Use of monophosphate deoxyribose fluorouracil nucleoside prodrug in preparation of drug for preventing and / or treating tumors

Abstract

Provided is use of a monophosphate deoxyribose fluorouracil nucleoside prodrug in the preparation of a drug for preventing and / or treating tumors. The monophosphate deoxyribose fluorouracil nucleoside prodrug is a derivative formed by substituting at least one thymine in nucleolin aptamer AS1411 with fluorouracil. The tumors include at least one of lung cancer, breast cancer, prostate cancer, pancreatic cancer, kidney cancer, cervical cancer, leukemia and lymphoma, melanoma, glioblastoma, neuroblastoma, sarcoma, and gastric cancer. The monophosphate deoxyribose fluorouracil nucleoside prodrug binds to the nucleolin protein and selectively enters tumor cells under the action of the nucleolin protein, and release an antimetabolite to inhibit thymine nucleotide synthase, thereby achieving an anti-tumor effect.

Description

Application of deoxyribose fluorouridine monophosphate prodrug in the preparation of drugs for preventing and / or treating tumors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Chinese patent application No. 202410293954.X filed on March 14, 2024, the contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the field of biomedicine technology, and in particular to the use of a deoxyribose fluorouridine monophosphate prodrug in the preparation of a drug for preventing and / or treating tumors. Background Art

[0004] Chemotherapy is a common treatment for malignant tumors. Fluorouracil (FU) is a broad-spectrum antimetabolite chemotherapy drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of various types of cancer, including adenocarcinoma, head and neck squamous cell carcinoma, cervical squamous cell carcinoma, and gastrointestinal squamous cell carcinoma. Its mechanism of action is that FU is bioconverted into deoxyribose fluorouracil monophosphate (FdUMP) in the body through ribosylation and phosphorylation. It then covalently binds to the active site of thymidylate synthase, inhibiting the enzyme's activity, resulting in a deoxynucleotide deficiency and hindering DNA synthesis. However, there are two major problems with the clinical application of fluorouracil: first, fluorouracil lacks tumor selectivity and carries the risk of toxic side effects during clinical use; second, the efficiency of fluorouracil conversion to FdUMP is very low [Invest.New Drugs 2000, 18, 299-313], with most of it converted into α-fluoro-β-alanine, which is toxic to the bone marrow [Biochem.Pharmacol.2000, 59, 953-960], and deoxyribose triphosphate fluorouracil, which is toxic to the mucosa [P.Natl.Acad.Sci.USA 1997, 94, 1795-1799]. The toxic and therapeutic doses of fluorouracil (FU) are close. Summary of the Invention

[0005] The present invention aims to overcome the problems in the prior art of the antimetabolite drug fluorouracil (FU, 5-fluorouracil, 5-fluorouracil, 5-FU) lacking tumor selectivity and relatively low efficiency of converting FU into its active form, FdUMP, in vivo. The present invention provides a deoxyribose fluorouracil monophosphate prodrug for use in the preparation of a medicament for preventing and / or treating tumors. The deoxyribose fluorouracil monophosphate prodrug can selectively enter tumor cells under the action of nucleolin protein, release the antimetabolite, and inhibit thymidine synthase. Compared with FU, it has improved anti-tumor activity and reduced in vivo toxicity, offering significant advantages.

[0006] In order to achieve the above object, the present invention provides a use of a deoxyribose fluorouracil monophosphate prodrug in the preparation of a drug for preventing and / or treating tumors, wherein the deoxyribose fluorouracil monophosphate prodrug is a derivative formed by replacing at least one thymine in the nucleolin aptamer AS1411 with fluorouracil;

[0007] The tumor is at least one of lung cancer, breast cancer, prostate cancer, pancreatic cancer, kidney cancer, cervical cancer, leukemia and lymphoma, melanoma, glioblastoma, neuroblastoma, sarcoma and gastric cancer.

[0008] Through the above technical solution, the monophosphate deoxyribose fluorouridine prodrug of the present invention binds to nucleolin protein and, under the action of nucleolin protein, selectively enters tumor cells to release antimetabolite drugs, inhibiting thymidine nucleotide synthase, thereby exerting an anti-tumor effect.

[0009] The monophosphate deoxyribose fluorouridine prodrug of the present invention has the following advantages: 1. It can solve the problem of the lack of tumor selectivity of FU; 2. It can solve the problem of the relatively low efficiency of FU conversion into an active form in vivo. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG1 is a laser confocal microscopy test image of each test group in Example 3;

[0011] FIG2 is a flow cytometer analysis result diagram of each test group in Example 6;

[0012] FIG3 is a flow cytometry image of each test group in Example 7;

[0013] FIG4 is a graph showing the fluorescence intensity of various organs of mice in each test group in Example 9;

[0014] FIG5 is a comparison of tumor tissue sizes in each test group in Example 10;

[0015] FIG6 is a HE staining image of various organs of mice in each test group in Example 11;

[0016] FIG7 shows the test results of mucosal toxicity and bone marrow suppression toxicity in Example 12, wherein FIG7(a) is a comparison of the length of the large intestine of mice in each test group; FIG7(b) is the white blood cell count of mice in each test group. DETAILED DESCRIPTION

[0017] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0018] The present invention provides a use of a deoxyribose fluorouracil monophosphate prodrug in the preparation of a drug for preventing and / or treating tumors. The deoxyribose fluorouracil monophosphate prodrug is a derivative formed by replacing at least one thymine in a nucleolin aptamer AS1411 with fluorouracil;

[0019] The tumor is at least one of lung cancer, breast cancer, prostate cancer, pancreatic cancer, kidney cancer, cervical cancer, leukemia and lymphoma, melanoma, glioblastoma, neuroblastoma, sarcoma and gastric cancer.

[0020] The deoxyribose fluorouridine monophosphate prodrug described in the present invention binds to nucleolin protein and, under the action of nucleolin, selectively enters tumor cells, releasing antimetabolites and inhibiting thymidine synthase, thereby exerting an anti-tumor effect. This can address the problem of FU's lack of tumor selectivity and the relatively low efficiency of FU's conversion to its active form in vivo.

[0021] According to a preferred embodiment of the present invention, the deoxyribose fluorouracil monophosphate prodrug is fluorouracil (FU) replacing 1-9 thymines in the nucleolin aptamer AS1411.

[0022] In the present invention, the nucleolin aptamer AS1411 has a nucleic acid sequence as shown in SEQ ID NO: 1 (5-GGT GGT GGT GGT TGT GGT GGT GGT GG-3').

[0023] During the research process, the inventors of the present invention discovered that replacing at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 thymines (T) in the nucleolin aptamer AS1411 with fluorouracil (FU) can solve the problem of FU's lack of tumor selectivity and the relatively low efficiency of FU's conversion into an active form in vivo.

[0024] 1-9FU substituted thymine (T) in AS1411, nucleic acid sequence:

[0025] When fluorouracil (FU) replaces 9 T (thymine) in AS1411 (9FU-AS1411), the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO: 2 (5-GG(FU)GG(FU)GG(FU)GG(FU)(FU)G(FU)GG(FU)GG(FU)GG-3').

[0026] When fluorouracil (FU) replaces one T (thymine) in AS1411 (1FU-AS1411), the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO: 3 (5-GGT GGT GGT GGT (FU) GT GGT GGT GGT GGT GG-3').

[0027] When fluorouracil (FU) replaces two Ts (thymines) in AS1411 (2FU-AS1411), the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO: 4 (5-GGT GG (FU) GGT GGT TGT GGT GG (FU) GGT GG-3').

[0028] When fluorouracil (FU) replaces three Ts (thymines) in AS1411 (3FU-AS1411), the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO: 5 (5-GGT GGT GGT GG (FU) (FU) G (FU) GGT GGT GGT GG-3').

[0029] When fluorouracil (FU) replaces four Ts (thymines) in AS1411 (4FU-AS1411), the nucleic acid sequence of the aptamer derivative is shown in SEQ ID NO: 6 (5-GG(FU)GGT GG(FU)GGT TGT GG(FU)GGT GG(FU)GG-3').

[0030] When fluorouracil (FU) replaces five Ts (thymines) in AS1411 (5FU-AS1411), the nucleic acid sequence of the aptamer derivative is as shown in SEQ ID NO:7 (5-GG(FU)GGT GG(FU)GGT(FU)GT GG(FU)GGT GG(FU)GG-3') and / or SEQ ID NO:8 (5-GGT GG(FU)GGT GG(FU)(FU)G(FU)GGT GG(FU)GGT GG-3'). The nucleic acid sequence of the nucleic acid aptamer derivative shown in SEQ ID NO:7 and the nucleic acid sequence of the nucleic acid aptamer derivative shown in SEQ ID NO:8 are designated as 5FU-AS1411(I) and 5FU-AS1411(II), respectively.

[0031] When fluorouracil (FU) replaces 6 T (thymine) in AS1411 (6FU-AS1411), the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO: 9 (5-GG(FU)GG(FU)GG(FU)GGT TGT GG(FU)GG(FU)GG(FU)GG-3').

[0032] When fluorouracil (FU) replaces 7 T (thymine) in AS1411 (7FU-AS1411), the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO: 10 (5-GG(FU)GGT GG(FU)GG(FU)(FU)G(FU)GG(FU)GGT GG(FU)GG-3').

[0033] When fluorouracil (FU) replaces 8 T (thymine) in AS1411 (8FU-AS1411), the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO: 11 (5-GG(FU)GG(FU)GG(FU)GG(FU)TG(FU)GG(FU)GG(FU)GG(FU)GG-3').

[0034] The present invention will be described in detail below through examples.

[0035] The cell line was provided by the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; the deoxyribose fluorouridine monophosphate prodrug was synthesized by Suzhou Beixin Biotechnology Co., Ltd.

[0036] Example 1 Binding rate of nFU-AS1411 to pancreatic cancer cells

[0037] The binding rate of nFU-AS1411 to pancreatic cancer cells MIA-PaCa-2, PANC-1 and Bxpc-3 was tested. The cells were digested with 0.25% trypsin and then washed with 3.0×10 4 Cells were seeded at a concentration of 100 cells / well in a 6-well culture plate and cultured in a 37°C, 5% CO2 incubator. The cells were divided into 12 groups: (1) blank control group; (2) FAM-labeled CRO (a non-specific nucleic acid aptamer for tumor cells, FAM-CRO) group; (3) FAM-labeled AS411 (FAM-AS1411) group; and (4-12) FAM-labeled nFU-AS1411 (FAM-nFU-AS1411, n=1-9) groups. When the cells reached 80% growth, they were collected in EP tubes. PBS buffer was added to the blank control group, and the corresponding drugs were added to the other eleven groups. The cells were incubated at 37°C for 60 minutes, washed twice with Hanks buffer, and analyzed by flow cytometry.

[0038] Table 1

[0039] As shown in Table 1, replacing thymine (T) in AS1411 with fluorouracil (FU) improves its binding to tumor cells. Given that 9FU-AS1411 has the highest binding rate and drug loading, the following experiments were conducted using 9FU-AS1411.

[0040] Example 2 Binding rate of 9FU-AS1411 to other tumor cells and normal cells

[0041] The binding rate of 9FU-AS1411 to tumor cells was tested using different tumor cells. The selectivity of 9FU-AS1411 to tumor cells and normal cells was compared. The cells were digested with 0.25% trypsin and then 3.0×10 4 Cells were seeded at a concentration of 1000 cells / well in a 6-well culture plate and cultured in a 37°C, 5% CO2 incubator. FAM-9FU-AS1411 was added and incubated at 37°C for 60 minutes. The cells were washed twice with Hanks buffer and analyzed by flow cytometry.

[0042] Table 2

[0043] As can be seen from Table 2, 9FU-AS1411 has a good binding rate to tumor cells; comparing the binding rates of tumor cells and normal cells, it is confirmed that 9FU-AS1411 has a good selectivity for tumor cells.

[0044] Example 3 9FU-AS1411 enters pancreatic cancer cells

[0045] Pancreatic cancer cells MIA-PaCa-2 were used to test how 9FU-AS1411 enters the tumor site. The cells were digested with 0.25% trypsin and then centrifuged at 1.0×10 4 The cells were seeded at a concentration of 500 μg / mL in a confocal dish and cultured in a 37°C, 5% CO2 incubator. When the cells grew to 80%, the old culture medium was discarded and FAM-9FU-AS1411 was added. The cells were incubated at 37°C for 15 minutes, 30 minutes, 1 hour, and 4 hours, respectively. The cells were photographed and analyzed using a laser confocal microscope. The test results are shown in Figure 1.

[0046] As can be seen from Figure 1, through fluorescence localization tracking, it was found that as the action time prolonged, FAM-9FU-AS1411 gradually penetrated into pancreatic cancer cells and could completely enter the tumor cells after 4 hours; however, its penetration into normal pancreatic cells hTERN-HPNE was very weak.

[0047] Example 4 Comparison of the activities of 9FU-AS1411, FU, and AS1411 on pancreatic cancer cells and normal cells

[0048] After the cells were digested with 0.25% trypsin, 5.0×10 3 Each well was inoculated with 100 μL of the working solution at a ratio of complete medium to CCK-8 (10:1). 100 μL of the solution was added to each well. After 1.5 hours of reaction in the dark, the OD value was measured at 462 nm using a microplate reader to calculate the IC value of the drug in each cell. 50 value.

[0049] Table 3

[0050] As shown in Table 3, 9FU-AS1411 exhibits stronger antitumor activity than FU against pancreatic cancer cells and lower toxicity than FU against normal cells. Compared with AS1411, 9FU-AS1411 exhibits significantly enhanced antitumor activity, resolving the current situation in which AS1411 exhibits low antitumor activity and FU has a therapeutic dose close to the toxic dose.

[0051] Example 5 Comparison of the activity of 9FU-AS1411 and FU against other tumor cells

[0052] After the cells were digested with 0.25% trypsin, 5.0×10 3Each well was inoculated with 100 μL of the 9FU-AS1411 solution and incubated overnight at 37°C. The cells were divided into (1) blank control group, (2) FU group, and (3) 9FU-AS1411 group according to the following concentration gradient (0, 0.001, 0.032, 0.01, 0.032, 0.1, 0.32, 1, 3.2, 10, and 32 μM). Six replicate wells were set up in each group. After 72 hours of culture, the old culture medium was discarded and the working solution was prepared at a ratio of complete culture medium: CCK-8 = 10:1. 100 μL was added to each well. After 1.5 hours of reaction in the dark, the OD value was measured at 462 nm using a microplate reader to calculate the IC value of the drug in various cells. 50 value.

[0053] Table 4

[0054] As can be seen from Table 4, 9FU-AS1411 showed stronger antitumor activity than FU against lung cancer, breast cancer, prostate cancer, kidney cancer, cervical cancer, leukemia and lymphoma, melanoma, glioblastoma, neuroblastoma, sarcoma and gastric cancer cells.

[0055] Example 6 9FU-AS1411 induces apoptosis in pancreatic cancer cells

[0056] Pancreatic cancer cells MIA-PaCa-2, PANC-1, and Bxpc-3 were used to verify the apoptosis-inducing effect of 9FU-AS1411 on pancreatic cancer cells. The cells were digested with 0.25% trypsin and then centrifuged at 5.0×10 4 The cells were inoculated into a 6 cm culture dish at a concentration of 10 × 10 / mL and incubated at 37°C with 5% CO2 overnight. 9FU-AS1411 (0.32 μmol / L), AS1411 (0.32 μmol / L), and FU (3.2 μmol / L) were added and incubated at 37°C for 72 h. The cells were then collected, added with 4°C pre-cooled PBS, and centrifuged again. Buffer (2 mL 10× Binding Buffer + 18 mL deionized water) was prepared. The cells were resuspended in 1× buffer to adjust the cell volume to 1.0 × 10 6 / mL; add 5μL Annexin V / FITC to every 100μL cell suspension and react in the dark for 5 minutes; add 7μL PI and 400μL PBS and analyze by flow cytometry.

[0057] The flow cytometry results are shown in Figure 2. The test results show that after treatment with 9FU-AS1411 (0.32 μmol / L), the apoptosis rates of pancreatic cancer MIA-PaCa-2.3, Bxpc-3, and Panc-1 cells were higher than those treated with FU (3.2 μmol / L) or AS1411 (0.32 μmol / L).

[0058] Example 7 9FU-AS1411 arrests cell cycle

[0059] Pancreatic cancer cells MIA-PaCa-2, PANC-1, and Bxpc-3 were used to verify the cell cycle arrest of 9FU-AS1411. The cells were digested with 0.25% trypsin and plated at 5.0×10 4 Cells were seeded at a concentration of 100 μg / well in a 6 cm culture dish and incubated overnight at 37°C with 5% CO2. 9FU-AS1411 (0.32 μmol / L), AS1411 (0.32 μmol / L), and FU (3.2 μmol / L) were added and incubated for 72 hours. Afterwards, the cells were harvested and resuspended in an appropriate amount of ice-cold PBS. Pre-chilled 70% ethanol was added and fixed at 4°C for 24 hours. 500 μL of PI staining solution was added to each sample, and the cells were incubated in the dark for 30 minutes before being analyzed by flow cytometry. The results are shown in Figure 3.

[0060] As can be seen from Figure 3, FU prevents tumor cells from entering mitosis (M phase). Corresponding to FU, 9FU-AS1411 can significantly arrest cells in the G1 phase.

[0061] Example 8 Construction of an orthotopic pancreatic cancer xenograft mouse model

[0062] Immunodeficient mice were provided by Jiangsu Jicui Yaokang Biotechnology Co., Ltd. and were raised in the animal room of Gannan Medical College with approval from the Animal Ethics Review Committee. After acclimation for 1 week, each mouse was fed 2×10 6 MIA-PaCa-2 cells were mixed with 300 μL of Matrigel and injected subcutaneously to form tumors.

[0063] Example 9 Distribution of 9FU-AS1411 in vivo

[0064] To test the tumor-site selectivity of 9FU-AS1411 in vivo, 12 tumor-bearing mice with similar tumor sizes were randomly divided into two groups (n=6 per group) one week after pancreatic cancer cell inoculation. 9FU-AS1411 labeled with the fluorescent group Cy3 was injected via the tail vein. All tumor-bearing mice were sacrificed two and four hours after injection, and major organs (heart, liver, spleen, kidney, lung, and tumor) were harvested and the fluorescence intensity of each organ was measured.

[0065] Small animal imaging, as shown in Figure 4, shows that 2 and 4 hours after administration, Cy3-labeled 9FU-AS1411 (red) primarily accumulated in tumor tissue, with some distribution in the liver and kidneys, but not in the heart, spleen, or lungs. These results demonstrate that 9FU-AS1411 selectively binds to tumor tissue in animals and is metabolized and excreted via the liver and kidneys.

[0066] Example 10 In vivo antitumor activity of 9FU-AS1411

[0067] To test the in vivo antitumor activity of 9FU-AS1411, 20 tumor-bearing mice with similar tumor sizes were randomly divided into four groups (n = 5 per group) one week after pancreatic cancer cell inoculation: (1) blank control group; (2) AS1411 group; (3) 9FU-AS1411 group; and (4) FU group. The blank control group was injected with PBS buffer solution via the tail vein. The other four groups were injected with the corresponding drugs (20 mg / kg for the FU group, 0.16 mg / kg for 9FU-AS1411, and equimolar amounts of AS1411 and 9FU-AS1411) every three days. After 28 days of administration, all mice were sacrificed, tumor tissues were isolated, and tumor sizes were compared. The test results are shown in Figure 5.

[0068] As can be seen from Figure 5, AS1411 exhibited weak antitumor activity, and 0.16 mg / kg (calculated as fluorouracil) and 20 mg / kg fluorouracil had similar antitumor activities.

[0069] Example 11 In vivo toxicity of 9FU-AS1411

[0070] To test the in vivo toxicity of 9FU-AS1411, 20 tumor-bearing mice with similar tumor sizes were randomly divided into four groups (n = 5 per group) one week after pancreatic cancer cell inoculation: (1) blank control group; (2) AS1411 group; (3) 9FU-AS1411 group; and (4) FU group. The blank control group was injected with PBS buffer solution via the tail vein. The other four groups were injected with the corresponding drugs (20 mg / kg for the FU group, 0.16 mg / kg for 9FU-AS1411, and equimolar amounts of AS1411 and 9FU-AS1411) every three days. After 28 days of administration, all mice were sacrificed, and the hearts, livers, spleens, lungs, and kidneys were isolated and stained with HE. The test results are shown in Figure 6.

[0071] As can be seen from the figure, the conjugate has a certain hepatotoxicity, which is slightly stronger than AS1411 (clinically proven to be almost non-toxic), but significantly weaker than high-dose fluorouracil. The remaining toxicities are comparable to those of PBS and AS1411, while fluorouracil shows a certain pulmonary toxicity.

[0072] Example 12 Mucosal Toxicity and Myelosuppressive Toxicity of 9FU-AS1411

[0073] To test the mucosal toxicity and myelosuppressive toxicity of 9FU-AS1411, 20 tumor-bearing mice with similar tumor sizes were randomly divided into four groups (n = 5 per group) one week after pancreatic cancer cell inoculation: (1) blank control group; (2) AS1411 group; (3) 9FU-AS1411 group; and (4) FU group. The blank control group was injected with PBS buffer solution via the tail vein. The other four groups were injected with the corresponding drugs (20 mg / kg for the FU group, 0.16 mg / kg for 9FU-AS1411, and equimolar amounts of AS1411 and 9FU-AS1411) every three days. After 28 days of administration, all mice were sacrificed, blood was collected to determine the number of white blood cells, and the large intestine was isolated and measured for large intestine length. The test results are shown in Figure 7.

[0074] As shown in Figure 7, the low-dose conjugate group (9FU-L, 0.16 mg / kg as fluorouracil) showed no significant changes in the large intestine; in contrast, the high-dose fluorouracil group (5FU-L, 20 mg / kg) showed a significant decrease in large intestine length, indicating significant mucosal toxicity. As shown in Figure 5b, the low-dose conjugate group (9FU-L, 0.16 mg / kg as fluorouracil) showed no significant changes in white blood cell count; in contrast, the high-dose fluorouracil group (5FU-L, 20 mg / kg) showed a significant decrease in white blood cell count, indicating strong myelosuppressive toxicity.

[0075] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as the contents disclosed by the present invention and fall within the scope of protection of the present invention.

Claims

1. Use of a deoxyribose fluorouridine monophosphate prodrug in the preparation of a drug for preventing and / or treating tumors, characterized in that: The monophosphate deoxyribose fluorouracil nucleoside prodrug is a derivative formed by replacing at least one thymine in the nucleolin aptamer AS1411 with fluorouracil; The tumor is at least one of lung cancer, breast cancer, prostate cancer, pancreatic cancer, kidney cancer, cervical cancer, leukemia and lymphoma, melanoma, glioblastoma, neuroblastoma, sarcoma and gastric cancer.

2. The use according to claim 1, wherein The monophosphate deoxyribose fluorouracil nucleoside prodrug is a derivative formed by replacing 1 to 9 thymines in the nucleolin aptamer AS1411 with fluorouracil.

3. The use according to claim 1 or 2, wherein: When fluorouracil replaces one thymine, the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO:

3.

4. The use according to claim 1 or 2, wherein: When fluorouracil replaces two thymines, the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO:

4.

5. The use according to claim 1 or 2, wherein: When fluorouracil replaces three thymines, the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO:

5.

6. The use according to claim 1 or 2, wherein: When fluorouracil replaces four thymines, the nucleic acid sequence of the nucleic acid aptamer derivative is as shown in SEQ ID NO:

6.

7. The use according to claim 1 or 2, wherein: When fluorouracil replaces 5 thymines, the nucleic acid sequence of the nucleic acid aptamer derivative is as shown in SEQ ID NO: 7 and / or SEQ ID NO:

8.

8. The use according to claim 1 or 2, wherein: When fluorouracil replaces 6 thymines, the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO:

9.

9. The use according to claim 1 or 2, wherein: When fluorouracil replaces 7 thymines, the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO:

10.

10. The use according to claim 1 or 2, wherein: When fluorouracil replaces 8 thymines, the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO:

11.

11. The use according to claim 1 or 2, wherein: When fluorouracil replaces 9 thymines, the nucleic acid sequence of the nucleic acid aptamer derivative is shown in SEQ ID NO:

2.

12. The use according to claim 1 or 2, wherein: The tumor is pancreatic cancer.

13. The use according to claim 1 or 2, wherein: The monophosphate deoxyribose fluorouracil nucleoside prodrug is a derivative formed by replacing 9 thymines in the nucleolin aptamer AS1411 with fluorouracil.

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