer solution to adjust the pH value to 8, centrifuging,
and putting the desalting column into a new centrifugal tube, adding the leukocyte differentiation antigen 4 monoclonal antibody into the desalting column, centrifuging, and collecting the purified leukocyte differentiation antigen 4 monoclonal antibody.
4. The method for preparing the nuclide molecular probe for targeting a CD4 receptor as claimed in claim 1, wherein the method comprises the following steps:
in step B, an excess of the reactant 6-hydrazino nicotinoyl succinimide ester hydrochloride is added.
5. The method for preparing the nuclide molecular probe for targeting a CD4 receptor as claimed in claim 4, wherein the method comprises the following steps:
purifying the 6-hydrazinonicotinamide-leukocyte differentiation antigen 4 monoclonal antibody by desalting column centrifugation.
6. The method for preparing the nuclide molecular probe for targeting a CD4 receptor as claimed in claim 1, wherein the method comprises the following steps:
mixing the leukocyte differentiation antigen 4 monoclonal antibody with 6-hydrazino nicotinoyl succinimide ester hydrochloride solution, and oscillating at 4-5 ℃ for lucifugal reaction.
7. The method for preparing the nuclide molecular probe for targeting a CD4 receptor as claimed in claim 1, wherein the method comprises the following steps:
in the step A, 6-hydrazino nicotinoyl succinimide ester hydrochloride is dissolved in dimethyl sulfoxide to form 6-hydrazino nicotinoyl succinimide ester hydrochloride solution,
the concentration of the 6-hydrazino nicotinoyl succinimide ester hydrochloric acid in the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution is 10-20 mg/ml;
the molar ratio of the 6-hydrazino nicotinoyl succinimide ester hydrochloride solution to the antibody is (10-30): 1.
8. the method for preparing the nuclide molecular probe for targeting a CD4 receptor as claimed in claim 1, wherein the method comprises the following steps: and the step D is specifically to carry out shaking reaction for 30-60min in a dark place.
9. The method for preparing the nuclide molecular probe for targeting a CD4 receptor as claimed in claim 1, wherein the method comprises the following steps: in the step C, the step C is carried out,
the concentration of the N-tris (hydroxymethyl) methylglycine is 100-120mg/ml,
the concentration of the stannous chloride is 7-10mg/ml,
the technetium radiation dose was 740-1110 MBq.
10. Use of a nuclear molecular probe targeting the CD4 receptor as defined in any one of claims 1 to 9 as an imaging agent for heart transplant rejection.
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| CN101979095A (en) * | 2001-05-02 | 2011-02-23 | 普渡研究基金会 | Treatment and diagnosis of macrophage mediated disease |
| US20120076727A1 (en) * | 2007-01-11 | 2012-03-29 | Immunomedics, Inc. | In Vivo Copper-Free Click Chemistry for Delivery of Therapeutic and/or Diagnostic Agents |
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