CN117624278B - 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 PDFInfo
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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; the SPECT imaging or PET imaging can be realized for tumor diagnosis by labeling the diagnostic nuclide 99m Tc or 68 Ga in the compound, and the tumor expressed by HSP90 can be treated by labeling the therapeutic nuclide 177 Lu, so that the compound has good clinical application prospect.
Description
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, is mainly 18 F-FDG applied to PET imaging at present, can simulate the metabolic pathway of glucose in vivo, is taken up by cells with high energy requirements, particularly tumor cells and stays in the cells, and is widely applied to aspects such as diagnosis, treatment and monitoring 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-Octreotide and its analogues 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 in vivo, such as the research of related mechanisms of HSP90 in cancer and senile dementia in the prior art, 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:
YQHSI-EC, HYNIC-NHS or DOTA-NHS are dissolved in a solvent, DIPEA is added for reaction, and separation and purification are carried out after the reaction is finished, so that a target compound is obtained; the synthetic route for YQHSI-EC is shown below:
。
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 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 synthetic route for 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS);
FIG. 4 is a synthetic route for 68 Ga-DOTA-YQHSI-EC;
FIG. 5 is a synthetic route for 177 Lu-DOTA-YQHSI-EC;
FIG. 6 is a SPECT imaging of 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) in colorectal cancer cell HCT116 tumor-bearing mice;
FIG. 7 is SPECT imaging of 99m 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. 8 shows the main organ radioactivity distribution of 99m 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 SPECT imaging of 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) after 1.5h of in situ colorectal cancer model mice;
FIG. 10 is a PET/CT image of 68 Ga-DOTA-YQHSI-EC in HCT116 colorectal cancer tumor-bearing mice;
FIG. 11 is a SPECT image of 177 Lu-DOTA-YQHSI-EC in HCT116 colorectal cancer tumor-bearing mice.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings.
Example 1 HYNIC-YQHSI Synthesis of EC
(1) YQHSI Synthesis of 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. A and 3mg of maleimide-PEG 2-succinimidyl ester of 5 mg were dissolved in 0.3 mL DMF and 1 μl of DIPEA was added to react for 2h at 40 ℃, the progress of the reaction was monitored by analytical liquid phase, and after completion of the reaction separation and purification by preparative liquid phase, conditions for preparative HPLC purification included: 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, 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 ] +.
Compound 2mg of compound 1 and 5mg of tripeptide CE βa were dissolved in 0.3 mL PBS and reacted at 40 ℃ for 2h, the progress of the reaction was monitored by analytical liquid phase, and after completion of the reaction, separation and purification were performed by preparative liquid phase to give 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 1mg and HYNIC-NHS of 1mg were dissolved in 0.3 mL DMF, 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 DOTA-YQHSI Synthesis of EC
YQHSI-EC of 1 mg and DOTA-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 performed by preparing a liquid phase to give 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 given a 2.5% dextran sulfate sodium salt (dextran sulfate sodium, DSS) drinking water one week and two weeks of pure water as a cycle after one week by intraperitoneal injection of a physiological saline solution (10 mg/kg) of azoxymethane (azoxymethane, AOM). 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) Preparation of 99m 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. When 99m Tc is marked, 1 mL Na 99m TcO4 solution (720 to MBq) is added into the freeze-dried powder, and a metal bath at 100 ℃ heats the penicillin bottle for 20 minutes. Naturally cooling to room temperature after the reaction is finished, and filtering by a 0.22 mu m sterile filter membrane to obtain the radioactive drug 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS), wherein the synthetic route is shown in figure 3.
(2) SPECT imaging of 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) tumor model mice
The animal model was injected with 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) (18.5 MBq, 200 μl) in physiological saline solution via the tail vein. After pre-anesthesia with 2% by volume of isoflurane-oxygen mixture, tumor-bearing mice were placed on Mediso Micro SPECT-CT scan bed, and 1.5% by volume of isoflurane-oxygen mixture was maintained for anesthesia and respiration was detected, and collected for 10min.
EXAMPLE 5 99m Tc-HYNIC-YQHSI-EC colorectal cancer SPECT imaging of 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, the contrast of images 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, the radiation signals of other main organs are less, and the target/non-target ratio is high.
EXAMPLE 6 SPECT imaging of 99m Tc-HYNIC-YQHSI-EC colorectal cancer HCT116 tumor-bearing mice
Cold compound HYNIC-YQHSI-EC was injected by tail vein at a weight of 10 mg/kg, 500 μCi of 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) was injected 2h later, and microSPECT imaging was performed 4h after injection and collected 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. Under the blocking of excessive unlabeled HYNIC-YQHSI-EC, colorectal cancer tumor HCT116 has insignificant uptake of the tracer, which indicates that the binding of 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) to HSP90 can be blocked by excessive unlabeled HYNIC-YQHSI-EC, and the binding of 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) to HSP90 is proved to have specificity.
EXAMPLE 7 SPECT imaging of 99m 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 were euthanized by tail vein injection 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) 0.74 MBq, 100. Mu.L of physiological saline solution, time points reached, the main organs were weighed, the radioactivity technique was measured, the% ID/g calculated, and each set of experiments was repeated 3 times. As shown in FIG. 8, the tumor uptake value of HCT116 was 5.77.+ -. 0.85% ID/g and 3.20.+ -. 0.97% ID/g higher than that of H460, 4 hours after 99m Tc-HYNIC-YQHSI-EC (tricine/TPPTS) injection, probably due to the difference in the expression level of HSP90 on tumors. Other tissue organ uptake was close to background.
Example 9 PET imaging of 68 Ga-DOTA-YQHSI-EC tumor model mice
(1) Preparation of 68 Ga-DOTA-YQHSI-EC
First, a solution 68GaCl3 was eluted from a 68Ge/68 Ga generator with 0.05 mol/L hydrochloric acid, 500. Mu.L sodium acetate buffer (ultrapure, pH=4.45) was added to a penicillin bottle, 150. Mu.g DOTA-YQHSI-EC was added, 68GaCl3 solution 2mL (370-450 MBq) was added, and the penicillin bottle was heated in a metal bath at 100℃for 20 minutes. After the reaction is finished, naturally cooling to room temperature, pushing the reaction liquid into an activated and balanced C18 small column for purification, and firstly flushing the C18 small column twice with 5mL deionized water to a waste liquid bottle so as to ensure that free 68 Ga is removed; 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 radioactive drug 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
Mice were PET-visualized using colorectal carcinoma HCT116 tumor model mice, and injected via the tail vein with a physiological saline solution of 68 Ga-DOTA-YQHSI-EC (3.7 MBq, 200. Mu.L). 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 Ga-DOTA-YQHSI-EC1.5h tumor sites have radiation signals, the radiation signals are still strong in 5h tumor sites, other organs have no obvious probe uptake, and better imaging contrast is achieved. 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 SPECT imaging of 177 Lu-DOTA-YQHSI-EC tumor model mice
(1) Preparation of 177 Lu-DOTA-YQHSI-EC
Into a penicillin bottle was added 500. Mu.L of sodium acetate buffer solution (super pure, pH=4.45), 150. Mu.g DOTA-YQHSI-EC was added, 177 LuCl solution 2mL (370-450 MBq) was added, and the penicillin bottle was heated in a metal bath at 100℃for 20 minutes. After the reaction is finished, naturally cooling to room temperature, pushing the reaction solution into an activated and balanced C18 small column for purification, and firstly flushing the C18 small column twice with 5 mL deionized water into a waste liquid bottle to ensure that free 177 Lu is removed; 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 radioactive drug 177 Lu-DOTA-YQHSI-EC, and the synthetic route is shown in figure 5.
(2) SPECT imaging of 177 Lu-DOTA-YQHSI-EC
Colorectal cancer HCT116 was selected by tail vein injection of 177 Lu-DOTA-YQHSI-EC (18.5 MBq, 200 μl) in physiological saline. After pre-anesthesia with 2% by volume of isoflurane-oxygen mixture, tumor-bearing mice were placed on Mediso Micro SPECT-CT scan bed and 1.5% by volume of isoflurane-oxygen mixture was maintained under anesthesia and respiration was detected. Carrying out microSPECT static imaging for 8h, 24h, 48h, 72h and 96h after injection, and collecting for 10min.
As shown in FIG. 11, 177 Lu-DOTA-YQHSI-EC probe can target tumor site, and the uptake of kidney is close to background value, after 120 hours, tumor still has obvious radioactive signal, and it is presumed that the probe enters tumor cell through targeting HSP90 on tumor cell surface and in tumor microenvironment and endocytosis, so that radioactive signal of tumor site can last to 96 hours, and the damage to kidney is small and safety is high, and the probe has potential for further developing as therapeutic nuclide probe.
TABLE 1 68 Ga-DOTA-YQHSI-EC Main organ radiation distribution in HCT116 colorectal cancer tumor-bearing mice
Claims (9)
1. A specific tumor diagnosis probe for targeting heat shock protein 90, which is characterized by the following structural formula:
The tumor is colorectal cancer or lung cancer.
2. A method of preparing a heat shock protein 90-targeting specific tumor diagnostic probe according to claim 1, comprising the steps of:
YQHSI-EC and HYNIC-NHS or DOTA-NHS are dissolved in a solvent, DIPEA is added for reaction, and separation and purification are carried out after the reaction is finished, so that a target compound is obtained; the synthetic route for YQHSI-EC is shown below:
。
3. The method for preparing a specific tumor diagnosis probe targeting heat shock protein 90 according to claim 2, wherein the mass ratio of YQHSI-EC to HYNIC-NHS or DOTA-NHS is 1:1-1:3.
4. The method for preparing a specific tumor diagnosis probe targeting heat shock protein 90 according to claim 2, wherein the reaction temperature is 30-50 ℃ and the reaction time is 0.5-5h.
5. The method for preparing a specific tumor diagnosis probe targeting heat shock protein 90 according to claim 2, wherein the method adopts an analytical liquid phase to monitor the reaction progress, and separation and purification are performed by preparing a liquid phase after the reaction is completed.
6. The method of claim 2, wherein the solvent is DMF.
7. A specific tumor diagnosis SPECT imaging agent targeting heat shock protein 90, comprising HSP90 specific probes and a diagnostic radionuclide, the diagnostic radionuclide being 99m Tc; the HSP90 specific probe is。
8. A specific tumor diagnosis PET imaging agent targeting heat shock protein 90, which is characterized by comprising an HSP90 specific probe and a diagnostic nuclide, wherein the diagnostic nuclide is 68 Ga; the HSP90 specific probe is。
9. A specific tumor therapeutic SPECT imaging agent targeting heat shock protein 90, comprising an HSP90 specific probe and a therapeutic radionuclide, the therapeutic radionuclide being 177 Lu; the HSP90 specific probe is。
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