CN114574495A - Aptamer R50 modified by nucleoside derivative - Google Patents
Aptamer R50 modified by nucleoside derivative Download PDFInfo
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Abstract
The invention relates to a nucleoside derivative modified aptamer, the sequence of which comprises a sequence shown as SEQ NO. 1, wherein at least one nucleotide of the aptamer is replaced by a nucleoside derivative, and/or the tail end of the aptamer is modified by the connection of the nucleoside derivative; preferably, the nucleoside derivative is a thymidine derivative or a cytidine derivative.
Description
Technical Field
The invention belongs to the technical field of biotechnology and genetic engineering, and particularly relates to a nucleic acid aptamer which is modified by nucleoside derivatives and used for improving the stability, increasing the pharmaceutical property, and improving the problems of short half-life period, renal clearance and the like when the nucleic acid aptamer is applied in vivo.
Background
Nucleic acid aptamer
Aptamers are a single-stranded piece of DNA or RNA, usually obtained by screening (exponential enrichment ligand evolution, SELEX) and have strong affinity and specificity for ligands [1,2 ]. There are currently hundreds of nucleic acid aptamers based on various targets, such as organs, cells, tissues, proteins, small molecules, and the like. Among them are hundreds based on tumor cells and tumor-associated proteins [3 ]. Many aptamers are currently in clinical research phase, but only one aptamer targeting VEGF for age-related macular degeneration is currently on the market after FDA approval [4 ]. Stability and rapid renal clearance are major problems in the application of nucleic acid aptamers.
Modification of aptamers
The current aptamer modification methods are many, and mainly comprise terminal modification, sugar ring modification, phosphodiester bond modification, base modification, mirror image modification, cyclization modification, dimerization, polymerization modification and the like. Wherein the terminal modification comprises biotin/fluorescein modification, cholesterol/fatty chain modification, PEG modification and the like. Sugar ring modifications include 2-position permutations, 4-position permutations, etc., locked nucleic acids, etc. Modifications of the phosphodiester bond include phosphorylation/methylation modifications, triazole modifications, and the like. Aptamers in the current clinical experimental stage are often modified in a way of combining multiple modifications, such as base 2F modification, terminal inverted T modification, terminal PEG modification and the like of the aptamer Macuge approved by the FDA [5 ].
Drug bases
At present, there are two types of drug bases, one is a drug base formed by modifying a drug on the basis of an original base, and the other is a drug base analogue which is synthesized by the drug and is convenient for solid phase synthesis and connection. Such as 5-FU (5-fluorouracil), in which the hydrogen in position 5 of uracil is replaced by fluorine; gemcitabine is fluoro modified on the sugar ring to form analogs of cytosine. The drugs have then been reported to be constructed as base analogues for solid phase synthesis onto DNA strands.
After the aptamer is connected with the drug base, the aptamer has drug activity, and the drug has the targeting property of the aptamer. According to the reports in the literature at present, the drug base does not affect the binding ability and affinity of the aptamer [6,7 ].
Aptamer R50
Aptamer R50 was selected in 2012 [8 ]. The stability of the medicine is improved through modification of medicine basic groups, the medicine forming performance of the medicine is improved, and the problems that the application half-life period of the medicine in vivo is short, kidney clearance is caused and the like are solved.
Reference:
[1]Craig Tuerk,Larry Gold.Science,1990,249,505-510.
[2]Andrew D Ellingtom,Jack W.Szostak.Nature,1990,346,818-822.
[3]Parashar,Abhishek.Journal of Clinical and Diagnostic Research.2016
[4]Keith E Maier and Matthew Levy.Molecular Therapy Methods&Clinical Development.2016,5,16014
[5]Jayeeta Banerjee.Marit N Hamilton.J Mol Med 2013.
[6]Sorah Yoon,Jhon J.Rossi,el al.Mol Ther Nucleic Acids,2017,6,80-88.
[7]Sven Kruspe,Ulrich Hahn,2014,9,1998-2011.
[8]Li Xu,Zhen Zhang,Zilong Zhao,et.al.American Journal of Biomedical Sciences.2013,5,47-58.
disclosure of Invention
The invention provides a nucleoside derivative modified aptamer, which is used for improving the stability and the druggability of the aptamer R50 and can be used for targeted imaging and treatment.
The invention relates to a nucleoside derivative modified aptamer, which comprises a sequence shown as SEQ NO. 1, wherein at least one nucleotide of the aptamer is replaced by a nucleoside derivative, and/or the tail end of the aptamer is modified by nucleoside derivative connection;
preferably, the nucleoside derivative is a thymidine derivative or a cytidine derivative.
The at least two nucleotides are replaced by nucleoside derivatives, preferably two nucleotides, four nucleotides or six nucleotides.
Preferably, the substitution occurs at position 15-30 and/or 39-45 of the nucleic acid aptamer; the nucleic acid aptamer is connected with a nucleotide fragment and/or a nucleotide analogue comprising at least one nucleotide analogue at the end.
In a specific embodiment of the present application, the nucleotide derivative is 5-FU or a derivative thereof, in place of thymine nucleotide at the target position of the nucleic acid aptamer; the 5-FU or the derivative thereof replaces one, two or more thymine nucleotides at the 15 th, 20 th, 23 th, 24 th, 27 th, 42 th and 44 th positions of the nucleic acid aptamer.
Preferably, the 5-FU or a derivative thereof replaces thymine nucleotides at positions 15, 20, 24 and 27 of the nucleic acid aptamer, optionally the 5-FU or a derivative thereof replaces thymine nucleotides at positions 42 and 44 of the nucleic acid aptamer; preferably, the 5-FU or a derivative thereof replaces thymine nucleotides at positions 15, 20, 24, 27, 42 and 44 of the nucleic acid aptamer.
In a specific embodiment of the present application, the aptamer is linked to one 5-FU or a derivative thereof at the 3 'end, and/or the aptamer is linked to a nucleotide fragment comprising at least one 5-FU or a derivative thereof at the 5' end, the nucleotide fragment being at least 5 nucleotides or a derivative thereof in length; preferably, the nucleotide fragment is 5' -FTFTFTF-.
In a specific embodiment of the present application, with respect to the above-mentioned nucleic acid aptamer, the nucleotide derivative is gemcitabine or a derivative thereof, which replaces a cytosine nucleotide of the nucleic acid aptamer; the gemcitabine or a derivative thereof replacing cytosine nucleotides at positions 39-45 of the nucleic acid aptamers, more preferably the gemcitabine or a derivative thereof replacing cytosine nucleotides at positions 39 and 45 of the nucleic acid aptamers; linking a nucleotide fragment comprising at least one gemcitabine or a derivative thereof to the 5' end of the aptamer, wherein the length of the nucleotide fragment is at least 5 nucleotides or a derivative thereof; preferably, the nucleotide fragment is 5' -T (Gem) -.
The invention also relates to a nucleotide derivative modified aptamer, which comprises a sequence shown as SEQ NO. 1, wherein nucleotides of the aptamer are simultaneously and respectively replaced by 5-FU or a derivative thereof and gemcitabine or a derivative thereof, and/or the tail end of the aptamer is modified by nucleoside derivative connection; the 5-FU or a derivative thereof replaces thymine nucleotides at positions 15, 20, 24, 27, 42 and 44 of the nucleic acid aptamer, and the gemcitabine or a derivative thereof replaces cytosine nucleotides at positions 39 and 45 of the nucleic acid aptamer; preferably, the 5-FU or a derivative thereof replaces thymine nucleotides at positions 15, 20, 24 and 27 of the nucleic acid aptamer.
Preferably, the 3 'end modification of the aptamer is linked to a DNA fragment comprising one or more nucleoside derivatives, and/or the 5' end modification of the aptamer comprises a DNA fragment substituted with one or more nucleoside derivatives.
Preferably, the DNA fragment replaced by the 5 'end modified and linked nucleoside derivative of the aptamer is 5' -T (Gem) -, or the DNA fragment replaced by the 5 'end modified and linked nucleoside derivative of the aptamer is 5' -FTFTFTF-.
Another aspect of the present application relates to a nucleoside derivative aptamer, any one of the nucleoside derivative-modified aptamers described above, which is modified at the end with C18, PEG or inverted dT (Invert dT).
Drawings
FIG. 1 is an unmodified nucleic acid aptamer R50;
FIG. 2 is a 6 5-FU modified nucleic acid aptamer;
FIG. 3 is a 3' end 3-FU modified nucleic acid aptamer;
FIG. 4 is a nucleic acid aptamer modified with 3-FU at the 5' end;
FIG. 5 is a schematic representation of 2 Gem-modified aptamers;
FIG. 6 is a set of 4 Gem-modified aptamers;
FIG. 7 is a nucleic acid aptamer double-modified with 5-FU and Gem;
FIG. 8 is an in vitro stability experiment;
FIG. 9 is a binding experiment at the cellular level;
FIG. 10 is a targeting experiment at the living body level;
FIG. 11 is an in vivo stability experiment;
FIG. 12 is an in vitro activity assay;
FIG. 13 is an in vivo activity assay.
Detailed Description
The invention is further described in connection with the drawings and the detailed description of the invention for the purpose of facilitating a better understanding of the invention, but is not to be construed as limiting the invention.
The aptamer according to the present invention is described for the first time in the above-mentioned document 8 (Li Xu, Zhen Zhang, locking Zhao, et. al. American Journal of biological sciences.2013,5, 47-58). The aptamer R50 is obtained by cell-SELEX screening, has high specificity and affinity to an EGFR receptor, has the capacity of inducing apoptosis and inhibiting cell proliferation, and can be used for potential candidate cancer drugs or drug carriers, such as lung cancer with high expression of EGFR; the structure of the aptamer R50 is shown in FIG. 1, and the sequence is as follows:
5’-TAAAGGGCGGGGGGTGGGGTGGTTGGTAGTTGTTTTTTCTGTTTC-3’(SEQ ID NO:1)。
the invention relates to a nucleic acid aptamer modified by nucleoside derivatives, which comprises a sequence shown as SEQ NO. 1, wherein the sequence of the nucleic acid aptamer is modified by the nucleoside derivatives, so that the nucleic acid aptamer is used for improving the stability of the nucleic acid aptamer R50, enhancing the drug forming property of R50, improving the problems that the internal part of R50 is easy to eliminate kidney and has short half life. Nucleoside derivatives (or nucleoside analogs) have structures or metabolites that are very similar to natural nucleotides, or are modified and engineered nucleoside compounds that are incorporated into DNA during anabolic processes. In one embodiment of the present application, a nucleoside derivative is used to replace one or more nucleotides of the aptamer, for example, in one embodiment, a nucleoside derivative replaces two nucleotides, four nucleotides, or six nucleotides.
In a specific embodiment of the invention, the nucleoside derivative is a thymidine derivative or a cytidine derivative. Thus, such nucleoside derivatives replace thymine or cytosine at specific positions of the aptamer, for example, at positions 15-30, 39-45 of the aptamer. In a specific embodiment of the present application, the nucleoside derivative used is 5-FU (5-fluorouracil, abbreviated as F) or a derivative thereof, in place of thymidine nucleotide of the above-mentioned aptamer; for example, 5-FU or a derivative thereof replaces one, two or more of thymine nucleotides at positions 15, 20, 23, 24, 27, 42 and 44 of the nucleic acid aptamer. In a specific embodiment, 5-FU or a derivative thereof replaces thymine nucleotides at the 15 th, 20 th, 24 th and 27 th positions of the above-mentioned nucleic acid aptamer, and in another preferred specific embodiment, 5-FU or a derivative thereof replaces thymine nucleotides at the 42 th and 44 th positions of the nucleic acid aptamer. In another embodiment, 5-FU or a derivative thereof replaces thymine nucleotides at positions 15, 20, 24, 27, 42 and 44 of the nucleic acid aptamer.
In another embodiment of the present invention, the nucleoside derivative is a cytosine nucleoside derivative, for example, gemcitabine (compound) or its derivative is used to replace cytosine nucleotide in the aptamer in an embodiment of the present invention. In this embodiment, gemcitabine (abbreviated as Gem) replaces the cytosine nucleotides at positions 39-45 of the aptamer, i.e., replaces the cytosine nucleotides at positions 39 and 45 of the aptamer.
The end of the aptamer modified by the aptamer or the nucleoside derivative can be modified to further improve the stability or the pharmaceutical property of the aptamer R50; for example, the end of the aptamer or the aptamer modified by nucleoside derivatives is connected with a nucleotide or nucleoside derivatives, or a nucleotide fragment replaced by nucleoside derivatives. For example, the aptamer is linked to a nucleoside derivative at its 3 'end, and simultaneously or independently, the aptamer is linked to a nucleotide fragment at its 5' end, the nucleotide fragment comprising at least 5 nucleotides in length, the nucleotide fragment comprising one or more nucleoside derivatives, e.g., one or more nucleotides of the nucleotide fragment are replaced by a nucleoside derivative. In a specific embodiment, the 3' end of the aptamer is linked to a 5-FU. In one embodiment of the invention, a 5 'linked nucleotide fragment of an aptamer is 5' -FTFTFTF- [ aptamer ], and in another embodiment of the invention, the 5 'linked nucleotide fragment of an aptamer is 5' -T (Gem) - [ aptamer ], Gem being gemcitabine.
One embodiment of the present invention relates to a nucleoside derivative-modified nucleic acid aptamer, wherein nucleotides of the nucleic acid aptamer are respectively replaced by 5-FU or a derivative thereof and gemcitabine or a derivative thereof, namely, 5-FU or a derivative thereof replaces one or more of thymine nucleotides at positions 15, 20, 24, 27, 42 and 44 of the nucleic acid aptamer, and gemcitabine or a derivative thereof replaces one or more of cytosine nucleotides at positions 39 and 45 of the nucleic acid aptamer. In a preferred embodiment, 5-FU or a derivative thereof replaces thymine nucleotides at positions 15, 20, 24 and 27 of the nucleic acid aptamer, and gemcitabine or a derivative thereof replaces cytosine nucleotides at positions 39 and 45 of the nucleic acid aptamer; in this example, the nucleoside derivative-modified aptamer is linked to a nucleotide fragment at the 5 'end, such as 5' -T (Gem) aptamer.
In another embodiment of the present invention, in order to improve the stability or usability of the aptamer according to the present invention, the end of the aptamer is modified with a stabilizing group; for example, the end of the aptamer is modified with C18, PEG or inverted dT (Invert dT).
The present application will be described in detail with reference to specific examples.
According to the sequence of the aptamer R50, 5-FU and gemcitabine are respectively used for replacing part of thymine nucleotides of the aptamer during synthesis by a solid phase synthesis technology, and a nucleotide fragment is connected to the 5' end.
Example 1
The sequence of the 5-FU-modified aptamer obtained in this example is as follows, the structure of which is shown in FIG. 2, and is designated as F1,
5’-(5-FU)T(5-FU)T(5-FU)TAAAGGGCGGGGGGTGGGGTGGTTGGTAGTTGTTTTTTCTG(5-FU)T(5-FU)C(5-FU)-3’。
example 2
The sequence of the 5-FU-modified aptamer of this example is as follows, the structure of which is shown in FIG. 3, designated F2,
5’-TAAAGGGCGGGGGGTGGGGTGGTTGGTAGTTGTTTTTTCTG(5-FU)T(5-FU)C(5-FU)-3’。
example 3
The sequence of the 5-FU-modified aptamer of this example is as follows, the structure of which is shown in FIG. 4, designated F3,
5’-(5-FU)T(5-FU)T(5-FU)TAAAGGGCGGGGGGTGGGGTGGTTGGTAGTTGTTTTTTCTGTTTC-3’。
example 4
The sequence of the gemcitabine (Gem) -modified aptamer of this example is shown below, and the structure is shown in FIG. 5, and is called G1,
5’TAAAGGGCGGGGGGTGGGGTGGTTGGTAGTTGTTTTTT(Gem)TGTTT(Gem)-3’。
example 5
The sequence of the gemcitabine (Gem) -modified aptamer of this example is shown below, and the structure is shown in FIG. 6, and is called G2,
5’-T(Gem)T(Gem)TAAAGGGCGGGGGGTGGGGTGGTTGGTAGTTGTTTTTT(Gem)TGTTT(Gem)-3’。
example 6
This example relates to 5-FU and gemcitabine (Gem) modified aptamers having the sequence shown below and the structure shown in FIG. 7, designated G2-F,
5’-T(Gem)T(Gem)TAAAGGGCGGGGGG(5-FU)GGGG(5-FU)GGT(5-FU)GG(5-FU)AGTTGTTTTTT(Gem)TGTTT(Gem)-3’。
example 7 in vitro stability assay
The modified aptamers obtained in examples 1 to 6 were incubated with the cell culture medium for various periods of time such as 0 to 72 hours, and the content of remaining nucleic acid was measured by the agarose gel technique (FIG. 8). As shown in the figure, the half-life of the aptamer alone is 0.5 hours, while the aptamer stability after modification can reach 3 hours.
Example 8 detection of binding Capacity of aptamer-cell level and Living body level
The modified aptamers (F1, F2, F3, G1 and G2) described above and the unmodified aptamer R50 were incubated with lung cancer cells H460 in a 200. mu.l buffer system for 30 minutes, the fluorescence intensity of the aptamer on the cell surface was detected after washing, and the change in the binding ability of the modified aptamer to the cells was examined (FIG. 9). As shown in FIG. 9, the fluorescence intensity of the cells themselves was 103Position of negative control (random sequence) lib at 104And the shift of the sequence R50 itself is at 105-106There was a clear positive signal. The shifts of the sequences F1, F2, F3, G1, G2 after the drug base modification are consistent with the shift of R50, indicating that the modification does not affect the targeted binding of the aptamer to the target.
A nude mouse subcutaneous transplantation tumor model of lung cancer cell H460 was constructed, and 20. mu.M of the above aptamers (R50 and F1) and 100. mu.l of the aptamers were injected into mice by tail vein injection. After 6 hours, the mice were euthanized and the subcutaneous transplants were dissected out and observed for the targeting effect of the aptamers at the tumor sites of the mice (fig. 10). The aptamer F1 modified by the drug base still has good targeting after 6 hours, while the tumor part of the simple aptamer group can not detect fluorescence, and the aptamer F1 can show red fluorescence.
Example 9 in vivo stability testing of aptamers
A nude mouse subcutaneous transplantation tumor model of lung cancer cells H460 is constructed, the modified aptamer F1-R50, 20 mu M and 100 mu l are injected into a mouse body in a tail vein injection mode, and the fluorescence enrichment condition and the maintenance time of a tumor part of the mouse are observed by comparing a fluorescence imager with simple R50 (figure 11). As shown in the figure, the imaging results within 0, 0.5, 1,2 and 3 hours are shown, the obvious targeting effect of the tumor part can be observed within 3 hours, and the targeting effect of the aptamer F1 modified by the drug base is better.
Example 10 in vitro pharmaceutical Activity of aptamers
Lung cancer cells H460 were inoculated into a 96-well plate, the modified aptamer was prepared at different concentrations of 1nM, 10nM, 50nM, 100nM, 500nM, 1000nM, 10000nM, etc., and added to each well, CCK-8 was added after 48 hours, the survival of the cells was examined, the survival rate of the cells was counted, and the potency of the modified aptamer was evaluated in comparison to R50 alone and the drug (FIG. 12). The results showed that the aptamer without cytotoxicity (not shown) was pure and the aptamer modified with drug base retained the potency of the drug compared to the pure drug, wherein IC50 of F1, F2, F3, G1, G2, G2-F (shown as G25FU1 AP3) was also 739.3nM, 2271nM, 991.4nM, 356.8nM, 95.32nM, and 8.325nM, respectively, as shown in FIG. 12.
Example 11 in vivo pharmaceutical Activity of aptamers
A model of subcutaneous transplantation tumor of lung cancer cell H460 was constructed, and 100. mu.l of the drug (5-FU 30 mg/kg; F1-R50100 mg/kg) was administered twice a week via tail vein injection to observe the growth curve of the tumor and the survival of the mice. The modified aptamers were evaluated for efficacy (FIG. 13). The result shows that the aptamer G2 modified by the drug base maintains the efficacy of the drug gemcitabine (Gem) and the treatment effect is better than that of the simple drug.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to limit the present invention, and those skilled in the art can make variations and modifications of the present invention without departing from the spirit and scope of the present invention by using the methods and technical contents disclosed above.
Sequence listing
<110> Shanghai university of traffic medical college affiliated renji hospital
<120> nucleoside derivative-modified aptamer R50
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 45
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 1
taaagggcgg ggggtggggt ggttggtagt tgttttttct gtttc 45
Claims (10)
1. The sequence of the aptamer modified by nucleoside derivatives comprises a sequence shown as SEQ NO. 1, and is characterized in that at least one nucleotide of the aptamer is replaced by the nucleoside derivatives, and/or the tail end of the aptamer is modified by the nucleoside derivatives in a connecting way;
preferably, the nucleoside derivative is a thymidine derivative or a cytidine derivative.
2. Nucleoside derivative-modified nucleic acid aptamers according to claim 1, characterized in that the at least two nucleotides are replaced by nucleoside derivatives, preferably two nucleotides, four nucleotides or six nucleotides; preferably, the substitution occurs at position 15-30 and/or 39-45 of the nucleic acid aptamer; the end of the aptamer is connected with a nucleotide fragment and/or a nucleotide analogue containing at least one nucleoside derivative.
3. A nucleoside derivative-modified nucleic acid aptamer according to claim 1 or 2, wherein the nucleotide derivative is 5-FU or a derivative thereof to replace thymine nucleotide at a target position of the aptamer; the 5-FU or the derivative thereof replaces one, two or more thymine nucleotides at the 15 th, 20 th, 23 th, 24 th, 27 th, 42 th and 44 th positions of the nucleic acid aptamer; preferably, the 5-FU or a derivative thereof replaces thymine nucleotides at positions 15, 20, 24 and 27 of the nucleic acid aptamer, optionally the 5-FU or a derivative thereof replaces thymine nucleotides at positions 42 and 44 of the nucleic acid aptamer; preferably, the 5-FU or a derivative thereof replaces thymine nucleotides at positions 15, 20, 24, 27, 42 and 44 of the nucleic acid aptamer.
4. The nucleoside derivative-modified aptamer according to claim 3, wherein the aptamer is linked to 5-FU or a derivative thereof at the 3 'end, and/or the aptamer is linked to a nucleotide fragment comprising at least one 5-FU or a derivative thereof at the 5' end, wherein the length of the nucleotide fragment is at least 5 nucleotides or a derivative thereof; preferably, the nucleotide fragment is 5' -FTFTFTF-.
5. A nucleoside derivative-modified nucleic acid aptamer according to any one of claims 1 to 4, wherein the nucleotide derivative is gemcitabine or a derivative thereof, which replaces the cytosine nucleotide of the nucleic acid aptamer; the gemcitabine or a derivative thereof replacing cytosine nucleotides at positions 39-45 of the nucleic acid aptamers, more preferably the gemcitabine or a derivative thereof replacing cytosine nucleotides at positions 39 and 45 of the nucleic acid aptamers; linking a nucleotide fragment comprising at least one gemcitabine or a derivative thereof to the 5' end of the aptamer, wherein the length of the nucleotide fragment is at least 5 nucleotides or a derivative thereof; preferably, the nucleotide fragment is 5' -T (Gem) -.
6. The aptamer modified by nucleoside derivatives is characterized by comprising a sequence shown as SEQ NO. 1, wherein nucleotides of the aptamer are simultaneously and respectively replaced by 5-FU or derivatives thereof and gemcitabine or derivatives thereof, and/or the tail end of the aptamer is modified by nucleoside derivative connection; the 5-FU or a derivative thereof replaces one or more of thymine nucleotides at positions 15, 20, 24, 27, 42 and 44 of the nucleic acid aptamer, and the gemcitabine or a derivative thereof replaces cytosine nucleotides at positions 39 and 45 of the nucleic acid aptamer; preferably, the 5-FU or a derivative thereof replaces thymine nucleotides at positions 15, 20, 24 and 27 of the nucleic acid aptamer.
7. A nucleoside derivative-modified aptamer according to any one of claim 6, wherein the 3 'terminal modification of the aptamer is linked to a nucleotide fragment comprising one or more nucleoside derivatives and/or the 5' terminal modification of the aptamer comprises one or more nucleotide fragments substituted with nucleoside derivatives.
8. The nucleoside derivative-modified aptamer according to claim 6, wherein the nucleotide fragment substituted by the nucleoside derivative linked to the 5 'terminal modification of the aptamer is 5' -T (Gem) -, or the nucleotide fragment substituted by the nucleoside derivative linked to the 5 'terminal modification of the aptamer is 5' -FTFTF-.
9. Nucleoside derivative-modified nucleic acid aptamer according to any one of claims 1 to 8, which has an increased or decreased sequence but comprises all or part of the sequence, or has its terminus modified with C18, PEG, or inverted dT.
10. A nucleoside derivative-modified nucleic acid aptamer according to any one of claims 1 to 9, for use in tumor-targeted imaging or photodynamic therapy for imaging and/or for the preparation of a medicament for the treatment of cell proliferative disorders.
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