CN117903385A - Abiraterone high-molecular polymer and preparation method and application thereof - Google Patents
Abiraterone high-molecular polymer and preparation method and application thereof Download PDFInfo
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- 229960000853 abiraterone Drugs 0.000 title claims abstract description 83
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 title claims abstract description 81
- 229920000642 polymer Polymers 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000000463 material Substances 0.000 claims abstract description 10
- 239000013543 active substance Substances 0.000 claims abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 84
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 56
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 30
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 26
- 239000002244 precipitate Substances 0.000 claims description 25
- 239000011259 mixed solution Substances 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 238000001556 precipitation Methods 0.000 claims description 21
- VHSHLMUCYSAUQU-UHFFFAOYSA-N 2-hydroxypropyl methacrylate Chemical compound CC(O)COC(=O)C(C)=C VHSHLMUCYSAUQU-UHFFFAOYSA-N 0.000 claims description 18
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 238000005119 centrifugation Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000003999 initiator Substances 0.000 claims description 9
- 239000013049 sediment Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 238000006116 polymerization reaction Methods 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 6
- 239000003814 drug Substances 0.000 abstract description 33
- 210000004027 cell Anatomy 0.000 abstract description 22
- 229940079593 drug Drugs 0.000 abstract description 13
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 abstract description 12
- 108010024636 Glutathione Proteins 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 229960003180 glutathione Drugs 0.000 abstract description 6
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 230000001093 anti-cancer Effects 0.000 abstract description 5
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 238000001727 in vivo Methods 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 230000000638 stimulation Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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Abstract
The invention discloses an abiraterone high molecular polymer, a preparation method and application of the abiraterone high molecular polymer serving as an active substance in preparation of anticancer drugs. The medicine prepared by the invention can prolong the circulation time of the medicine in vivo, so that more medicines are enriched in tumor cells through the EPR effect, and after entering the cells, the high molecular medicine can release the active medicine abiraterone under the stimulation of glutathione with high tumor cell content, thereby avoiding that the pure small molecular medicine can be discharged in large quantity in the cells. The nature of the drug stimulus response also reduces the toxicity of the drug to normal cells. The high polymer carrier PEG is an auxiliary material approved by the FDA, so that the high polymer medicine shows good biocompatibility, the toxicity of the anti-cancer medicine is further reduced, the damage to normal tissues is reduced, the molecular weight of the Abiraterone high polymer is lower than the renal threshold (50 kDa), and the Abiraterone high polymer can be degraded and discharged from the body, and has good application prospect in preparing the anti-tumor medicine.
Description
Technical Field
The invention belongs to the field of polymer chemistry, and particularly relates to an Abiraterone polymer, a preparation method and application thereof.
Background
In recent years, the deep research of tumor microenvironments and the application of nanotechnology in the field of medicaments are benefited by scientific researchers, and various nano-drug delivery systems for stimulating release of tumor microenvironments are widely reported. The glutathione content in tumor cells is several times higher than that of normal cells, and the drug-carrying system for releasing glutathione in response is designed to have very small toxic and side effects on normal cells, so that the drug can be released in tumor cells, the side effects of the drug are reduced to the greatest extent, and the circulation time of the drug in vivo can be prolonged, thereby improving the bioavailability and the treatment efficiency of the drug.
Disclosure of Invention
One of the purposes of the invention is to provide an abiraterone high molecular polymer;
The second purpose of the invention is to provide a preparation method of the abiraterone high-molecular polymer;
The invention further aims to provide an application of the abiraterone high-molecular polymer serving as an active substance in preparation of anticancer drugs.
In order to achieve the above purpose, the invention adopts the following technical scheme:
An abiraterone high molecular polymer, wherein the structural formula of the compound is as follows:
wherein: the mole percentage of n is 70-99%, and the mole percentage of m is 1-30%;
the average molecular weight of the compound is 5kDa to 50kDa.
The preparation method of the abiraterone high-molecular polymer comprises the following steps:
s1, preparation of mPEG-b-poly (HPMA):
Dissolving mPEG-CTA and methacrylic acid-beta-hydroxypropyl ester in dimethyl sulfoxide, adding an initiator, carrying out polymerization reaction for 24 hours at 65 ℃ under the protection of nitrogen, adding a mixed solution of acetone and diethyl ether, and centrifuging after precipitation is finished to obtain mPEG-b-poly (HPMA), wherein the mPEG-b-poly (HPMA) has the following structural formula:
the mole percentage of n is 70-99%, and the mole percentage of m is 1-30%;
S2, preparation of mPEG-b-poly (HPMA) -COOH:
Under the protection of nitrogen, the mPEG-b-poly (HPMA) obtained in S1 and 4,4' -dithio-diyl-dibutyric acid are dissolved in dimethyl sulfoxide, catalysts EDCl and NHS are added, after reaction is carried out for 20-24 hours at 0-30 ℃, a mixed solution of acetone and diethyl ether is added, precipitation and filtration are carried out to obtain a precipitate, the precipitate is dissolved by absolute methanol, and the precipitate is centrifuged to obtain the mPEG-b-poly (HPMA) -COOH high molecular polymer, wherein the structural formula of the mPEG-b-poly (HPMA) -COOH is as follows:
the mole percentage of n is 70-99%, and the mole percentage of m is 1-30%;
S3, preparing an Abiraterone high-molecular polymer:
Under the protection of nitrogen, the mPEG-b-poly (HPMA) -COOH obtained by S2 and abiraterone are dissolved in dimethyl sulfoxide, catalysts EDCl and NHS are added, after reaction is carried out for 20-24 hours at 0-30 ℃, mixed solution of acetone and diethyl ether is added, sediment is obtained by precipitation and filtration, the sediment is dissolved by absolute methanol, and the abiraterone high polymer is obtained by centrifugation.
In order to further realize the invention, the volume ratio of the acetone to the diethyl ether in the mixed solution of the acetone and the diethyl ether in the S1-S3 is 7:3-7:1.
In order to further realize the invention, the initiator in S1 is azodiisobutyronitrile, and the addition amount of the azodiisobutyronitrile is 5-10% of the mass of the methacrylic acid-beta-hydroxypropyl ester.
In order to further carry out the present invention, the mPEG-CTA in S1 has a molecular weight of 3.5kDa to 35kDa.
To further realize the present invention, the sum of the mass of EDCl and NHS in S2 is 1.5-15 times of the mass of 4,4' -dithiodiyl dibutyric acid; the sum of the mass of EDCl and NHS in S3 is 2-20 times of the mass of Abiraterone.
To further carry out the present invention, the amount of 4,4' -dithiodiyldibutyric acid material in S2 is the same as the amount of HPMA material in mPEG-b-poly (HPMA).
In order to further carry out the invention, the amount of the substance of abiraterone in S3 is the same as the amount of the substance of COOH in mPEG-b-poly (HPMA) -SS-COOH.
The application of Abiraterone high molecular polymer as active substance in preparing anticancer medicine is provided.
Compared with the prior art, the invention has the beneficial effects that:
The invention links the abiraterone and the high polymer carrier through disulfide bonds, and the drug can be reduced by excessive glutathione in cancer cells, so that the small molecular drug abiraterone is released from the high polymer carrier.
The high molecular polymer consists of a hydrophilic PEG segment and a hydrophobic poly abiraterone, has amphipathy and is self-assembled into nano particles in aqueous solution.
The medicine prepared by the abiraterone polymer can prolong the circulation time of the medicine in vivo, so that more medicines are enriched in tumor cells through the EPR effect, and after entering the cells, the polymer medicine can release the active medicine abiraterone under the stimulation of glutathione with high tumor cell content, thereby avoiding that pure small-molecular medicines are discharged in large quantity in the cells. Because the content of glutathione in normal cells is extremely low, the characteristic of the stimulus response of the high molecular medicine can also reduce the toxicity of the medicine to normal cells. The high polymer carrier PEG is an auxiliary material approved by the FDA, so that the high polymer medicine shows good biocompatibility, and the toxicity of the anticancer medicine is further reduced, thereby reducing the damage to normal tissues, and the Abiraterone high polymer has the molecular weight lower than the renal threshold (50 kDa) and can be degraded and discharged out of the body, so that the Abiraterone high polymer has good application prospect in preparing the antitumor medicine.
Drawings
FIG. 1 is a hydrogen nuclear magnetic resonance spectrum of an Abiraterone polymer prepared in example 1 according to the present invention;
FIG. 2 is an infrared absorption spectrum of an Abiraterone polymer prepared in example 1 according to the present invention;
FIG. 3 is a transmission electron microscope of the Abiraterone polymer prepared in example 1 of the present invention;
FIG. 4 is a graph showing cytotoxicity of Abiraterone polymer prepared in example 1 against MCF-7 according to the present invention.
Detailed Description
The invention is further described below with reference to the drawings and the detailed description.
An abiraterone high molecular polymer, wherein the structural formula of the compound is as follows:
wherein: the mole percentage of n is 70-99%, and the mole percentage of m is 1-30%;
the average molecular weight of the compound is 5kDa to 50kDa.
The preparation method of the abiraterone high-molecular polymer comprises the following steps:
s1, preparation of mPEG-b-poly (HPMA):
mPEG-CTA and beta-hydroxypropyl methacrylate were dissolved in dimethyl sulfoxide, with the molecular weight of mPEG-CTA ranging from 3.5kDa to 35kDa.
Adding initiator azodiisobutyronitrile, wherein the addition amount of the azodiisobutyronitrile is 5-10% of the mass of beta-hydroxypropyl methacrylate, carrying out polymerization reaction for 24 hours at 65 ℃ under the protection of nitrogen, adding mixed solution of acetone and diethyl ether, wherein the volume ratio of the acetone to the diethyl ether is 7:3-7:1, and centrifuging after precipitation is finished to obtain mPEG-b-poly (HPMA), wherein the mPEG-b-poly (HPMA) has the following structural formula:
the mole percentage of n is 70-99%, and the mole percentage of m is 1-30%;
S2, preparation of mPEG-b-poly (HPMA) -COOH:
Under the protection of nitrogen, the mPEG-b-poly (HPMA) obtained in S1 and 4,4' -dithio-diyl-dibutyric acid are dissolved in dimethyl sulfoxide together, catalysts EDCl and NHS are added, after reaction is carried out for 20-24 hours at 0-30 ℃, a mixed solution of acetone and diethyl ether is added, the volume ratio of the acetone to the diethyl ether is 7:3-7:1, precipitation and filtration are carried out to obtain a precipitate, the precipitate is dissolved by absolute methanol, and the precipitate is centrifuged to obtain the mPEG-b-poly (HPMA) -COOH high molecular polymer, wherein the structural formula of the mPEG-b-poly (HPMA) -COOH is as follows:
the mole percentage of n is 70-99%, and the mole percentage of m is 1-30%;
S3, preparing an abiraterone (mPEG-b-poly) high molecular polymer:
Under the protection of nitrogen, the mPEG-b-poly (HPMA) -COOH obtained in S2 and abiraterone are dissolved in dimethyl sulfoxide, catalysts EDCl and NHS are added, after reaction is carried out for 20-24h at 0-30 ℃, mixed solution of acetone and diethyl ether is added, the volume ratio of the acetone to the diethyl ether is 7:1-7:3, sediment is obtained by precipitation and filtration, the sediment is dissolved by absolute methanol, and the abiraterone high polymer is obtained by centrifugation.
The sum of the mass of EDCl and NHS in S2 is 1.5-15 times of the mass of 4,4' -dithio-diyl-dibutyric acid; the sum of the mass of EDCl and NHS in S3 is 2-20 times of the mass of Abiraterone.
The amount of 4,4' -dithiodiyldibutyric acid in S2 was equal to the amount of HPMA in mPEG-b-poly (HPMA).
The amount of abiraterone material in S3 is equal to the amount of COOH material in mPEG-b-poly (HPMA) -COOH.
The application of Abiraterone high molecular polymer as active substance in preparing anticancer medicine is provided.
Example 1:
s1, preparation of mPEG-b-poly (HPMA):
0.400g of mPEG-CTA with molecular weight of 3.5kDa and 0.5g of methacrylic acid-beta-hydroxypropyl ester are dissolved in 5mL of dimethyl sulfoxide, 0.025g of azodiisobutyronitrile as an initiator is added, the adding amount of azodiisobutyronitrile is 5 percent of the mass of the methacrylic acid-beta-hydroxypropyl ester, the mixture is polymerized for 24 hours under the protection of nitrogen at 65 ℃, the mixed solution with the volume ratio of acetone to diethyl ether of 7:3 is added, and after precipitation is finished, the mixture is centrifuged to obtain mPEG-b-poly (HPMA), wherein the mPEG-b-poly (HPMA) has the following structural formula:
n is 70 mol percent and m is 30 mol percent;
Mn＝2.3×104,Mw/Mn＝1.68.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH2-CH2-O)-of PEG),1.33-1.80(-CH2-of HPMA)；
S2, preparation of mPEG-b-poly (HPMA) -COOH:
Under the protection of nitrogen, 0.5g of mPEG-b-poly (HPMA) obtained in S1 and 0.05g of 4,4 '-dithio-diyl-dibutyric acid are dissolved in 5mL of dimethyl sulfoxide together, 0.03g of catalyst EDCl and 0.0475g of NHS are added, the sum of the mass of EDCl and the mass of NHS is 1.5 times of that of 4,4' -dithio-diyl-dibutyric acid, after the reaction is carried out for 24 hours at 0 ℃, a mixed solution with the volume ratio of acetone to diethyl ether being 7:3 is added, precipitate is obtained by precipitation and filtration, the precipitate is dissolved by absolute methanol, and the mPEG-b-poly (HPMA) -COOH high molecular polymer is obtained by centrifugation, wherein the structural formula of mPEG-b-poly (HPMA) -COOH is as follows:
n is 70 mol percent and m is 30 mol percent;
Mn＝2.38×104,Mw/Mn＝1.98.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH 2-CH2-O)-,PEG),1.33-1.80(-CH2-HPMA),4.03-4.18(-CH2 -, 4' -dithiodiyl dibutyric acid);
S3, preparing an Abiraterone high-molecular polymer:
under the protection of nitrogen, 0.25g of mPEG-b-poly (HPMA) -COOH obtained in S2 and 0.015g of abiraterone are dissolved in 5mL of dimethyl sulfoxide, 0.01g of EDCl and 0.02g of NHS serving as catalysts are added, the mass sum of EDCl and NHS is 2 times that of abiraterone, after the mixture is reacted for 20 hours at 25 ℃, a mixed solution with the volume ratio of acetone to diethyl ether being 7:3 is added, a precipitate is obtained through precipitation and filtration, absolute methanol is used for dissolving the precipitate, and the abiraterone high-molecular polymer is obtained through centrifugation, wherein the structural formula of the abiraterone high-molecular polymer is as follows:
n is 70 mol percent and m is 30 mol percent;
the average molecular weight of the compound was 5kDa.
Mn＝2.78×104,Mw/Mn＝1.38.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH 2-O) -PEG), 1.33-1.80 (-CH 2-HPMA),4.03-4.18(-CH2 -,4,4' -dithiodiyldibutyric acid), 7.08 (CH of pyridine), 7.43 (CH of pyridine).
As can be seen from the analysis of the hydrogen nuclear magnetic resonance spectrum in FIG. 1, the characteristic peaks of-CH 2-CH2 -in PEG appear at 3.64ppm, the characteristic peaks of-CH 2 -and-CH 3 on HPMA appear at 0.9-1.3ppm, the characteristic peaks of-CH 2 -for 4,4' -dithiodiyl-dibutyric acid appear at chemical shifts of 4.02-4.10 ppm, and the characteristic peaks of two sets of-CH-appear at 7.08 and 7.43ppm on the abiraterone pyridine ring, indicating that the products obtained by the above method are consistent with the structures described in this application.
In FIG. 2, the presence of Abiraterone in the polymer by the occurrence of the vibration absorption peak of the pyridine ring at wavenumbers 1557-1400cm -1 demonstrates that the product obtained by the above method is consistent with the structure of the previous application.
In fig. 3, it can be seen from a transmission electron microscope photograph that the prepared polymer drug is assembled into spherical nano particles in an aqueous solution due to an amphiphilic structure, and the particles have a regular structure and a smooth surface.
The survival rate of MCF-7 cells with the addition of the polymeric drug in fig. 4 is significantly lower than that with the addition of pure abiraterone.
Example 2:
s1, preparation of mPEG-b-poly (HPMA):
2.00g of mPEG-CTA with the molecular weight of 16.5kDa and 0.5g of methacrylic acid-beta-hydroxypropyl ester are dissolved in 5mL of dimethyl sulfoxide, 0.05g of azodiisobutyronitrile as an initiator is added, the adding amount of azodiisobutyronitrile is 10 percent of the mass of the methacrylic acid-beta-hydroxypropyl ester, the mixture is polymerized for 24 hours under the protection of nitrogen at the temperature of 65 ℃, then a mixed solution with the volume ratio of acetone to diethyl ether of 7:3 is added, and after precipitation is finished, the mixture is centrifuged to obtain mPEG-b-poly (HPMA), wherein the mPEG-b-poly (HPMA) has the following structural formula:
n is 70 mol percent and m is 30 mol percent;
Mn＝2.3×104,Mw/Mn＝1.68.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH2-CH2-O)-of PEG),1.33-1.80(-CH2-of HPMA)；
S2, preparation of mPEG-b-poly (HPMA) -COOH:
Under the protection of nitrogen, 0.5g of mPEG-b-poly (HPMA) obtained in S1 and 0.05g of 4,4 '-dithio-diyl-dibutyric acid are dissolved in 5mL of dimethyl sulfoxide together, 0.1g of catalyst EDCl and 0.15g of NHS are added, the sum of the mass of EDCl and the mass of NHS is 5 times of that of 4,4' -dithio-diyl-dibutyric acid, after the reaction is carried out for 24 hours at 0 ℃, a mixed solution with the volume ratio of acetone to diethyl ether being 7:2 is added, precipitate is obtained by precipitation and filtration, the precipitate is dissolved by absolute methanol, and the mPEG-b-poly (HPMA) -COOH high molecular polymer is obtained by centrifugation, wherein the structural formula of the mPEG-b-poly (HPMA) -COOH is as follows:
n is 70 mol percent and m is 30 mol percent;
Mn＝2.38×104,Mw/Mn＝1.98.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH 2-CH2-O)-,PEG),1.33-1.80(-CH2-HPMA),4.03-4.18(-CH2 -, 4' -dithiodiyl dibutyric acid);
S3, preparing an Abiraterone high-molecular polymer:
Under the protection of nitrogen, 0.35g of mPEG-b-poly (HPMA) -COOH obtained in S2 and 0.020g of abiraterone are dissolved in 5mL of dimethyl sulfoxide, 0.06g of EDCl and 0.02g of NHS serving as catalysts are added, the sum of the mass of EDCl and the mass of NHS is 4 times that of abiraterone, after the mixture is reacted for 24 hours at 25 ℃, a mixed solution with the volume ratio of acetone to diethyl ether being 7:2 is added, a precipitate is obtained through precipitation and filtration, the precipitate is dissolved by absolute methanol, and the abiraterone high-molecular polymer is obtained through centrifugation, wherein the structural formula of the abiraterone high-molecular polymer is as follows:
n is 70 mol percent and m is 30 mol percent;
the average molecular weight of the compound was 20kDa.
Mn＝2.78×104,Mw/Mn＝1.38.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH 2-O) -PEG), 1.33-1.80 (-CH 2-HPMA),4.03-4.18(-CH2 -,4,4' -dithiodiyldibutyric acid), 7.08 (CH of pyridine), 7.43 (CH of pyridine).
Example 3:
s1, preparation of mPEG-b-poly (HPMA):
Dissolving 4.00g of mPEG-CTA with molecular weight of 33kDa and 0.5g of methacrylic acid-beta-hydroxypropyl ester in 5mL of dimethyl sulfoxide, adding an initiator azodiisobutyronitrile with the addition amount of 0.05g of azodiisobutyronitrile being 10% of the mass of the methacrylic acid-beta-hydroxypropyl ester, carrying out polymerization reaction for 24 hours under the protection of nitrogen at 65 ℃, adding a mixed solution with the volume ratio of acetone to diethyl ether being 7:3, and centrifuging after precipitation is finished to obtain mPEG-b-poly (HPMA), wherein the structural formula of the mPEG-b-poly (HPMA) is as follows:
n is 70 mol percent and m is 30 mol percent;
Mn＝2.3×104,Mw/Mn＝1.68.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH2-CH2-O)-of PEG),1.33-1.80(-CH2-of HPMA)；
S2, preparation of mPEG-b-poly (HPMA) -COOH:
Under the protection of nitrogen, 0.5g of mPEG-b-poly (HPMA) obtained in S1 and 0.05g of 4,4 '-dithio-diyl-dibutyric acid are dissolved in 5mL of dimethyl sulfoxide together, 0.35g of catalyst EDCl and 0.15g of NHS are added, the sum of the mass of EDCl and the mass of NHS is 10 times of that of 4,4' -dithio-diyl-dibutyric acid, after the reaction is carried out for 20h at 30 ℃, a mixed solution with the volume ratio of acetone to diethyl ether being 7:1 is added, precipitate is obtained by precipitation and filtration, the precipitate is dissolved by absolute methanol, and the mPEG-b-poly (HPMA) -COOH high molecular polymer is obtained by centrifugation, wherein the structural formula of the mPEG-b-poly (HPMA) -COOH is as follows:
n is 70 mol percent and m is 30 mol percent;
Mn＝2.38×104,Mw/Mn＝1.98.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH 2-CH2-O)-,PEG),1.33-1.80(-CH2-HPMA),4.03-4.18(-CH2 -, 4' -dithiodiyl dibutyric acid);
S3, preparing an Abiraterone high-molecular polymer:
under the protection of nitrogen, 0.45g of mPEG-b-poly (HPMA) -COOH obtained in S2 and 0.04g of abiraterone are dissolved in 5mL of dimethyl sulfoxide, 0.25g of EDCl and 0.15g of NHS serving as catalysts are added, the mass sum of EDCl and NHS is 10 times that of abiraterone, after the mixture is reacted for 20 hours at the temperature of 0 ℃, a mixed solution with the volume ratio of acetone to diethyl ether being 7:1 is added, a precipitate is obtained through precipitation and filtration, absolute methanol is used for dissolving the precipitate, and the abiraterone high-molecular polymer is obtained through centrifugation, wherein the structural formula of the abiraterone high-molecular polymer is as follows:
n is 70 mol percent and m is 30 mol percent;
the average molecular weight of the compound was 45kDa. (the average molecular weight range of 5kDa to 50kDa is currently given, please achieve values of 5, 50 or between 5 and 50)
Mn＝2.78×104,Mw/Mn＝1.38.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH 2-O) -PEG), 1.33-1.80 (-CH 2-HPMA),4.03-4.18(-CH2 -,4,4' -dithiodiyldibutyric acid), 7.08 (CH of pyridine), 7.43 (CH of pyridine).
Example 4:
s1, preparation of mPEG-b-poly (HPMA):
6.00g of mPEG-CTA with molecular weight of 35kDa and 0.5g of methacrylic acid-beta-hydroxypropyl ester are dissolved in 5mL of dimethyl sulfoxide, 0.05g of azodiisobutyronitrile as an initiator is added, the addition amount of the azodiisobutyronitrile is 10% of that of the methacrylic acid-beta-hydroxypropyl ester, the mixture is polymerized for 24 hours under the protection of nitrogen at 65 ℃, then a mixed solution with the volume ratio of acetone to diethyl ether of 7:1 is added, and after precipitation is finished, the mixture is centrifuged to obtain mPEG-b-poly (HPMA), wherein the mPEG-b-poly (HPMA) has the following structural formula:
wherein the mole percentage of n is 99% and the mole percentage of m is 1%;
Mn＝2.3×103,Mw/Mn＝1.68.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH2-CH2-O)-of PEG),1.33-1.80(-CH2-of HPMA)；
S2, preparation of mPEG-b-poly (HPMA) -COOH:
Under the protection of nitrogen, 0.5g of mPEG-b-poly (HPMA) obtained in S1 and 0.05g of 4,4 '-dithio-diyl-dibutyric acid are dissolved in 5mL of dimethyl sulfoxide together, 0.6g of catalyst EDCl and 0.15g of NHS are added, the sum of the mass of EDCl and the mass of NHS is 15 times of that of 4,4' -dithio-diyl-dibutyric acid, after the reaction is carried out for 20h at 30 ℃, a mixed solution with the volume ratio of acetone to diethyl ether being 7:1 is added, precipitate is obtained by precipitation and filtration, the precipitate is dissolved by absolute methanol, and the mPEG-b-poly (HPMA) -COOH high molecular polymer is obtained by centrifugation, wherein the structural formula of the mPEG-b-poly (HPMA) -COOH is as follows:
the mole percentage of n is 99%, and the mole percentage of m is 1%;
Mn＝2.38×104,Mw/Mn＝1.98.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH 2-CH2-O)-,PEG),1.33-1.80(-CH2-HPMA),4.03-4.18(-CH2 -, 4' -dithiodiyl dibutyric acid);
S3, preparing an Abiraterone high-molecular polymer:
Under the protection of nitrogen, 0.25g of mPEG-b-poly (HPMA) -COOH obtained in S2 and 0.015g of abiraterone are dissolved in 5mL of dimethyl sulfoxide, 0.2g of EDCl and 0.1g of NHS serving as catalysts are added, the mass sum of EDCl and NHS is 20 times that of abiraterone, after the mixture is reacted for 20 hours at 30 ℃, a mixed solution with the volume ratio of acetone to diethyl ether of 7:1 is added, a precipitate is obtained through precipitation and filtration, the precipitate is dissolved by absolute methanol, and the abiraterone high-molecular polymer is obtained through centrifugation, wherein the structural formula of the abiraterone high-molecular polymer is as follows:
the mole percentage of n is 99%, and the mole percentage of m is 1%;
The average molecular weight of the compound was 50kDa.
Mn＝2.78×104,Mw/Mn＝1.38.1H-NMR(400MHz,CDCl3,δ,ppm):3.68
(-CH 2-O) -PEG), 1.33-1.80 (-CH 2-HPMA),4.03-4.18(-CH2 -,4,4' -dithiodiyldibutyric acid), 7.08 (CH of pyridine), 7.43 (CH of pyridine).
Experimental example, in vitro experiment for inhibiting breast cancer cell growth:
The MCF-7 cell line was tested by tetrazolium salt reduction (MTT method): MCF-7 cells in log phase were taken, cell concentration was adjusted to 2X 104 cells/mL, 90. Mu.L/well was added to 96 well plates, and the edge wells were filled with sterile PBS. After incubation at 5% CO2 and 37 ℃, placing the solution to be attached in an incubator, adding 5 gradient solutions of which the concentrations are 2.5, 5, 10, 20 and 40 mug/mL respectively into pure abiraterone and the mPEG-b-poly (abiraterone) polymer obtained by the embodiment 1, continuously culturing the cells for 24 hours after adding the solution, taking out and centrifuging the cells, discarding the supernatant culture solution in a 96-well plate, flushing 2-3 times by PBS, adding 20 mug MTT (tetrazole, 5mg/mL, namely 0.5% MTT) solution into each hole, and continuously culturing the cells in a 37 ℃ carbon dioxide incubator for 4 hours. The culture was terminated, the culture solution in the wells was aspirated, 150. Mu.L of DMSO was added to each well, and the mixture was shaken on a shaker for 10min at low speed to allow the crystals to be sufficiently dissolved. The absorbance OD of each well was measured at 490nm in a microplate reader. The cell growth inhibition rate was calculated as follows:
Survival = [ (average OD value of experimental group)/average OD value of control group ] ×100%
The test results are shown in table 1 and fig. 4, wherein Abiraterone has an IC 50=4.5 μg/ml and Abiraterone has an IC 50=2.5 μg/ml.
TABLE 1 Abiraterone Polymer in vitro 48h anticancer Activity data
The result shows that the abiraterone high molecular polymer prepared by the invention has good anti-breast cancer activity, can be aggregated on the cell surface and endocytosed by cells, increases the uptake of MCF-7 cells to the polymer, and obviously enhances the inhibition effect on the MCF-7 cells. From the results analysis, it was found that the Abiraterone with IC50=2.7. Mu.g/ml and the Abiraterone with IC50=1.5. Mu.g/ml, which is pure, indicated that the synthetic high molecular polymer is an effective anticancer drug delivery.
Claims (9)
1. The abiraterone high molecular polymer is characterized in that the structural formula of the compound is as follows:
wherein: the mole percentage of n is 70-99%, and the mole percentage of m is 1-30%;
the average molecular weight of the compound is 5kDa to 50kDa.
2. A process for the preparation of the abiraterone polymer of claim 1, comprising the steps of:
s1, preparation of mPEG-b-poly (HPMA):
Dissolving mPEG-CTA and methacrylic acid-beta-hydroxypropyl ester in dimethyl sulfoxide, adding an initiator, carrying out polymerization reaction for 24 hours at 65 ℃ under the protection of nitrogen, adding a mixed solution of acetone and diethyl ether, and centrifuging after precipitation is finished to obtain mPEG-b-poly (HPMA);
S2, preparation of mPEG-b-poly (HPMA) -COOH:
Under the protection of nitrogen, the mPEG-b-poly (HPMA) obtained in the S1 and 4,4' -dithio-diyl-dibutyric acid are dissolved in dimethyl sulfoxide, catalysts EDCl and NHS are added, after the reaction is carried out for 20 to 24 hours at the temperature of 0 to 30 ℃, a mixed solution of acetone and diethyl ether is added, precipitation and filtration are carried out to obtain a precipitate, the precipitate is dissolved by absolute methanol, and the precipitate is centrifuged to obtain the mPEG-b-poly (HPMA) -COOH high polymer;
S3, preparing an Abiraterone high-molecular polymer:
Under the protection of nitrogen, the mPEG-b-poly (HPMA) -COOH obtained by S2 and abiraterone are dissolved in dimethyl sulfoxide, catalysts EDCl and NHS are added, after reaction is carried out for 20-24 hours at 0-30 ℃, mixed solution of acetone and diethyl ether is added, sediment is obtained by precipitation and filtration, the sediment is dissolved by absolute methanol, and the abiraterone high polymer is obtained by centrifugation.
3. The process for preparing abiraterone polymer as claimed in claim 2, wherein: in the mixed solution of the acetone and the diethyl ether in the S1-S3, the volume ratio of the acetone to the diethyl ether is 7:3-7:1.
4. The process for preparing abiraterone polymer as claimed in claim 2, wherein: the initiator in S1 is azodiisobutyronitrile, and the addition amount of the azodiisobutyronitrile is 5-10% of the mass of the methacrylic acid-beta-hydroxypropyl ester.
5. The process for preparing abiraterone polymer as claimed in claim 2, wherein: the molecular weight of the mPEG-CTA in S1 is 3.5kDa-35kDa.
6. The process for preparing abiraterone polymer as claimed in claim 2, wherein: the sum of the mass of EDCl and NHS in S2 is 1.5-15 times of the mass of 4,4' -dithio-diyl-dibutyric acid; the sum of the mass of EDCl and NHS in S3 is 2-20 times of the mass of Abiraterone.
7. The process for preparing abiraterone polymer as claimed in claim 2, wherein: the amount of 4,4' -dithiodiyldibutyric acid material in S2 is the same as the amount of HPMA material in mPEG-b-poly (HPMA).
8. The process for preparing abiraterone polymer as claimed in claim 2, wherein: the amount of Abiraterone material in S3 is the same as the amount of COOH material in mPEG-b-poly (HPMA) -SS-COOH.
9. The use of abiraterone polymers as claimed in claim 1 as active substances for the preparation of anticancer drugs.
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