Zwitterionic fluoropolymers, methods of making the same, and applications in fluorine magnetic resonance imaging and radionuclide delivery

Abstract

This invention belongs to the field of biomedical material preparation technology, specifically relating to a zwitterionic fluoropolymer, its preparation method, and its application in fluorine magnetic resonance imaging and radionuclide delivery. This invention provides a zwitterionic fluoropolymer with a high fluorine content (≥15wt%) and consistent chemical shifts of fluorine atoms, enabling highly sensitive fluorine magnetic resonance imaging. This invention modifies the fluorine-containing fragments to enhance hydrophilicity, introducing a hydrophilic zwitterionic structure near the fluorine atoms. This ensures that even at high polymer concentrations, the fluorine atoms maintain good hydrophilicity, avoiding signal degradation caused by fluorine-fluorine hydrophobic interactions. Furthermore, the zwitterionic structure endows the probe with good water solubility and anti-protein adsorption capabilities, enabling effective delivery of chemotherapeutic drugs and radionuclides. Simultaneously, the probe exhibits good biocompatibility, facilitating detection in deep tissues in vivo.

Description

Technical Field

[0001] This invention belongs to the field of biomedical material preparation technology, specifically relating to a zwitterionic fluoropolymer, its preparation method, and its application in fluorine magnetic resonance imaging and radionuclide delivery. Background Technology

[0002] Magnetic resonance imaging (MRI) is a non-ionizing, non-invasive molecular imaging diagnostic technique with high spatial resolution and deep tissue penetration capability. Currently, 1 1H MRI technology has been widely used in clinical medicine for imaging examinations to screen for lesions. However, human tissues contain a large number of water molecules, making... 1 In clinical applications, 1H MRI suffers from significant background interference, and the differences in water content between tissues are not obvious. These differences are even more difficult to distinguish in the early stages of tumors or inflammatory lesions, leading to… 1 MRI is prone to misdiagnosis or missed diagnosis during disease diagnosis, limiting its application in early disease diagnosis. In contrast, only trace amounts of fluorine exist in solid form in bones and teeth, exhibiting a background signal far below the detection limit of MRI. Furthermore, the fluorine atom content shows a linear relationship with MRI signal intensity, which is beneficial for quantification and tracing. This allows for effective tracing and quantification of chemotherapy drugs and radionuclides, providing a non-invasive visualization method for cancer diagnosis and treatment efficacy evaluation. Therefore, 19 fMRI technology has shown great potential for development in the field of magnetic resonance imaging.

[0003] 19 fMRI polymer probes have attracted widespread attention from researchers due to their simple preparation methods, ease of modification, and good biocompatibility. 19 fMRI polymer probes are mainly obtained by copolymerizing hydrophobic fluorinated monomers or fluorinated chain transfer agents with hydrophilic monomers. However, due to the hydrophobic nature of fluorine atoms, these fluorinated polymers are prone to fluorine atom aggregation with increasing fluorine content, leading to a decrease in the activity of fluorine nuclei. 19 The reduced signal-to-noise ratio of F-magnetic resonance imaging limits its practical applications. Summary of the Invention

[0004] The purpose of this invention is to provide a zwitterionic fluoropolymer, its preparation method, and its application in fluorine magnetic resonance imaging and radionuclide delivery. This invention introduces a hydrophilic zwitterionic structure near fluorine atoms, ensuring that the environment in which the fluorine atoms in the fluoropolymer are located maintains good hydrophilicity and is not prone to aggregation. Furthermore, this fluoropolymer possesses the ability to retain in a slightly acidic environment in tumors, allowing for effective accumulation within tumors.

[0005] To achieve the objectives of this invention, the following technical solutions are provided: An amphoteric fluoropolymer, wherein the comonomers of the polymer include fluorinated monomers, methyl ether methacrylate monomers, and acrylic monomers; The polymer has the following chemical structure: .

[0006] This invention also provides a method for preparing the zwitterionic fluoropolymer described above, comprising the following steps: Potassium (halomethyl)trifluoroborate and ethyl 2-(dimethylamino)acrylate were subjected to a substitution reaction to obtain a fluorinated polymer monomer with a zwitterionic structure. The fluoropolymer monomer has the following chemical structure: ; The fluoropolymer monomer, polyethylene glycol methyl ether methacrylate, and acrylic acid are subjected to free radical polymerization under initiator conditions to obtain the zwitterionic fluoropolymer.

[0007] Preferably, the molar ratio of potassium (halomethyl)trifluoroborate and ethyl 2-(dimethylamino)acrylate is 1:1~5; The substitution reaction is carried out at a temperature of 50-80°C for 12-48 hours.

[0008] Preferably, the molar ratio of the fluoropolymer monomer, polyethylene glycol methyl ether methacrylate, and acrylic acid is 5~25:0~5:1; The free radical polymerization reaction is carried out at a temperature of 50~80℃ for 4~48h.

[0009] Preferably, the organic solvent used in the substitution reaction is acetonitrile or methanol; The organic solvent used in the free radical polymerization reaction is dimethyl sulfoxide or N,N-dimethylformamide.

[0010] The present invention also provides the application of the zwitterionic fluoropolymer described in the above technical solution or the zwitterionic fluoropolymer prepared by the preparation method described in the above technical solution in the preparation of fluorine magnetic resonance imaging probes or the preparation of radionuclide delivery drugs.

[0011] This invention provides a zwitterionic fluoropolymer, wherein the comonomers of the polymer include a fluorinated monomer, a methyl ether methacrylate monomer, and an acrylic monomer; the polymer has the chemical structure shown below. The zwitterionic fluoropolymer provided by this invention has a fluorine content ≥15wt%, and the fluorine atoms have consistent chemical shifts, enabling high-sensitivity fluorine magnetic resonance imaging. This invention modifies the fluorinated fragments to enhance hydrophilicity, specifically by introducing hydrophilic zwitterionic structures near the fluorine atoms, ensuring that even at higher polymer concentrations (≤350 mg / mL), the fluorine atoms maintain good hydrophilicity, avoiding the reduction in fluorine magnetic signal caused by fluorine-fluorine hydrophobic interactions. Results from the embodiments of this invention show that as the concentration of the zwitterionic fluoropolymer increases, 19 The fMRI signal showed linear enhancement, overcoming the problem of weak imaging signal commonly faced by fluoropolymer nanoprobes due to the increased concentration of fluorine atoms and the limited activity of fluorine-fluorine hydrophobic interactions.

[0012] Furthermore, the zwitterionic fluoropolymer provided by this invention possesses excellent hydrophilicity and biocompatibility, as well as good resistance to protein adsorption, which is beneficial for in vivo applications. Moreover, the polymer contains carboxyl functional groups, making it easy to couple and modify other molecules (such as small molecule drugs, probes, etc.), effectively loading chemotherapeutic drugs and radionuclides, increasing drug accumulation at tumor sites to enhance tumor treatment efficacy, while simultaneously reducing drug accumulation in normal tissues and organs, thus reducing toxic side effects. Attached Figure Description

[0013] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0014] Figure 1 The zwitterionic fluoropolymer obtained in Example 1 at different concentrations 19 F NMR signal; Figure 2 The zwitterionic fluoropolymer probe obtained in Example 1 at different concentrations 19 Linear relationship between F NMR signal and probe concentration; Figure 3 The results show the cytotoxicity of the zwitterionic fluoropolymer obtained in Example 1 on the 4T1 cell line. Figure 4 The results of hemolysis tests on the zwitterionic fluoropolymer obtained in Example 1 at different concentrations are shown. Figure 5The zwitterionic fluoropolymer obtained in Example 1 at different concentrations 1 H MRI and 19 f MRI imaging; Figure 6 The zwitterionic fluoropolymer obtained in Example 1 at different concentrations 19 The linear relationship between fMRI signal-to-noise ratio and probe concentration; Figure 7 The results are MRI imaging results of intratumoral injection of the zwitterionic fluoropolymer obtained in Example 1 into tumor-bearing mice and MRI imaging results of tail vein injection into subcutaneous tumor and lung metastasis model mice. Figure 8 SPECT / CT imaging results in tumor-bearing mice of the zwitterionic fluoropolymer loaded with a radionuclide prepared in Example 1. Figure 9 The inhibition curve of the zwitterionic fluoropolymer loaded with radionuclides prepared in Example 1 on tumor-bearing mice is shown. Detailed Implementation

[0015] The present invention provides an amphoteric fluoropolymer, wherein the comonomer of the polymer includes a fluorinated monomer, a methyl ether methacrylate monomer, and an acrylic monomer; The polymer has the following chemical structure: .

[0016] In this invention, the zwitterionic fluoropolymer contains ≥15wt% fluorine, specifically 15-25wt%, and in specific embodiments 16 or 20wt%; the weight-average molecular weight of the zwitterionic fluoropolymer is 5000-50000. The zwitterionic fluoropolymer provided by this invention has a fluorine content ≥15wt%, high magnetic equivalence fluorine content, and fluorine atoms exhibit consistent chemical shifts, enabling high-sensitivity fluorine magnetic resonance imaging. The zwitterionic structure in this invention contains N... + The center also contains negatively charged BF3. - The central point is that the methyl ether methacrylate monomer and the acrylic monomer in this invention can improve the hydrophilicity of the polymer; at the same time, the acrylic monomer can also introduce carboxyl groups into the zwitterionic fluorinated polymer, which facilitates subsequent coupling modification of various small molecules (such as ligand molecules that chelate radionuclides, peptides, fluorescent molecules, etc.).

[0017] This invention also provides a method for preparing the zwitterionic fluoropolymer described above, comprising the following steps: Potassium (halomethyl)trifluoroborate and ethyl 2-(dimethylamino)acrylate were subjected to a substitution reaction to obtain a fluoropolymer monomer with an amphoteric structure, the fluoropolymer monomer having the chemical structure shown below: ; The fluoropolymer monomer, polyethylene glycol methyl ether methacrylate, and acrylic acid are subjected to free radical polymerization under initiator conditions to obtain the zwitterionic fluoropolymer.

[0018] In this invention, unless otherwise specified, all raw materials used in the preparation are commercially available products well known to those skilled in the art or prepared using conventional methods in the art.

[0019] In this invention, the potassium (halomethyl)trifluoroborate can be potassium (chloromethyl)trifluoroborate, potassium (bromomethyl)trifluoroborate, or potassium (iodomethyl)trifluoroborate; the molar ratio of potassium (halomethyl)trifluoroborate to ethyl 2-(dimethylamino)acrylate is 1:1 to 5, and in specific embodiments it can be 1:2, 1:3, or 1:4.

[0020] In this invention, the temperature of the substitution reaction is 50-80°C, and in specific embodiments it can be 50, 60, 65, 70, 75 or 80°C; the time is 12-48 h, and in specific embodiments it can be 16, 24 or 36 h; the solvent used in the substitution reaction is acetonitrile or methanol; the substitution reaction is carried out under a protective atmosphere, which can be nitrogen. In the substitution reaction process of this invention, the haloalkyl group in potassium (halomethyl)trifluoroborate substitutes the dimethylamino group in ethyl 2-(dimethylamino)acrylate to obtain a fluoropolymer monomer.

[0021] In one embodiment of the present invention, the system obtained by the substitution reaction is further subjected to concentration, precipitation, solid-liquid separation, washing and drying in sequence; the precipitant used for precipitation is tert-butyl methyl ether and ethanol, and the volume ratio of tert-butyl methyl ether to ethanol is 5~10:1; the present invention does not have any special limitations on concentration, solid-liquid separation, washing and drying, and conventional methods in the art can be used.

[0022] In this invention, the molar ratio of the fluorinated polymer monomer, polyethylene glycol methyl ether methacrylate, and acrylic acid is 5~25:0~5:1, and in specific embodiments it can be 10:1:1, 15:4:1, or 18:2:1; the initiator is an azo radical initiator, and in specific embodiments it can be azobisisobutyronitrile, and the amount of the initiator is 0.5~10% of the total molar number of the fluorinated polymer monomer, polyethylene glycol methyl ether methacrylate, and acrylic acid; the solvent used in the free radical polymerization reaction is dimethyl sulfoxide or N,N-dimethylformamide.

[0023] In this invention, the temperature of the free radical polymerization reaction is 50~80℃, and in specific embodiments it can be 60, 65 or 70℃, and the time is 4~48h, and in specific embodiments it can be 4 or 8h.

[0024] In this invention, the system obtained by the free radical polymerization reaction is further subjected to concentration, precipitation, solid-liquid separation and drying in sequence; the concentration, precipitation, solid-liquid separation and drying are the same as those described above, and will not be repeated here.

[0025] The present invention also provides the application of the zwitterionic fluoropolymer described in the above technical solution or the zwitterionic fluoropolymer prepared by the preparation method described in the above technical solution in the preparation of fluorine magnetic resonance imaging probes or the preparation of radionuclide delivery drugs.

[0026] In this invention, the fluorine magnetic resonance imaging probe can be... 19 F magnetic resonance imaging probe, wherein the zwitterionic fluoropolymer is used as a contrast agent.

[0027] In this invention, the radionuclide delivery drug is a radionuclide delivery carrier; the radionuclide factor in the radionuclide delivery carrier can be... 68 Ga、 86 Y、 177 Lu and 225 One or more of Ac.

[0028] To further illustrate the present invention, the zwitterionic fluoropolymers provided by the present invention, their preparation methods, and their applications in fluorine magnetic resonance imaging and radionuclide delivery are described in detail below with reference to the accompanying drawings and embodiments. However, these descriptions should not be construed as limiting the scope of protection of the present invention.

[0029] Example 1 0.2 g of potassium (bromomethyl)trifluoroborate and 0.29 g of ethyl 2-(dimethylamino)acrylate were dissolved in 10 mL of acetonitrile and mixed thoroughly. The mixture was subjected to a substitution reaction at 70 °C for 24 h under a nitrogen atmosphere. The resulting solution was concentrated and precipitated using a 10 mL mixture of tert-butyl methyl ether and ethanol (v:v = 5:1). The supernatant was discarded by centrifugation, and the precipitate was washed three times with tert-butyl methyl ether and dried to obtain 0.16 g of fluoropolymer monomer.

[0030] The characterization of the obtained fluoropolymer monomers is as follows: 1 H NMR (400 MHz, DMSO- d 6 ): δ 6.37 (dd, J = 17.2, 1.5 Hz, 1H, vinyl),6.20 (dd, J = 17.3, 10.4 Hz, 1H, vinyl), 6.00 (dd, J= 10.4, 1.5 Hz, 1H, vinyl),4.55 – 4.48 (m, 2H, OCH2CH2), 3.63 – 3.56 (m, 2H, OCH2CH2), 3.03 (s, 6H, N(CH3)2), 2.38 (q, J = 4.7 Hz, 2H, NCH2BF3) ppm. 19 F NMR (377 MHz, DMSO- d 6 ) δ -133.32 – -138.17 (m) ppm.

[0031] Weigh 1.7 g of the above-mentioned fluoropolymer monomer, 0.95 g of polyethylene glycol methyl ether methacrylate (ALADDIN, polyethylene glycol methyl ether methacrylate-P109711, average molecular weight 475), and 36 mg of acrylic acid and dissolve them in 20 mL of N,N-dimethylformamide. Add 164 mg of azobisisobutyronitrile and mix thoroughly. Polymerize under nitrogen atmosphere at 60 °C for 4 h. Concentrate the resulting reaction solution and precipitate it using 10 mL of a tert-butyl methyl ether / ethanol mixture (v:v=5:1). Centrifuge and discard the supernatant. After drying, obtain 2.1 g of zwitterionic fluoropolymer. Disperse the obtained zwitterionic fluoropolymer in deionized water to obtain a hydrophilic zwitterionic polymer. 19 f MRI polymer probe.

[0032] Example 2 0.2 g of potassium (bromomethyl)trifluoroborate and 0.15 g of ethyl 2-(dimethylamino)acrylate were dissolved in 10 mL of acetonitrile and mixed thoroughly. The mixture was then subjected to quaternization reaction at 70 °C for 48 h under a nitrogen atmosphere. The resulting solution was concentrated and precipitated using a tert-butyl methyl ether / ethanol mixture (v:v = 5:1). The supernatant was discarded by centrifugation, and the precipitate was washed three times with tert-butyl methyl ether and dried to obtain 0.1 g of fluoropolymer monomer. Weigh 1.7 g of the above-mentioned fluoropolymer monomer, 0.95 g of polyethylene glycol methyl ether methacrylate, and 36 mg of acrylic acid and dissolve them in 20 mL of N,N-dimethylformamide. Add 164 mg of azobisisobutyronitrile and mix thoroughly. Polymerize under nitrogen atmosphere and at 60 °C for 4 h. The resulting reaction solution is precipitated using a tert-butyl methyl ether / ethanol mixed solution (v:v=5:1). Centrifuge and discard the supernatant. After drying, 2.1 g of zwitterionic fluoropolymer is obtained. Disperse the obtained zwitterionic fluoropolymer in deionized water to obtain a hydrophilic zwitterionic polymer. 19 f MRI polymer probe.

[0033] Example 3 0.2 g of potassium (bromomethyl)trifluoroborate and 0.58 g of ethyl 2-(dimethylamino)acrylate were dissolved in 10 mL of acetonitrile and mixed thoroughly. The mixture was then subjected to quaternization reaction at 70 °C for 48 h under a nitrogen atmosphere. The resulting solution was concentrated and precipitated using a tert-butyl methyl ether / ethanol mixture (v:v = 5:1). The supernatant was discarded by centrifugation, and the precipitate was washed three times with tert-butyl methyl ether and dried to obtain 0.19 g of fluoropolymer monomer. Weigh 2.03 g of the above-mentioned fluoropolymer monomer, 0.48 g of polyethylene glycol methyl ether methacrylate, and 36 mg of acrylic acid and dissolve them in 20 mL of N,N-dimethylformamide. Add 164 mg of azobisisobutyronitrile and mix thoroughly. Polymerize under nitrogen atmosphere and at 60 °C for 12 h. The resulting reaction solution is precipitated using a tert-butyl methyl ether / ethanol mixed solution (v:v=10:1). Centrifuge and discard the supernatant. After drying, 1.9 g of zwitterionic fluoropolymer is obtained. Disperse the obtained zwitterionic fluoropolymer in deionized water to obtain a hydrophilic zwitterionic polymer. 19 f MRI polymer probe.

[0034] Example 4 0.2 g of potassium (bromomethyl)trifluoroborate and 0.58 g of ethyl 2-(dimethylamino)acrylate were dissolved in 10 mL of acetonitrile and mixed thoroughly. The mixture was then subjected to quaternization reaction at 70 °C for 48 h under a nitrogen atmosphere. The resulting solution was concentrated and precipitated using a tert-butyl methyl ether / ethanol mixture (v:v = 5:1). The supernatant was discarded by centrifugation, and the precipitate was washed three times with tert-butyl methyl ether and dried to obtain 0.2 g of fluoropolymer monomer. Weigh 1.7 g of the above-mentioned fluoropolymer monomer, 0.95 g of polyethylene glycol methyl ether methacrylate, and 36 mg of acrylic acid and dissolve them in 20 mL of N,N-dimethylformamide. Add 164 mg of azobisisobutyronitrile and mix thoroughly. Polymerize under nitrogen atmosphere and at 60 °C for 12 h. The resulting reaction solution is precipitated using a tert-butyl methyl ether / ethanol mixture (v:v = 10:1). Centrifuge and discard the supernatant. After drying, 2.1 g of zwitterionic fluoropolymer is obtained. Disperse the obtained zwitterionic fluoropolymer in deionized water to obtain a hydrophilic zwitterionic polymer. 19 f MRI polymer probe.

[0035] Application examples Method for labeling radionuclides with zwitterionic fluoropolymers: The zwitterionic fluoropolymers obtained in Example 4 are used to label radionuclides. 177 Lu or 225Ac, the specific method is described in the experimental procedures in the reference (ACS Appl. Mater. Interfaces 2022, 14, 3, 3875-3884). Specifically, 26 mg of the obtained zwitterionic fluoropolymer and 177 LuCl3 (10 mCi) was dissolved in sodium acetate buffer solution (pH = 4.8) and labeled at 90 °C for 30 min.

[0036] Test case (1) 19 F NMR signal test The hydrophilic substance containing zwitterions obtained in Example 1 19 f MRI polymer probe solution was used for 19 F-NMR spectroscopy was performed using a single-pulse sequence (Bruker "zg"). A D2O capillary was added inside the sample NMR tube for field locking. The scan count was set to 128, and the test temperature was 298 K. Polymer probes at different concentrations were also tested. 19 F NMR signal test results are as follows Figure 1 and Figure 2 As shown. By Figure 1 and Figure 2 The results show that the polymer probe prepared in this invention has a single chemical shift and good... 19 FNMR signal, has 19 fMRI test performance, and polymer's 19 The F NMR signal exhibits a good linear correlation with the polymer probe concentration, overcoming the problem of weak imaging signals caused by the increased concentration and limited mobility of fluorine atoms, which is a common issue with existing fluorinated polymer nanoprobes.

[0037] (2) Relaxation time test 19 F NMR spin-lattice relaxation time ( T 1 The test used an inversion-recovery (t1ir) pulse sequence, and the specific test parameters were: relaxation delay (D1=10 s); number of empty scans (DS=4); number of scans (NS=4). 19 F NMR spin-spin relaxation time ( T 2 The test used the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence, with the following parameters: relaxation delay (D1=10 s); number of empty scans (DS=4); number of scans (NS=4). D20 was 2.0 ms; P2 was 0.0352 ms.

[0038] Polymer probes at different pH valuesT 1 , T 2 The relaxation times are shown in Table 1. Table 1 shows that the zwitterionic polymer probe prepared in this invention exhibits the following relaxation times at pH 5.5: T 1 , T 2 The value was slightly lower than the physiological condition pH (7.4), but the polymer probe's... 19 The F NMR signal remained almost unchanged, indicating that the imaging performance of the polymer probe was not affected by the tumor's slightly acidic environment.

[0039] Table 1. Polymer probes obtained in Example 1 at different pH values. T 1 , T 2 Relaxation time

[0040] (3) Anti-protein adsorption test A polymer probe solution containing 10 mg / mL of 10% fetal bovine serum (FBS) was incubated at 37 °C for 1 h. PBS was added as a control group. The protein filtrate was separated by centrifugation using an ultrafiltration tube with a molecular weight of 30000, and the protein adsorption rate was tested. The results showed that the polymer probe prepared in this invention had an anti-protein adsorption rate as high as 91.9%, indicating that the obtained polymer probe has excellent anti-protein adsorption ability.

[0041] (4) Cytotoxicity test The cytotoxicity results of the polymer probe in the 4T1 cell line are as follows: Figure 3 As shown. By Figure 3 The results show that when the polymer probe prepared in this invention has a concentration of 5 mg / mL, the cell viability remains above 85% after incubation with cells for 48 hours, indicating that it has excellent biocompatibility.

[0042] (5) Hemolysis test Polymer probes of different concentrations were incubated with erythrocyte suspension at 37 °C for 2 h, and the supernatant was obtained by centrifugation. The hemolysis rate was then tested, and the results are as follows: Figure 4 As shown. By Figure 4 The results showed that the positive control ultrapure water group had hemolytic activity, while the negative control PBS group had no hemolytic activity. The supernatant of the polymer probe group (0.2~10 mg / mL) obtained in this invention was almost colorless. When the polymer probe concentration was 10 mg / mL, the hemolysis rate was only 4%, indicating that it had good blood compatibility.

[0043] (6) 1 H MRI and 19f MRI imaging test In in vitro MRI imaging tests, 19 The f MRI used the UTE sequence with the following parameters set as follows: matrix size of 100×100, TR and TE of 100 ms and 0.276 ms, respectively, flip angle of 39°, field of view of 40 mm×40 mm, and total experimental time of 3 min 8 s. 1 H MRI uses T 2 -TurboRARE sequence, with the following parameters set: matrix size 256×256, TR and TE 4529 ms and 40 ms respectively, field of view set to 40 mm×40 mm, and total experimental time 57 s 120 ms.

[0044] In in vivo MRI imaging tests, 19 The f MRI used the UTE sequence with the following parameters set: matrix size of 100×100, TR and TE of 100 ms and 0.276 ms respectively, flip angle of 39°, field of view of 40 mm×40 mm, and total experimental time of 10 min 28 s. 1 H MRI uses T 2 -TurboRARE sequence, with the following parameters set: matrix size 256×256, TR and TE 4529 ms and 40 ms respectively, field of view set to 40 mm×40 mm, and total experimental time 3 min 46 s 451 ms.

[0045] polymer probes at different concentrations 1 H MRI and 19 fMRI images and 19 The linear relationship between fMRI signal-to-noise ratio and probe concentration is as follows: Figure 5 and Figure 6 As shown. By Figure 5 and Figure 6 The results show that as the concentration of the polymer probe increases, 19 The higher the signal intensity in fMRI, the better. Simultaneously, the polymer probe concentration and... 19 The fMRI signal intensity also showed a good linear relationship (y=0.116C+0.336, R). 2 =0.998) This indicates that the polymer probe has good performance. 19 The effect of fMRI imaging.

[0046] Figure 7The images show the intratumoral MRI imaging results of the zwitterionic fluoropolymer obtained in Example 1, and the tail vein MRI imaging results of subcutaneous tumor and lung metastasis model mice. The intratumoral MRI imaging results of the tumor-bearing mice are as follows: Figure 7 As shown in a, Figure 7 The left side of image a is a mouse. 1 The MRI layer clearly shows the anatomical structure of the mouse, with the mouse in the center. 19 The fMRI layer shows a clear difference between the tumor tissue and normal tissue; the right side is... 1 H MRI and 19 The superposition of two fMRI layers indicates that the zwitterionic magnetic resonance polymer probe prepared in this invention exhibits good performance. 19 fMRI features allow for in vivo imaging of deep tissues.

[0047] MRI imaging was used to diagnose subcutaneous tumor and lung metastasis models in mice, and the results were as follows: Figure 7 b and Figure 7 As shown in c, fluoropolymers can accumulate at the tumor site via tail vein injection, exhibiting a significant difference from normal tissue. 19 The difference in fMRI signals indicates that the zwitterionic magnetic resonance polymer probe prepared in this invention has a good tumor retention and enrichment effect, and can be effectively used for tumor diagnosis.

[0048] (7) Test of antitumor activity of radionuclides loaded on zwitterionic fluoropolymer carriers Tumor volume reached 70 mm 3 BALB / c tumor-bearing mice were randomly divided into three groups (n=4 per group): PBS group, Free ... 177 Lu group and PTFBPA-RGD- 177 Group Lu received intravenous administration every three days (Day 0 and Day 3), at the following dosage: 177 Lu equivalent 0.3 mCi. Free 24 h after the first dose 177 Lu group and PTFBPA-RGD- 177 The Lu group underwent SPECT / CT imaging to observe the distribution of radionuclides in mice. Tumor volume changes in mice were observed for 14 days.

[0049] The results are as follows Figure 8 and Figure 9 As shown, by Figure 8 and Figure 9 The results showed that PTFBPA-RGD- 24 hours after intravenous injection 177 The SPECT signal at the tumor site in the Lu group was significantly higher than that in the Free group. 177The Lu group showed no significant distribution in normal tissues and organs, while the Free group... 177 The Lu group showed significant enrichment in the liver region. In the anti-tumor growth assay, PTFBPA-RGD- 177 Compared to the PBS group, Lu significantly inhibited tumor growth, while compared to Free... 177 Lu group, PTFBPA-RGD- 177 The Lu group showed better tumor growth inhibition.

[0050] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A zwitterionic fluoropolymer, characterized in that, The comonomers of the polymer include fluorinated monomers, methyl ether methacrylate monomers, and acrylic monomers; The polymer has the following chemical structure: 。 2. The method for preparing the zwitterionic fluoropolymer according to claim 1, characterized in that, Includes the following steps: Potassium (halomethyl)trifluoroborate and ethyl 2-(dimethylamino)acrylate were subjected to a substitution reaction to obtain a fluorinated polymer monomer with a zwitterionic structure. The fluoropolymer monomer has the following chemical structure: ； The fluoropolymer monomer, polyethylene glycol methyl ether methacrylate, and acrylic acid are subjected to free radical polymerization under initiator conditions to obtain the zwitterionic fluoropolymer.

3. The preparation method according to claim 2, characterized in that, The molar ratio of potassium trifluoroborate (halomethyl) to ethyl 2-(dimethylamino)acrylate is 1:1~5; The substitution reaction is carried out at a temperature of 50-80°C for 12-48 hours.

4. The preparation method according to claim 2, characterized in that, The molar ratio of the fluoropolymer monomer, polyethylene glycol methyl ether methacrylate, and acrylic acid is 5~25:0~5:1; The free radical polymerization reaction is carried out at a temperature of 50~80℃ for 4~48h.

5. The preparation method according to any one of claims 2 to 4, characterized in that, The organic solvent used in the substitution reaction is acetonitrile or methanol; The organic solvent used in the free radical polymerization reaction is dimethyl sulfoxide or N,N-dimethylformamide.

6. The use of the zwitterionic fluoropolymer of claim 1 or the zwitterionic fluoropolymer prepared by any one of claims 2 to 5 in the preparation of fluorine magnetic resonance imaging probes or radionuclide delivery drugs.

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