CN108904821B - 188Re-labeled tumor-targeted cyclic nonapeptide molecular probe and preparation method thereof - Google Patents

188Re-labeled tumor-targeted cyclic nonapeptide molecular probe and preparation method thereof Download PDF

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CN108904821B
CN108904821B CN201810788678.9A CN201810788678A CN108904821B CN 108904821 B CN108904821 B CN 108904821B CN 201810788678 A CN201810788678 A CN 201810788678A CN 108904821 B CN108904821 B CN 108904821B
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molecular probe
cyclic nonapeptide
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tumor targeting
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陈萱
陈钰
臧嘉
周洁
杨蕊
周彦君
唐秋莎
陈道桢
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Wuxi Maternal and Child Health Hospital
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Abstract

The invention discloses a188Re-labeled tumor-targeted cyclic nonapeptide molecular probe and preparation method thereof, and the Re-labeled tumor-targeted cyclic nonapeptide molecular probe188The Re-labeled tumor targeting cyclic nonapeptide molecular probe comprises polypeptide and radionuclide188Re, radionuclides188Re was linked to the polypeptide by DTPA. In the cyclic nonapeptide molecular probe of the invention,188compared with the conventional pre-tinning method, the stability of the Re-labeled cyclononapeptide molecule serum is obviously different, the tumor uptake of tumor-bearing nude mice is obviously improved, and the SPECT imaging effect is obvious. The invention uses cuprous chloride to pre-reduce188Re is acted by a weak oxidant after pre-reduction, so that the direct action of a strong reducing agent and a disulfide bond is avoided, the stability of a cyclopeptide structure is maintained, the reduction of tumor targeting biological functions caused by the destruction of the disulfide bond by a direct method is effectively avoided, and the stability in vivo and in vitro of the cyclic nonapeptide marked by the method is higher than that of the direct method.

Description

188Re-labeled tumor-targeted cyclic nonapeptide molecular probe and preparation method thereof
Technical Field
The invention relates to the technical field of molecular imaging, in particular to a method for measuring the molecular weight of a sample188Re-labeled tumor targeting cyclic nonapeptide molecular probe and a preparation method thereof.
Background
At present, radionuclide-labeled polypeptides are increasingly applied to diagnosis and treatment of diseases such as tumors, infections, thrombi and the like as a novel targeted drug. The ligand is used as a carrier of radionuclide, and the purposes of increasing the local concentration of the medicine in the focus, improving the synergy and reducing the target treatment are achieved through ligand-receptor targeting mediation by utilizing the characteristics of specificity, selectivity, saturation, strong affinity, obvious biological effect and the like of the combination of the receptor and the ligand thereof, so that the method is one of the most active frontier fields of the current research. In the development process of the targeted drugs, the selection and modification of the polypeptide are the basis, and the radiolabelling technology is the key.
The cyclic nonapeptide is a cyclic polypeptide containing nine amino acid molecules, and the cyclic polypeptide is a compound with stable and uniform conformation in peptide molecules, and has high selective affinity capacity to receptors, strong metabolic stability and high oral availability. The cyclic polypeptide compound is used as a medicine molecule and has wide biological activities of resisting tumor, virus, bacteria, malaria, sleep, platelet aggregation, blood pressure, enzyme inhibitor, immunosuppression and the like.
The rhenium 188 can synchronously release gamma rays when killing cancer cells, can track the diagnosis and treatment effect through computed tomography, and has two effects of treatment and diagnosis. At present, the food is at home and abroad188The conventional labeling means for Re mainly include direct methods and indirect methods.
The direct labeling method is mostly applied to the labeling of injected antibodies and fragments thereof of macromolecular proteins, the labeling process is relatively simple, and in most cases,188re is bonded with free sulfhydryl after degrading disulfide bond in polypeptide molecule. However, the labeling process of the direct labeling method is difficult to control, and the number of atoms of the polypeptide participating in the reaction and the geometrical shape of radionuclide complexation during labeling are difficult to understand, and stannous chloride is mostly used for reduction (pre-stannization method) in the labeling method, so that the disulfide bond of the polypeptide is opened in the labeling process, the structure of the polypeptide is easily changed, the activity of the protein is damaged, and the biological activity of the targeted tumor is weakened. The direct labeling method is not suitable for the polypeptide without disulfide bonds, and even for the polypeptide with disulfide bonds, the biological activity of the polypeptide is greatly influenced by the small change of the cyclic structure.
Indirect labeling is a method currently in common use, i.e. the polypeptide forms a stable complex indirectly with radioactive metal ions via a bifunctional chelating agent (BFCA). Polypeptide radiopharmaceuticals prepared by indirect labeling methods typically include three essential moieties: polypeptides, radionuclides, and BFCA. The polypeptide is used as a targeting vector, and radionuclides emitting characteristic rays are carried to target tissues in a body to enable the target tissues to play tracing and therapeutic roles. BFCA can be covalently bound with the inactive sequence end of polypeptide, and can form stable complex with metal ion. In order to minimize the interaction between the polypeptide and BFCA, a linker group (linker) or spacer group (spacer) is introduced between the two, and the linker group can be a long polyethylene glycol or hydrocarbon chain, or a polyamino acid such as gly-gly-gly, cys-gly-cys, gly-gly-gly-cys, etc. Thus, the influence of the marker on the biological activity of the polypeptide is reduced, the requirement on a coordination group of BFCA is reduced, and the selection of BFCA and radionuclide is facilitated.
The common labeling of disulfide bond ring-forming targeted polypeptide is direct method, while some labeling with indirect method can combine the bifunctional chelating linker and disulfide bond competitively due to improper method188Re, all cause a decrease in the biological activity of the polypeptide.
Disclosure of Invention
In order to solve the problems of the prior art, the embodiment of the invention provides a method188Re-labeled tumor targeting cyclic nonapeptide molecular probe and a preparation method thereof. The technical scheme is as follows:
in one aspect, a188Re-labeled tumor-targeting cyclic nonapeptide molecular probe comprising polypeptide and radionuclide188Re, the radionuclide188Re was linked to the polypeptide by DTPA.
Further, the polypeptide is CGRRAGGSC, the amino acid sequence is shown as SEQ ID NO.1, and the molecular probe is188Re-DTPA-c(CGRRAGGSC)。
In another aspect, a188The preparation method of the Re-labeled tumor targeting cyclic nonapeptide molecular probe comprises the following steps:
(1) in that188ReO4 -Filling gas into the solution, adding reducing agent, and addingAdding sodium gluconate, adjusting pH of the reaction system, reacting, and adding Na after the reaction is finished2S2O3The color of the reaction solution was adjusted to blue-green (same as that of the aqueous CuCl solution) to obtain a prereduced188A Re reaction solution;
(2) the N-terminus of tumor targeting polypeptide CGRRAGGSC was directly linked to DTPA and then added to the pre-reduction188The Re reaction solution is reacted to obtain the188Re-labeled tumor targeting cyclic nonapeptide molecular probe188Re-DTPA-c(CGRRAGGSC)。
Further, the reducing agent is CuCl.
Further, the mass ratio of CuCl to sodium gluconate is 1-10: 1.
Further, the mass ratio of the polypeptide CGRRAGGSC to CuCl is 1: 2-20.
Further, in the step (1), dilute hydrochloric acid is added to adjust the pH value of the reaction system to 5.0-6.0, the reaction temperature is 20-60 ℃, and the reaction time is 30-90 min.
Further, the reaction temperature in the step (2) is 25-60 ℃, and the reaction time is 30-90 min.
Further, in188ReO4 -The gas filled in the solution is nitrogen.
The technical scheme provided by the embodiment of the invention has the following beneficial effects: according to the invention188In the Re-marked tumor targeting cyclic nonapeptide molecular probe,188compared with the conventional pre-tinning method, the stability of the Re-labeled cyclononapeptide molecule serum is obviously different, the tumor uptake of tumor-bearing nude mice is obviously improved, and the SPECT imaging effect is obvious. The invention uses cuprous chloride to pre-reduce188Re, and fully utilize its discoloring effect after oxidizing, through the weak oxidizing agent function after prereduction, has avoided strong reducing agent and disulfide bond direct action, has maintained the stability of cyclopeptide structure, has avoided the reduction of targeting biological function of tumor that the direct method destroys the disulfide bond effectively, the cyclic nonapeptide marked through the method of the invention, the stability in vivo and in vitro is higher than the direct method. Compared with the molecular probe obtained by the direct method, the targeting property of the molecular probe is improved by about 2-3 times.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below.
FIG. 1 is a photograph of a sample prepared in example 4 of the present invention188An radiochemical purity TLC map of Re-DTPA-c (CGRRAGGSC);
FIG. 2 shows experimental groups in example 5 of the present invention188Re-DTPA-c (CGRRAGGSC) serum stability profile;
FIG. 3 shows MDA-MB-468 tumor-bearing mice in example 6 of the present invention188SPECT image of Re-DTPA-c (CGRRAGGS C).
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in detail with reference to the accompanying drawings.
Example 1188Preparation of Re-DTPA-c (CGRRAGGSC) molecular probe
At 200. mu. Ci188ReO4 -The solution is filled with nitrogen for oxidation prevention, then 2mg of CuCl is added as a reducing agent, 2mg of sodium gluconate is added, the pH value of the reaction system is adjusted to 5.0 by dilute hydrochloric acid, and the reaction is carried out for 90min at 20 ℃. Then adding a proper amount of Na into the reaction solution2S2O3To be pre-reduced188After the color of the Re reaction solution was adjusted to blue-green, 100. mu.g of DTPA-c (CGRRAGGSC) was added and reacted at 25 ℃ for 90 min. CGRRAGGSC is shown in SEQ ID NO. 1.
Example 2188Preparation of Re-DTPA-c (CGRRAGGSC) molecular probe
At 200. mu. Ci188ReO4 -The solution is filled with nitrogen for oxidation prevention, then 2mg of CuCl is added as a reducing agent, 10mg of sodium gluconate is added, the pH value of the reaction system is adjusted to 5.8 by dilute hydrochloric acid, and the reaction is carried out for 30min at 60 ℃. Then adding a proper amount of Na into the reaction solution2S2O3To be pre-reduced188After the color of the Re reaction solution was adjusted to blue-green, 150. mu.g of DTPA-c (CGRRAGGSC) was added and reacted at 60 ℃ for 30 min. CGRRAGGSC is shown in SEQ ID NO. 1.
Example 3188Preparation of Re-DTPA-c (CGRRAGGSC) molecular probe
At 200. mu. Ci188ReO4 -The solution is filled with nitrogen for oxidation prevention, then 2mg of CuCl is added as a reducing agent, 20mg of sodium gluconate is added, the pH value of the reaction system is adjusted to 5.5 by dilute hydrochloric acid, and the reaction is carried out for 70min at 45 ℃. Then adding a proper amount of Na into the reaction solution2S2O3To be pre-reduced188After the color of the Re reaction solution was adjusted to blue-green, 1000. mu.g of DTPA-c (CGRRAGGSC) was added and reacted at 45 ℃ for 60 min. CGRRAGGSC is shown in SEQ ID NO. 1.
Example 4188Preparation of Re-DTPA-c (CGRRAGGSC) molecular probe
At 200. mu. Ci188ReO4 -The solution was charged with nitrogen for oxidation prevention, then 2mg of CuCl was added as a reducing agent, 5mg of sodium gluconate was added, the pH of the reaction system was adjusted to 6.0 with dilute hydrochloric acid, and the reaction was carried out at room temperature (25 ℃ C.) for 30 min. Then adding a proper amount of Na into the reaction solution2S2O3To be pre-reduced188After the color of the Re reaction solution was adjusted to blue-green, 300. mu.g of DTPA-c (CGRRAGGSC) was added and reacted at 37 ℃ for 90 min. CGRRAGGSC is shown in SEQ ID NO. 1.
Developing with silica gel plate as stationary phase and acetone/water 4:1(V/V) as mobile phase by TLC method188Re-DTPA-c (CGRRAGGSC) has an Rf value of 0.5 to 0.6 and an radiochemical purity of about 95%, the results are shown in FIG. 1.
Example 5 serum stability test
Taking the product prepared in example 4188Re-DTPA-c (CGRRAGGSC) is used as an experimental group, a molecular probe is prepared as a control group by a direct method, 90 mu L of fresh mouse serum is respectively added into the experimental group and the control group, the incubation is carried out in a water bath box at 37 ℃, the radiochemical purity of the experimental group and the radiochemical purity of the control group are measured at regular time (1, 2, 4 and 8h), and the result of the experimental group is shown in figure 2. The serum stability of the experimental group is good, the degradation is about 4% in 1 hour, the degradation is about 10% in 2 hours, the radiochemical purity is more than 75% in 8 hours, the radiochemical purity of the control group is reduced to be below 60% in 2 hours, and the radiochemical purity is about 35% in 8 hours.
Example 6 in vivo distribution experiment
MDA-MB-468 tumor-bearing mice were divided into two groups, one group was injected with 100. mu. Ci via tail vein, prepared in example 4188Re-DTPA-c (CGRRAGGSC) is used as an experimental group, the other group is used as a control group by preparing a molecular probe through a tail vein injection direct method, the experimental group and the control group are subjected to SPECT imaging, the experimental group result is shown in figure 3, the arrow in figure 3 indicates a tumor part, the image is clearer, and the preparation success of the imaging probe is indicated. Mice were sacrificed at 2h and the distribution data in the two groups of mice were compared, and the results are shown in table 1, where the tumor/contralateral muscle in the experimental group was about 2 times that in the control group, with significant differences. The tumor tissue uptake of 5.55 + -0.43% ID/g was found by comparing the radioactivity in the tumor site over 2h with that in the contralateral muscle, and the target/non-target ratio was 6.3 + -0.55, respectively. The markers are distributed in the liver and kidney, and the radioactive uptake in the heart, blood, muscle and other major organs is much lower than that in tumor sites.
TABLE 1188Re-DTPA-c (CGRRAGGSC) distribution results
Figure BDA0001734284460000051
Figure BDA0001734284460000061
According to the invention188In the Re-marked tumor targeting cyclic nonapeptide molecular probe,188compared with the conventional pre-tinning method, the stability of the Re-labeled cyclononapeptide molecule serum is obviously different, the tumor uptake of tumor-bearing nude mice is obviously improved, and the SPECT imaging effect is obvious. The invention uses cuprous chloride to pre-reduce188Re, and fully utilize its discoloring effect after oxidizing, through the weak oxidizing agent function after prereduction, has avoided strong reducing agent and disulfide bond direct action, has maintained the stability of cyclopeptide structure, has avoided the reduction of targeting biological function of tumor that the direct method destroys the disulfide bond effectively, the cyclic nonapeptide marked through the method of the invention, the stability in vivo and in vitro is higher than the direct method. The more direct method of the inventionThe targeting property of the probe can be improved by about 2-3 times.
The above-mentioned serial numbers of the embodiments of the present invention are merely for description and do not represent the merits of the embodiments.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Sequence listing
<110> Wuxi city women and children health care hospital
<120> 188Re marked tumor targeting cyclic nonapeptide molecular probe and preparation method thereof
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 9
<212> PRT
<213> Artificial Synthesis ()
<400> 1
Cys Gly Arg Arg Ala Gly Gly Ser Cys
1 5

Claims (8)

1. A kind of188The preparation method of the Re-labeled tumor targeting cyclic nonapeptide molecular probe is characterized by comprising the following steps of:
(1) in that188ReO4 -Filling gas into the solution, adding a reducing agent, adding sodium gluconate, adjusting the pH value of the reaction system, reacting, and adding Na after the reaction is finished2S2O3Adjusting the color of the reaction solution to blue-green to obtain pre-reduction188A Re reaction solution;
(2) the N-terminus of tumor targeting polypeptide CGRRAGGSC was directly linked to DTPA and then added to the pre-reduction188The Re reaction solution is reacted to obtain the188Re-labeled tumor targeting cyclic nonapeptide molecular probe188Re-DTPA-c(CGRRAGGSC)。
2. The method of claim 1188The preparation method of the Re-labeled tumor targeting cyclic nonapeptide molecular probe is characterized in that the reducing agent is CuCl.
3. The method of claim 2188The preparation method of the Re-labeled tumor targeting cyclic nonapeptide molecular probe is characterized in that the mass ratio of the CuCl to the sodium gluconate is 1-10: 1.
4. The method of claim 2188The preparation method of the Re-labeled tumor targeting cyclic nonapeptide molecular probe is characterized in that the mass ratio of the polypeptide CGRRAGGSC to CuCl is 1: 2-20.
5. The method of claim 1188The preparation method of the Re-labeled tumor targeting cyclic nonapeptide molecular probe is characterized in that in the step (1), dilute hydrochloric acid is added to adjust the pH value of a reaction system to 5.0-6.0, the reaction temperature is 20-60 ℃, and the reaction time is 30-90 min.
6. The method of claim 1188The preparation method of the Re-labeled tumor targeting cyclic nonapeptide molecular probe is characterized in that the reaction temperature in the step (2) is 25-60 ℃, and the reaction time is 30-90 min.
7. The method of claim 1188The preparation method of the Re-labeled tumor targeting cyclic nonapeptide molecular probe is characterized in that188ReO4 -The gas filled in the solution is nitrogen.
8. A kind of188The Re-labeled tumor targeting cyclic nonapeptide molecular probe is characterized by comprising polypeptide CGRRAGGSC, wherein the amino acid sequence is shown as SEQ ID NO.1, and the molecular probe is188Re-DTPA-c (CGRRAGGSC), wherein the molecular probe is prepared by the method of any one of claims 1 to 7.
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* Cited by examiner, † Cited by third party
Title
"Na188ReO4、188Re-DTPA和188Re-MAG3的生物分布及排泄比较";贾兵等;《同位素》;20051130;第18卷(第4期);标题，摘要 *
"人乳腺癌MCF-7裸鼠模型的99mTc-DTPA-CGRRAGGSC显像研究";胡瑶等;《南京医科大学学报（自然科学版）》;20170227;第37卷(第2期);摘要 *

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