CN117624278A - Specific tumor diagnosis probe and imaging agent for targeting heat shock protein 90 - Google Patents

Specific tumor diagnosis probe and imaging agent for targeting heat shock protein 90 Download PDF

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CN117624278A
CN117624278A CN202410102890.0A CN202410102890A CN117624278A CN 117624278 A CN117624278 A CN 117624278A CN 202410102890 A CN202410102890 A CN 202410102890A CN 117624278 A CN117624278 A CN 117624278A
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probe
tumor
heat shock
shock protein
hsp90
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CN117624278B (en
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顾月清
常琦
王勇
叶卓仪
邹乐男
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China Pharmaceutical University
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Abstract

The invention discloses a specific tumor diagnosis probe of a targeted heat shock protein 90 and an imaging agent, wherein the HSP90 targeted probe can improve the in vivo dynamics characteristic of a compound, prolong the residence time of the compound in a tumor and further improve the imaging effect of the compound in the tumor; by labelling diagnostic nuclides in compounds 99m Tc or 68 Ga enables SPECT imaging or PET imaging for tumor diagnosis by labeling therapeutic nuclides 177 Lu, carry outThe composition has good clinical application prospect in treating HSP90 expressed tumors.

Description

Specific tumor diagnosis probe and imaging agent for targeting heat shock protein 90
Technical Field
The invention relates to a probe and an imaging agent, in particular to a specific tumor diagnosis probe and an imaging agent targeting heat shock protein 90.
Background
The nuclear medicine imaging can realize noninvasive, visual, qualitative/quantitative monitoring at molecular and cellular level and participate in physiological and pathological processes in the tumorigenesis and development process, can simultaneously provide anatomical and functional information, has important significance for improving the cure rate and life quality of patients, and has become an important means for clinical tumor detection. Positron emission computed tomography (Positron Emission Tomography, PET) has the advantages of high sensitivity and resolution, and is currently mainly applied to PET imaging 18 F-FDG can simulate the metabolic pathway of glucose in vivo, and is absorbed by cells with high energy demand, especially tumor cells, and retained in the cells, so that the F-FDG can be widely applied to the aspects of diagnosis, treatment monitoring and the like of various clinical tumor diseases. Single photon emission computed tomography (Single photon emission computed tomography, SPECT) has the advantages of higher popularity and moderate examination cost, and is generally applied to aspects such as myocardial perfusion imaging, brain function imaging, and the like. Recently, with the advent of some novel molecular probes, SPECT imaging has also played an important role in tumor diagnosis, such as 99m Tc-Octreotides and analogs thereof are useful in neuroendocrine tumor imaging. The development of a novel tumor placement diagnostic probe has important clinical significance in PET or SPECT imaging through different radioactive labels.
Heat shock protein 90 (Heat Shock protein, HSP 90) is an important chaperone protein that, by binding to client proteins and other chaperones, plays a key role in participating in basic physiological activities of cells and regulating various biological processes, such as apoptosis, cell cycle, signaling, cell viability, protein folding and degradation. HSP90 has 4 subtypes in total, and has high conservation. HSP90 a and HSP90 β are present in the cytoplasm; tumor necrosis factor receptor-related protein 1 (Tumor necrosis factor receptor-associated protein, TRAR 1) is present in mitochondria; glucose regulatory protein 94 (94-kDa Glucose-regulated protein, GRP 94) is present in the endoplasmic reticulum. HSP90 is present only in the cytoplasm in normal cells, where HSP90 is activated and localized to the cell membrane of tumor cells and is secreted extracellularly by exosomes. Post-translational modifications such as acetylation, phosphorylation alter HSP90 localization in cells, and this ectopic promotes malignant progression of various tumors. Studies have shown that HSP90 concentration in the plasma of clinical patients shows a positive correlation with the malignancy of tumors. HSP90 plays an important role in metastasis and invasion of tumor cells, and highly invasive tumor cells can secrete a large amount of HSP90, activate matrix metalloproteinase 2 (MMP-2) and further induce expression of MMP-3, and drive tumor invasion. Researchers demonstrated that blocking or neutralizing secreted HSP90 inhibited tumor metastasis. The HSP90 content on the surface of tumor cells is higher than that of normal cells, the characteristic enables the HSP90 on the surface of the cells to be a potential tumor diagnosis and treatment target, more than ten drugs targeting the HSP90 such as PU-H71, ganetespib and the like are currently available and enter clinical tests, so that the development of the molecular imaging probe targeted by the HSP90 has important value for evaluating the HSP90 target and monitoring the curative effect of the drugs.
Plasma Hsp90 alpha has been approved as a liver cancer marker, and the kit has been used in clinic in batch for the current condition monitoring and efficacy evaluation of lung cancer and liver cancer. In addition, a plurality of researches show that HSP90 alpha is remarkably high expressed in serum of patients with lung cancer and colorectal cancer, and when the detection value is more than 82.06 ng/ml, the risk of suffering from malignant tumor is high. When HSP90 alpha and other serum markers such as CEA are detected in a combined way, the diagnosis coincidence rate, specificity and sensitivity are obviously higher than those of single detection. The clinical application of HSP90 in tumor diagnosis is mostly in vitro, but some researchers are exploring the value of HSP90 in tumor diagnosis, such as the research of the related mechanism of HSP90 in cancer and senile dementia in the prior art, and the developed HSP90 nuclide probe [ 124 I]PU-HZ151 can detect subcutaneous tumor and brain tumor of mice, and can detect lung tumor of lung cancer patients. However, the nuclide probe has poor in-vivo metabolic properties, and the tumor targeting capability is required to be improved.
Disclosure of Invention
The invention aims to: the invention aims to provide a specific tumor diagnosis probe of a targeted heat shock protein 90, which can effectively diagnose colorectal cancer or lung cancer; it is another object of the present invention to provide a specific tumor diagnostic imaging agent targeting heat shock protein 90.
The technical scheme is as follows: the specific tumor diagnosis probe of the targeted heat shock protein 90 has the following structural formula:
。
further, the tumor is colorectal cancer or lung cancer tumor.
The preparation method of the specific tumor diagnosis probe for targeting the heat shock protein 90 comprises the following steps:
dissolving YQHSI-EC, HYNIC-NHS or DOTA-NHS in a solvent, adding DIPEA for reaction, and separating and purifying after the reaction is completed to obtain a target compound; the synthetic route of the YQHSI-EC is as follows:
。
further, the mass ratio of YQHSI-EC, HYNIC-NHS or DOTA-NHS is 1:1-1:3, the reaction temperature is 30-50 ℃, the reaction time is 0.5-5h, and the solvent is DMF.
Further, the method adopts an analytical liquid phase to monitor the reaction progress, and separation and purification are carried out by preparing a liquid phase after the reaction is completed.
The specific tumor diagnosis SPECT imaging agent targeting the heat shock protein 90 comprises an HSP90 specific probe and a diagnostic nuclide, wherein the diagnostic nuclide is 99m Tc; the HSP90 specific probe is。
The specific tumor diagnosis PET imaging agent of the targeted heat shock protein 90 comprises an HSP90 specific probe and a diagnostic nuclide, wherein the diagnostic nuclide is 68 Ga; the HSP90 specificThe specific probe is。
The specific tumor therapy SPECT imaging agent targeting the heat shock protein 90 comprises an HSP90 specific probe and a therapeutic nuclide, wherein the diagnostic nuclide is 177 Lu; the HSP90 specific probe is。
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) Compared with the prior art, the HSP90 specific radioactive probe provided by the invention has high target/non-target ratio, can achieve better diagnosis and treatment effects, and is not available in other HSP90 probes at present;
(2) The HSP90 specific radioactive probe verifies the effectiveness in colorectal cancer and lung cancer tumor models, is favorable for the commercialized application and clinical popularization of the probe, and the preparation method of the modified radionuclide probe provided by the invention is simple and easy to implement, low in cost, strong in practicability, good in biological safety and high in application value.
Drawings
FIG. 1 is a mass spectrum of HYNIC-YQHSI-EC;
FIG. 2 is a mass spectrum of DOTA-YQHSI-EC;
FIG. 3 is a schematic view of 99m Synthetic route of Tc-HYNIC-YQHSI-EC (tricine/TPPTS);
FIG. 4 is a diagram of 68 A synthetic route of Ga-DOTA-YQHSI-EC;
FIG. 5 is a schematic view of a display 177 Synthetic route of Lu-DOTA-YQHSI-EC;
FIG. 6 is a diagram of 99m SPECT imaging of Tc-HYNIC-YQHSI-EC (tricine/TPPTS) in colorectal cancer cell HCT116 tumor-bearing mice;
FIG. 7 is a diagram of 99m Tc-HYNIC-YQHSI-EC(ttricine/TPPTS) SPECT imaging after 4H injection in colorectal cancer cells HCT116, lung cancer H460, and HCT116 blocking group (Block) tumor-bearing mice;
FIG. 8 is a diagram of 99m Major organ radioactivity distribution of Tc-HYNIC-YQHSI-EC (tricine/TPPTS) after 4H injection in colorectal cancer cells HCT116, lung cancer H460, and HCT116 blocking group (Block) tumor-bearing mice;
FIG. 9 is a diagram of 99m SPECT imaging of Tc-HYNIC-YQHSI-EC (tricine/TPPTS) after 1.5h of in vivo injection in situ colorectal cancer model mice;
FIG. 10 is a diagram of 68 PET/CT imaging of Ga-DOTA-YQHSI-EC in HCT116 colorectal cancer tumor-bearing mice;
FIG. 11 is a diagram of 177 SPECT imaging of Lu-DOTA-YQHSI-EC in HCT116 colorectal tumor-bearing mice.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings.
EXAMPLE 1 Synthesis of HYNIC-YQHSI-EC
(1) Synthesis of YQHSI-EC
Sources of a as starting material are described in the following documents: j.med.chem.2010,53,5956-5969; eur.j.med.chem. 2023,260,115690. 5mg a and 3mg of maleimide-PEG 2-succinimidyl ester were dissolved in 0.3 mL DMF and 1 μl DIPEA was added to react for 2h at 40 ℃, the progress of the reaction was monitored by analytical liquid phase, and separation and purification were performed by preparative liquid phase after completion of the reaction, conditions for preparative HPLC purification include: mobile phase a was 0.1% tfa-acetonitrile and mobile phase B was 0.1% tfa-water; the elution mode is gradient elution; the conditions of the gradient elution are as follows: 0-25 min, wherein the volume fraction of the mobile phase A is increased from 10% to 90%; the flow rates of the mobile phase A and the mobile phase B are 5mL/min. Compound 1, MS (ESI+)：m/z 706.34 [M+H] + 。
2mg of compound 1 and 5mg of tripeptide CE beta A are dissolved in 0.3 mL of PBS and reacted for 2 hours at 40 ℃, the reaction progress is monitored by an analytical liquid phase, and after the reaction is completed, separation and purification are carried out by preparing a liquid phase to obtain YQHSI-EC, MS (ESI+): m/z 513.28 [ M+2H ]] 2+ /2。
(2) Synthesis of bifunctional chelating agent HYNIC-NHS
Adding 6-chloronicotinic acid and 80% hydrazine hydrate into ethanol, heating and refluxing for reaction, decompressing and steaming the solvent after the reaction is completed, adding the obtained sticky substance into distilled water, adjusting the PH to about 5.5, separating out solid, filtering and drying to obtain yellow solid, and determining the product to be 6-dihydrazide nicotinic acid through ESI-MS mass spectrum and nuclear magnetic hydrogen spectrum. Adding the obtained 6-dihydrazide nicotinic acid and para-aminobenzaldehyde into dimethyl sulfoxide (DMSO), heating for reaction for 5-6 hours, adding into water for precipitation after the reaction is completed, filtering to obtain a solid, drying the solid, adding the solid into DMSO together with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and N-hydroxysuccinimide (NHS) for reaction at room temperature, adding into water for precipitation after the reaction is completed, purifying the solid through a silica gel column, and determining the solid as a target product HYNIC-NHS through ESI-MS mass spectrum and nuclear magnetic hydrogen spectrum, wherein MS (ESI+): 382.1 [ M+H ]] + 。
(3) Synthesis of HYNIC-YQHSI-EC
YQHSI-EC of 1 mg and HYNIC-NHS of 1 mg were dissolved in 0.3 mL DMF and 1. Mu.L of DIPEA was added to react for 2 hours at 40℃and the progress of the reaction was monitored by analytical liquid phase, and after completion of the reaction, separation and purification were carried out by preparing a liquid phase to give HYNIC-YQHSI-EC, MS (ESI+): m/z 647.26[ M+2H ]] 2+ 2 (FIG. 1).
EXAMPLE 2 Synthesis of DOTA-YQHSI-EC
Dissolving YQHSI-EC of 1 mg and DOTA-NHS of 1 mg in 0.3 mL DMF, adding 1 μl of DIPEA, reacting at 40deg.C for 2h, monitoring the reaction progress with analytical liquid phase, and separating and purifying by preparing liquid phase after the reaction is completed to obtain DOTA-YQHSI-EC，MS(ESI+)：m/z 707.35 [M+2H] + 2 (FIG. 2).
Example 3 AOM-DSS induced colorectal cancer in situ mouse model
C57bl/6 mice were purchased from St Bei Fu (Suzhou) Biotechnology Co., ltd, and were intraperitoneally injected with an Azoxymethane (AOM) physiological saline solution (10 mg/kg), and after one week 2.5% dextran sulfate sodium salt (dextran sulfate sodium, DSS) was administered as drinking water for one week, and purified water for two weeks for one cycle. Repeating four cycles, wherein the total modeling time is 13 weeks, the protrusion of the colorectal end of the model mouse can be observed through dissection, and the success of in-situ colorectal cancer modeling can be verified by combining histopathological sections, so that the next experiment can be carried out.
EXAMPLE 4 SPECT imaging of tumor model mice
(1) 99m Preparation of Tc-HYNIC-YQHSI-EC (tricine/TPPTS) complex
A mixture 1 mL containing 20. Mu.g HYNIC-YQHSI-EC, 6.5 mg tricine, 5mg TPPTS, 12.7 mg succinic acid and 38.5 mg disodium succinate was prepared, added to a 10 mL sterile penicillin bottle, and the mixture was lyophilized for use. Marking 99m Tc, 1 mL Na was added to the lyophilized powder 99m TcO4 solution (720 MBq), and heating the penicillin bottle for 20 minutes by a metal bath at the temperature of 100 ℃. Naturally cooling to room temperature after the reaction is finished, and filtering by a sterile filter membrane with the diameter of 0.22 mu m to obtain the radiopharmaceuticals 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS), and the synthetic route is shown in FIG. 3.
(2) 99m SPECT imaging of Tc-HYNIC-YQHSI-EC (tricine/TPPTS) tumor model mice
Tail intravenous injection of animal model 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) (18.5 MBq, 200. Mu.l) in physiological saline. After pre-anesthesia with 2% by volume of isoflurane-oxygen mixture, tumor-bearing mice were placed on a Mediso Micro SPECT-CT scanning bed, and the isoflurane-oxygen mixture with 1.5% by volume was maintained under anesthesia and respiration was detected, and collected for 10min.
Example 5 99m SPECT imaging of Tc-HYNIC-YQHSI-EC colorectal cancer HCT116 tumor-bearing mice
As shown in fig. 6, in colorectal cancer HCT116 tumor-bearing mice, microSPECT static imaging is performed 1h, 2h, 4h and 6h after injection, tumor sites can be clearly displayed at 1h, image contrast is high after probe 4h is injected, radiation signals are mainly in kidneys and bladders, the metabolic pathway of the probe is through renal metabolism, other main organs have fewer radiation signals, and target/non-target ratio is high.
Example 6 99m SPECT imaging of Tc-HYNIC-YQHSI-EC colorectal cancer HCT116 tumor-bearing mice
Cold compound HYNIC-YQHSI-EC was injected via the tail vein at a weight of 10 mg/kg, 500 μCi after 2h 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS), and carrying out microSPECT imaging 4h after injection, and collecting for 10min. As shown in fig. 7, the probes were targeted at both colorectal cancer HCT116 and lung cancer H460 after 4H of probe injection. The uptake of the above-mentioned tracer by colorectal carcinoma tumor HCT116 was not significant in the case of an excess of unlabeled HYNIC-YQHSI-EC blockade, indicating that 99m The binding of Tc-HYNIC-YQHSI-EC (tricine/TPPTS) to HSP90 was blocked by an excess of unlabeled HYNIC-YQHSI-EC, demonstrating 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) has specificity to bind HSP 90.
Example 7 99m SPECT imaging of Tc-HYNIC-YQHSI-EC colorectal cancer in situ model mice
As shown in fig. 9, in the in situ colorectal cancer model mouse, the radiation signals are obviously accumulated in the bladder and colorectal parts after 1.5h of probe injection, the kidneys have fewer radiation signals, and the mouse is dissected in vitro to find that the colorectal parts have obvious canceration bulges and still have the radiation signals.
Example 8 99m Tc-HYNIC-YQHSI-EC radioactive biodistribution
Tumor-bearing mice are injected by tail vein 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) 0.74 MBq, 100. Mu.L physiological saline solution, mice were euthanized at the time point of arrival, the main organs were weighed, the radioactivity technique was determined, the% ID/g calculated, and each set of experiments was repeated 3 times. As shown in figure 8 of the drawings, 99m tumor uptake of HCT116 was 5.77.+ -. 0.85% ID/g, which is 3.20.+ -. 0.97% ID/g higher than H460 tumor uptake, 4H after Tc-HYNIC-YQHSI-EC (tricine/TPPTS) injection, which may beDue to the difference in the expression level of HSP90 on tumors. Other tissue organ uptake was close to background.
Example 9 68 PET imaging of Ga-DOTA-YQHSI-EC tumor model mice
(1) 68 Preparation of Ga-DOTA-YQHSI-EC
First, 0.05 mol/L hydrochloric acid is used for preparing the product 68 Ge/ 68 Eluting from Ga generator 68 GaCl 3 Solution, 500. Mu.L of sodium acetate buffer (ultrapure, pH=4.45) was added to a penicillin bottle, 150. Mu.g DOTA-YQHSI-EC was added 68 GaCl 3 Solution 2 mL (370-450 MBq) the vial was heated for 20 minutes in a metal bath at 100 ℃. Naturally cooling to room temperature after the reaction, pushing the reaction solution into activated and balanced C18 column for purification, and washing the C18 column twice with 5mL deionized water to ensure that the free C18 column is removed 68 Ga; finally, 200 mu L of ethanol (volume fraction 60%) is used for leaching and collecting the solution, and the solution is diluted by proper physiological saline to obtain the radiopharmaceuticals 68 Ga-DOTA-YQHSI-EC, and the synthetic route is shown in figure 4.
(2) 68 Ga-DOTA-YQHSI-EC tumor model mouse PET imaging
PET imaging of small animals is carried out by selecting colorectal cancer HCT116 tumor model mice, and the mice are injected through tail vein 68 Ga-DOTA-YQHSI-EC (3.7 MBq, 200. Mu.L) in physiological saline. After pre-anesthesia with 2% by volume of isoflurane-oxygen mixture, tumor-bearing mice were placed on a PET-CT scanning bed and 1.5% by volume of isoflurane-oxygen mixture was maintained under anesthesia and respiration was detected. And carrying out microPET/CT static imaging 1.5h, 3h and 5h after injection, and collecting for 10min.
As shown in fig. 10 68 The Ga-DOTA-YQHSI-EC1.5h tumor part has a radiation signal, the radiation signal is still stronger in 5h tumor, and other organs have no obvious probe uptake, so that the imaging contrast is better. The radioactive biodistribution result of the tumor-bearing mice after 5h of probe injection shows that the uptake of tumors is 4.40+/-0.39% ID/g, the uptake of kidneys is 3.21+/-0.37% ID/g, and the uptake of other main organs is close to the background value, thus indicating that the safety and targeting of the probe are higher. 68 The main organ emission profile of Ga-DOTA-YQHSI-EC in HCT116 colorectal cancer tumor-bearing mice is shown in Table 1.
Example 10 177 SPECT imaging of Lu-DOTA-YQHSI-EC tumor model mice
(1) 177 Preparation of Lu-DOTA-YQHSI-EC
Into a penicillin bottle was added 500. Mu.L of sodium acetate buffer (ultrapure, pH=4.45), 150. Mu.g DOTA-YQHSI-EC was added 177 LuCl solution 2 mL (370-450 MBq) and the penicillin bottles were heated for 20 minutes in a metal bath at 100deg.C. Naturally cooling to room temperature after the reaction, pushing the reaction solution into activated and balanced C18 column for purification, and washing the C18 column twice with 5mL deionized water to ensure that the free C18 column is removed 177 Lu; finally, 200 mu L of ethanol (volume fraction 60%) is used for leaching and collecting the solution, and the solution is diluted by proper physiological saline to obtain the radiopharmaceuticals 177 The synthesis route of Lu-DOTA-YQHSI-EC is shown in FIG. 5.
(2) 177 SPECT imaging of Lu-DOTA-YQHSI-EC
Colorectal cancer HCT116 is selected for tail vein injection 177 Saline solution of Lu-DOTA-YQHSI-EC (18.5 MBq, 200. Mu.l). After pre-anesthesia with 2% by volume of isoflurane-oxygen mixture, tumor-bearing mice were placed on a Mediso Micro SPECT-CT scanning bed and 1.5% by volume of isoflurane-oxygen mixture was maintained under anesthesia and respiration was detected. And carrying out microSPECT static imaging 8h, 24h, 48h, 72h and 96h after injection, and collecting for 10min.
As shown in the figure 11 of the drawings, 177 the Lu-DOTA-YQHSI-EC probe can target a tumor part, the kidney uptake is close to a background value, after 120 hours, the tumor still has obvious radioactive signals, and the probe is presumed to enter the tumor cells through targeting HSP90 on the surface of tumor cells and in the tumor microenvironment and endocytosis, so that the radioactive signals of the tumor part can be sustained for 96 hours, the damage to the kidney is small, the safety is high, and the potential for further developing the probe into a therapeutic nuclide probe is provided.
TABLE 1 68 Main organ radiation distribution of Ga-DOTA-YQHSI-EC in HCT116 colorectal cancer tumor-bearing mice

Claims (10)

1. A specific tumor diagnosis probe for targeting heat shock protein 90, which is characterized by the following structural formula:
。
2. the specific tumor diagnostic probe targeting heat shock protein 90 according to claim 1, wherein the tumor is colorectal or lung cancer tumor.
3. A method of preparing a heat shock protein 90-targeting specific tumor diagnostic probe according to claim 1 or 2, comprising the steps of:
dissolving YQHSI-EC, HYNIC-NHS or DOTA-NHS in a solvent, adding DIPEA for reaction, and separating and purifying after the reaction is completed to obtain a target compound; the synthetic route of the YQHSI-EC is as follows:
。
4. the method for preparing a specific tumor diagnosis probe targeting heat shock protein 90 according to claim 3, wherein the mass ratio of YQHSI-EC, HYNIC-NHS or DOTA-NHS is 1:1-1:3.
5. The method for preparing a specific tumor diagnosis probe targeting heat shock protein 90 according to claim 3, wherein the reaction temperature is 30-50 ℃ and the reaction time is 0.5-5h.
6. The method for preparing a specific tumor diagnosis probe targeting heat shock protein 90 according to claim 3, wherein the method adopts an analytical liquid phase to monitor the reaction progress, and separation and purification are carried out by preparing a liquid phase after the reaction is completed.
7. The method of claim 3, wherein the solvent is DMF.
8. A specific tumor diagnosis SPECT imaging agent targeting heat shock protein 90 is characterized by comprising an HSP90 specific probe and a diagnostic nuclide, wherein the diagnostic nuclide is 99m Tc; the HSP90 specific probe is。
9. A specific tumor diagnosis PET imaging agent targeting heat shock protein 90 is characterized by comprising an HSP90 specific probe and a diagnostic nuclide, wherein the diagnostic nuclide is 68 Ga; the HSP90 specific probe is。
10. A specific tumor therapy SPECT imaging agent targeting heat shock protein 90, which is characterized by comprising an HSP90 specific probe and a therapeutic radionuclide, wherein the diagnostic radionuclide is 177 Lu; the HSP90 specific probe is。
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