CN111298131B - Adriamycin prodrug targeted by F3 polypeptide and having pH sensitivity and preparation method thereof - Google Patents
Adriamycin prodrug targeted by F3 polypeptide and having pH sensitivity and preparation method thereof Download PDFInfo
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Abstract
The invention provides an adriamycin prodrug targeted by F3 polypeptide and having pH sensitivity and a preparation method thereof, wherein the adriamycin prodrug targeted by F3 polypeptide and having pH sensitivity is prepared by connecting 6-maleimidocaproic acid hydrazide and adriamycin through a pH-sensitive acylhydrazone bond and then carrying out Michael addition reaction on the 6-maleimidocaproic acid hydrazide and a sulfhydryl on F3 peptide, wherein the 6-maleimidocaproic acid hydrazide is prepared by 6-maleimidocaproic acid through hydrazide reaction. According to the invention, 6-maleimidocaproic acid is used as a drug carrier, the 13-carbonyl group of adriamycin is connected with the carrier through an acylhydrazone bond, the drug loading capacity is improved, and the acylhydrazone bond is broken under the tumor acidic condition to release the adriamycin; the F3 polypeptide realizes the aim of targeted and accurate drug delivery by performing Michael addition on a sulfydryl on a cysteine residue and a maleimide group of 6-maleimidocaproic acid hydrazide.
Description
Technical Field
The invention relates to the technical field of chemical drug synthesis, in particular to an adriamycin prodrug targeted by F3 polypeptide and having pH sensitivity and a preparation method thereof.
Background
Doxorubicin (doxorubicin), belonging to the anthracycline antitumor antibiotic, has since the market been combined with other drugs to form the standard treatment for a variety of tumors. The traditional Chinese medicine composition is mainly used for treating solid tumors such as breast cancer, ovarian cancer, lung cancer, thyroid cancer, liver cancer and the like in clinic. But the toxic and side effects are prominent, and the main manifestations are as follows: bone marrow depression, leading to cumulative cardiotoxicity and even heart failure. The greatest drawback of conventional anticancer therapies is therefore the lack of selectivity.
The acylhydrazone bond has pH sensitivity, the pH of the environment between normal tissue cells and blood of a human body is about 7.4, the pH outside tumor cells is about 6.8-7.2, the pH in the lysosome is about 5.0-5.5 and is far lower than that of the normal cells and blood, and by utilizing the characteristic, the drug linked with the acylhydrazone bond can be concentrated in the tumor environment for hydrolysis, the drug is released, the release of the drug in the normal tissues is avoided, and the toxic and side effects are reduced.
The receptor of the F3 peptide is nucleolin which is a marker molecule on the surfaces of neovascular endothelial cells and tumor cells, nucleolin of normal cells can be only expressed in cell nucleus, and nucleolin can be expressed on the surfaces of cells in tumor cells and tumor neovascular endothelial cells. The F3 peptide can be combined with all tested tumor cells and tumor vascular endothelial cells with high selectivity, and can bring the carried drug molecules into the tumor cells, so the F3 peptide can be used as a good carrier for tumor diagnosis test and tumor tissue targeted drug delivery, and early diagnosis and targeted therapy of tumors are realized.
Disclosure of Invention
In view of the above, the present invention aims to provide an doxorubicin prodrug targeted by F3 polypeptide and having pH sensitivity, so as to solve the problem that the existing doxorubicin has low selectivity and causes prominent toxic and side effects.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
an adriamycin prodrug targeted by an F3 polypeptide and having pH sensitivity is prepared by 6-maleimidocaproic acid hydrazide and adriamycin through a pH-sensitive acylhydrazone bond, and then carrying out Michael addition reaction on the 6-maleimidocaproic acid hydrazide and a sulfhydryl group on an F3 peptide, wherein the 6-maleimidocaproic acid hydrazide is prepared by 6-maleimidocaproic acid through hydrazide reaction.
The second purpose of the invention is to provide a method for preparing the adriamycin prodrug targeted by the F3 polypeptide and having pH sensitivity, which comprises the following steps:
1) dissolving 6-maleimidocaproic acid in a solvent, cooling, adding N-methylmorpholine, isobutyl chloroformate and tert-butyl carbazate to perform hydrazide reaction, purifying after the completion of the hydrazide reaction, and drying in vacuum to obtain 6-maleimidocaproic acid hydrazide;
2) dissolving doxorubicin hydrochloride and the 6-maleimidocaproic acid hydrazide in a solvent, adding a catalyst, stirring at room temperature in a dark place, carrying out acylhydrazone bond connection reaction, concentrating the solvent under reduced pressure after the acylhydrazone bond connection reaction is finished, then recrystallizing, and after the recrystallization is finished, carrying out centrifugal separation, washing and vacuum drying to obtain maleic anhydride hydrazone bond doxorubicin;
3) under the protection of nitrogen, dissolving F3 polypeptide in PBS buffer solution with pH of 7.4, adding an activating agent to perform a sulfhydryl activation reaction, adjusting the pH to 7.0-8.0 after the sulfhydryl activation reaction is finished, then adding the maleic anhydride hydrazone doxorubicin to perform a Michael addition reaction, dialyzing after the Michael addition reaction is finished, and freeze-drying to obtain the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity.
Optionally, the molar ratio of the 6-maleimidocaproic acid, the N-methylmorpholine, the isobutyl chloroformate and the tert-butyl carbazate in the step 1) is 1 to (1-1.5) to (1-2).
Optionally, the reaction temperature of the hydrazide reaction in the step 1) is room temperature, and the reaction time is 1-2 h; the vacuum drying in the step 1) has the room temperature vacuum degree of 0.08-0.09Mpa and the vacuum drying time of 20-24 h.
Optionally, the solvent in step 1) is anhydrous tetrahydrofuran.
Optionally, the mass ratio of the doxorubicin hydrochloride to the 6-maleimidocaproic acid hydrazide in the step 2) is 50: (70-90).
Optionally, the solvent in the step 2) is anhydrous methanol, and the catalyst is trifluoroacetic acid.
Optionally, the reaction time of the acylhydrazone bond-connecting reaction in the step 2) is 24-36h under the condition of stirring at room temperature in a dark place; the recrystallization temperature of the recrystallization in the step 2) is 4 ℃, and the recrystallization time is 48 h; the vacuum drying in the step 2) is carried out at the room temperature of 0.08-0.09Mpa for 10-12 h.
Optionally, the mass ratio of the F3 polypeptide to the maleated hydrazone-bonded doxorubicin in the step 3) is 10 to (3-7), the mass ratio of the F3 polypeptide to the activating agent is 50 to (3-6), and the activating agent is tris (2-carboxyethyl) phosphine.
Optionally, the reaction time of the thiol activation reaction in the step 3) is 1-2 h; the reaction temperature of the Michael addition reaction in the step 3) is room temperature, and the reaction time is 12-15 h.
The structural formula of the adriamycin prodrug which is targeted by the F3 polypeptide and has pH sensitivity is as follows:
compared with the prior art, the adriamycin prodrug targeted by the F3 polypeptide and having pH sensitivity has the following advantages:
the adriamycin prodrug targeted by the F3 polypeptide and having pH sensitivity takes 6-maleimide caproic acid as a drug carrier, the carbonyl at the 13-position of adriamycin is connected with the carrier through a dynamic chemical bond acylhydrazone bond, the drug loading capacity is improved, the acylhydrazone bond is broken under the tumor acidic condition to release the adriamycin, the adriamycin is prevented from being released in normal tissues, the toxic and side effects are reduced, and the F3 polypeptide is subjected to Michael addition with the maleimide group of the 6-maleimide caproic acid hydrazide through the sulfydryl on a cysteine residue, so that the target of targeted and accurate delivery of an anticancer drug DOX to tumor tissues can be realized.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 shows the NMR of doxorubicin with a maleated hydrazone bond of example 1 of the present invention: (1HNMR) atlas;
FIG. 2 shows NMR of pH-sensitive doxorubicin prodrug targeted by F3 polypeptide in example 1 of the present invention: (1HNMR) atlas.
Detailed Description
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
The present invention will be described in detail below with reference to the drawings and examples.
Example 1
An adriamycin prodrug targeted by an F3 polypeptide and having pH sensitivity is prepared by 6-maleimidocaproic acid hydrazide and adriamycin through a pH-sensitive acylhydrazone bond, and then carrying out Michael addition reaction on the 6-maleimidocaproic acid hydrazide and a sulfhydryl group on an F3 peptide, wherein the 6-maleimidocaproic acid hydrazide is prepared by 6-maleimidocaproic acid through hydrazide reaction.
The adriamycin prodrug targeted by the F3 polypeptide and having pH sensitivity is prepared by the following method:
1) preparation of 6-maleimidocaproic acid hydrazide: dissolving 400mg of 6-maleimidocaproic acid in anhydrous tetrahydrofuran, cooling to 4 ℃, sequentially adding 208 mu L N-methylmorpholine and 257mg of isobutyl chloroformate, adding 250mg of tert-butyl carbazate after 5min, keeping at 4 ℃ for 30min, stirring at room temperature for 1h to perform hydrazidation reaction, filtering after the hydrazidation reaction is finished, evaporating the solvent, dissolving the residue in ethyl acetate, washing with water, and then using MgSO (MgSO) for washing4Drying, filtering and vacuum drying to obtain a crude product;
primarily purifying the crude product by using ethyl acetate/petroleum ether gradient of 1: 1, stirring the primarily purified product in ice-cold trifluoroacetic acid for 10min, evaporating to remove acid, precipitating in cold ether, and then, drying the precipitated product in vacuum for 20h under the condition that the vacuum degree at room temperature is 0.09Mpa to obtain 6-maleimidocaproic acid hydrazide;
2) preparation of maleic anhydride hydrazone bond doxorubicin: dissolving 50mg of doxorubicin hydrochloride and 70mg of 6-maleimidocaproic acid hydrazide in 15mL of anhydrous methanol, adding 30 mu L of trifluoroacetic acid, stirring at room temperature in a dark place for 24 hours, carrying out acylhydrazone bond-connecting reaction, concentrating the solvent to 1mL under reduced pressure after the acylhydrazone bond-connecting reaction is finished, then adding acetonitrile, standing at 4 ℃ for 48 hours for recrystallization, after the recrystallization is finished, carrying out centrifugal separation to obtain a red solid, washing the red solid with methanol/acetonitrile (1: 10), and carrying out vacuum drying for 10 hours under the condition that the vacuum degree at room temperature is 0.09Mpa to obtain the maleinated hydrazone bond doxorubicin;
3) preparation of the PH-sensitive targeting prodrug F3-DOX: under the protection of nitrogen, 50mg of F3 polypeptide is dissolved in 5mL of PBS buffer solution with the pH value of 7.4, 3mg of tris (2-carboxyethyl) phosphine (TCEP) is added to react for 1h to fully perform a sulfhydryl activation reaction, after the sulfhydryl activation reaction is finished, the pH value is adjusted to 7.0 by using alkali, then 15mg of maleic anhydride hydrazone bond doxorubicin is added to react for 12h at room temperature to fully perform a Michael addition reaction, after the Michael addition reaction is finished, the reaction solution is transferred to a dialysis bag with the molecular weight cutoff of 3500Da and dialyzed by using deionized water for 36h, and then freeze drying is performed to obtain the doxorubicin prodrug targeted by the F3 polypeptide and with pH sensitivity, namely the pH sensitive targeted prodrug F3-DOX.
The nuclear magnetic resonance test of the maleylated hydrazone-linked doxorubicin of this example was carried out, and its nuclear magnetic resonance: (1HNMR) map is shown in fig. 1.
As can be seen from fig. 1, the chemical shift δ of the hydrogen in the double bond of maleimide in the maleylated hydrazone-linked doxorubicin of this example was 6.70 ppm.
Nuclear magnetic resonance assay of pH-sensitive doxorubicin prodrug targeted by the F3 polypeptide of this example1HNMR) map is shown in fig. 2.
As can be seen from FIG. 2, the peak of hydrogen in the double bond of maleimide disappeared, and two new characteristic peaks, SCH (3.10ppm) and CH2(3.85ppm), appeared, indicating that the double bond of maleimide reacted with the thiol group of the polypeptide.
Example 2
An adriamycin prodrug targeted by an F3 polypeptide and having pH sensitivity is prepared by 6-maleimidocaproic acid hydrazide and adriamycin through a pH-sensitive acylhydrazone bond, and then carrying out Michael addition reaction on the 6-maleimidocaproic acid hydrazide and a sulfhydryl group on an F3 peptide, wherein the 6-maleimidocaproic acid hydrazide is prepared by 6-maleimidocaproic acid through hydrazide reaction.
The adriamycin prodrug targeted by the F3 polypeptide and having pH sensitivity is prepared by the following method:
1) preparation of 6-maleimidocaproic acid hydrazide: dissolving 400mg of 6-maleimidocaproic acid in anhydrous tetrahydrofuran, cooling to 4 ℃, and sequentially adding 270 mu L N-methylmorpholine and 334mg of chloroformic acid isopropylAdding 325mg of tert-butyl carbazate after 5-10min, keeping at 4 ℃ for 40min, stirring at room temperature for 1.5h to perform hydrazidation, filtering after the hydrazidation is finished, evaporating the solvent, dissolving the residue in ethyl acetate, washing with water, and MgSO4Drying, filtering and vacuum drying to obtain a crude product;
primarily purifying the crude product by using ethyl acetate/petroleum ether gradient of 1: 1, stirring the primarily purified product in ice-cold trifluoroacetic acid for 20min, evaporating to remove acid, precipitating in cold ether, and then, drying the precipitated product in vacuum for 22h under the condition that the vacuum degree at room temperature is 0.09Mpa to obtain 6-maleimidocaproic acid hydrazide;
2) preparation of maleic anhydride hydrazone bond doxorubicin: dissolving 50mg of doxorubicin hydrochloride and 80mg of 6-maleimidocaproic acid hydrazide in 15mL of anhydrous methanol, adding 30 mu L of trifluoroacetic acid, stirring at room temperature in a dark place for 30 hours, carrying out acylhydrazone bond-connecting reaction, concentrating the solvent to 1.5mL under reduced pressure after the acylhydrazone bond-connecting reaction is finished, then adding acetonitrile, standing at 4 ℃ for 48 hours for recrystallization, carrying out centrifugal separation after the recrystallization is finished to obtain a red solid, washing the red solid with methanol/acetonitrile (1: 10), and carrying out vacuum drying for 12 hours under the condition that the vacuum degree at room temperature is 0.09Mpa to obtain the maleinized hydrazone bond doxorubicin;
3) preparation of the PH-sensitive targeting prodrug F3-DOX: under the protection of nitrogen, 40mg of F3 polypeptide is dissolved in 5mL of PBS buffer solution with the pH value of 7.4, 4mg of tris (2-carboxyethyl) phosphine (TCEP) is added for reaction for 1.5h to fully perform sulfhydryl activation reaction, after the sulfhydryl activation reaction is finished, the pH value is adjusted to 7.5 by using alkali, then 25mg of maleic anhydride hydrazone bond doxorubicin is added for reaction for 13h at room temperature to fully perform Michael addition reaction, after the Michael addition reaction is finished, the reaction solution is transferred to a dialysis bag with the molecular weight cutoff of 3500Da and dialyzed by deionized water for 40h, and then freeze drying is performed to obtain the doxorubicin prodrug targeted by the F3 polypeptide and with pH sensitivity, namely the pH sensitive targeted prodrug F3-DOX.
Example 3
An adriamycin prodrug targeted by an F3 polypeptide and having pH sensitivity is prepared by 6-maleimidocaproic acid hydrazide and adriamycin through a pH-sensitive acylhydrazone bond, and then carrying out Michael addition reaction on the 6-maleimidocaproic acid hydrazide and a sulfhydryl group on an F3 peptide, wherein the 6-maleimidocaproic acid hydrazide is prepared by 6-maleimidocaproic acid through hydrazide reaction.
The adriamycin prodrug targeted by the F3 polypeptide and having pH sensitivity is prepared by the following method:
1) preparation of 6-maleimidocaproic acid hydrazide: dissolving 400mg of 6-maleimidocaproic acid in anhydrous tetrahydrofuran, cooling to 4 ℃, sequentially adding 312 mu L N-methylmorpholine and 386mg of isobutyl chloroformate, adding 375mg of tert-butyl carbazate after 5-10min, keeping at 4 ℃ for 50min, stirring for 2h at room temperature to perform hydrazidation reaction, filtering after the hydrazidation reaction is finished, evaporating the solvent, dissolving the residue in ethyl acetate, washing with water, and then using MgSO (MgSO) for washing4Drying, filtering and vacuum drying to obtain a crude product;
primarily purifying the crude product by using ethyl acetate/petroleum ether gradient of 1: 1, stirring the primarily purified product in ice-cold trifluoroacetic acid for 30min, evaporating to remove acid, precipitating in cold ether, and then, drying the precipitated product in vacuum for 24h under the condition that the vacuum degree at room temperature is 0.09Mpa to obtain 6-maleimidocaproic acid hydrazide;
2) preparation of maleic anhydride hydrazone bond doxorubicin: dissolving 50mg of doxorubicin hydrochloride and 90mg of 6-maleimidocaproic acid hydrazide in 15mL of anhydrous methanol, adding 30 mu L of trifluoroacetic acid, stirring at room temperature in a dark place for 30 hours, carrying out acylhydrazone bond-connecting reaction, concentrating the solvent to 1.5mL under reduced pressure after the acylhydrazone bond-connecting reaction is finished, then adding acetonitrile, standing at 4 ℃ for 48 hours for recrystallization, carrying out centrifugal separation after the recrystallization is finished to obtain a red solid, washing the red solid with methanol/acetonitrile (1: 10), and carrying out vacuum drying for 14 hours under the condition of the vacuum degree of 0.09Mpa at room temperature to obtain the maleinized hydrazone bond doxorubicin;
3) preparation of the PH-sensitive targeting prodrug F3-DOX: under the protection of nitrogen, 40mg of F3 polypeptide is dissolved in 5mL of PBS buffer solution with the pH value of 7.4, 5mg of tris (2-carboxyethyl) phosphine (TCEP) is added for reaction for 2h to fully perform sulfhydryl activation reaction, after the sulfhydryl activation reaction is finished, the pH value is adjusted to 8.0 by alkali, then 35mg of maleic anhydride hydrazone bond doxorubicin is added for reaction for 15h at room temperature to fully perform Michael addition reaction, after the Michael addition reaction is finished, the reaction solution is transferred to a dialysis bag with the molecular weight cutoff of 3500Da and dialyzed for 48h by deionized water, and then freeze drying is performed to obtain the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity, namely the pH sensitive targeted prodrug F3-DOX.
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An adriamycin prodrug targeted by an F3 polypeptide and having pH sensitivity is characterized in that the adriamycin prodrug is prepared by 6-maleimidocaproic acid hydrazide and adriamycin which are connected through a pH-sensitive acylhydrazone bond, and then the adriamycin prodrug and sulfhydryl on an F3 peptide are subjected to Michael addition reaction, wherein the 6-maleimidocaproic acid hydrazide is prepared by 6-maleimidocaproic acid through hydrazide reaction;
the adriamycin prodrug targeted by the F3 polypeptide and having pH sensitivity is prepared by the following method:
1) dissolving 6-maleimidocaproic acid in a solvent, cooling, adding N-methylmorpholine, isobutyl chloroformate and tert-butyl carbazate to perform hydrazide reaction, purifying after the completion of the hydrazide reaction, and drying in vacuum to obtain 6-maleimidocaproic acid hydrazide;
2) dissolving doxorubicin hydrochloride and the 6-maleimidocaproic acid hydrazide in a solvent, adding a catalyst, stirring at room temperature in a dark place, carrying out acylhydrazone bond connection reaction, concentrating the solvent under reduced pressure after the acylhydrazone bond connection reaction is finished, then recrystallizing, and after the recrystallization is finished, carrying out centrifugal separation, washing and vacuum drying to obtain maleic anhydride hydrazone bond doxorubicin;
3) under the protection of nitrogen, dissolving F3 polypeptide in PBS buffer solution with pH of 7.4, adding an activating agent to perform a sulfhydryl activation reaction, adjusting the pH to 7.0-8.0 after the sulfhydryl activation reaction is finished, then adding the maleic anhydride hydrazone doxorubicin to perform a Michael addition reaction, dialyzing after the Michael addition reaction is finished, and freeze-drying to obtain the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity.
2. A method of making a pH-sensitive doxorubicin prodrug targeted by the F3 polypeptide of claim 1, comprising the steps of:
1) dissolving 6-maleimidocaproic acid in a solvent, cooling, adding N-methylmorpholine, isobutyl chloroformate and tert-butyl carbazate to perform hydrazide reaction, purifying after the completion of the hydrazide reaction, and drying in vacuum to obtain 6-maleimidocaproic acid hydrazide;
2) dissolving doxorubicin hydrochloride and the 6-maleimidocaproic acid hydrazide in a solvent, adding a catalyst, stirring at room temperature in a dark place, carrying out acylhydrazone bond connection reaction, concentrating the solvent under reduced pressure after the acylhydrazone bond connection reaction is finished, then recrystallizing, and after the recrystallization is finished, carrying out centrifugal separation, washing and vacuum drying to obtain maleic anhydride hydrazone bond doxorubicin;
3) under the protection of nitrogen, dissolving F3 polypeptide in PBS buffer solution with pH of 7.4, adding an activating agent to perform a sulfhydryl activation reaction, adjusting the pH to 7.0-8.0 after the sulfhydryl activation reaction is finished, then adding the maleic anhydride hydrazone doxorubicin to perform a Michael addition reaction, dialyzing after the Michael addition reaction is finished, and freeze-drying to obtain the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity.
3. The method for preparing an doxorubicin prodrug targeted by an F3 polypeptide and having pH sensitivity according to claim 2, wherein the molar ratio of 6-maleimidocaproic acid, N-methylmorpholine, isobutyl chloroformate and tert-butyl carbazate in step 1) is 1: 1-1.5: 1-2.
4. The method for preparing the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity according to claim 2, wherein the reaction temperature of the hydrazylation reaction in the step 1) is room temperature, and the reaction time is 1-2 h; the vacuum drying in the step 1) has the room temperature vacuum degree of 0.08-0.09Mpa and the vacuum drying time of 20-24 h.
5. The method for preparing the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity according to claim 2, wherein the solvent in the step 1) is anhydrous tetrahydrofuran.
6. The method for preparing the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity according to claim 2, wherein the mass ratio of the doxorubicin hydrochloride and the 6-maleimidocaproic acid hydrazide in the step 2) is 50 to (70-90).
7. The method for preparing the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity according to claim 2, wherein the solvent in the step 2) is absolute methanol, and the catalyst is trifluoroacetic acid.
8. The method for preparing the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity according to claim 2, wherein the reaction time of the acylhydrazone bond linkage reaction in the step 2) is 24-36h under stirring at room temperature and in the absence of light; the recrystallization temperature of the recrystallization in the step 2) is 4 ℃, and the recrystallization time is 48 h; the vacuum drying in the step 2) is carried out at the room temperature of 0.08-0.09Mpa for 10-12 h.
9. The method for preparing the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity according to claim 2, wherein the mass ratio of the F3 polypeptide to the maleimidoylated hydrazone-bonded doxorubicin in the step 3) is 10 to (3-7), the mass ratio of the F3 polypeptide to the activating agent is 50 to (3-6), and the activating agent is tris (2-carboxyethyl) phosphine.
10. The method for preparing the doxorubicin prodrug targeted by the F3 polypeptide and having pH sensitivity according to claim 2, wherein the reaction time of the sulfhydryl group activation reaction in the step 3) is 1-2 h; the reaction temperature of the Michael addition reaction in the step 3) is room temperature, and the reaction time is 12-15 h.
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| CN103127525A (en) * | 2013-02-27 | 2013-06-05 | 万礼 | Tree-like polymer nanometer drug delivery carrier targeting doxorubicin and its preparation method |
| CN107551277A (en) * | 2017-08-14 | 2018-01-09 | 天津医科大学 | The sensitive targeting phosphatide polyhistidyl nanoparticles of pH for containing antineoplastic |
| CN108403644A (en) * | 2018-03-16 | 2018-08-17 | 安徽工程大学 | Anticancer drug nanoparticle and preparation method thereof |
| CN109939081A (en) * | 2019-03-12 | 2019-06-28 | 武汉理工大学 | The nanometer organic metal framework material (nMOFs) and preparation method thereof of F3 polypeptide targeting |
| CN110393700A (en) * | 2019-04-02 | 2019-11-01 | 武汉理工大学 | The PAMAM of F3 polypeptide guiding is the preparation and application of the tumour medicine nano-carrier of core |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103127525A (en) * | 2013-02-27 | 2013-06-05 | 万礼 | Tree-like polymer nanometer drug delivery carrier targeting doxorubicin and its preparation method |
| CN107551277A (en) * | 2017-08-14 | 2018-01-09 | 天津医科大学 | The sensitive targeting phosphatide polyhistidyl nanoparticles of pH for containing antineoplastic |
| CN108403644A (en) * | 2018-03-16 | 2018-08-17 | 安徽工程大学 | Anticancer drug nanoparticle and preparation method thereof |
| CN109939081A (en) * | 2019-03-12 | 2019-06-28 | 武汉理工大学 | The nanometer organic metal framework material (nMOFs) and preparation method thereof of F3 polypeptide targeting |
| CN110393700A (en) * | 2019-04-02 | 2019-11-01 | 武汉理工大学 | The PAMAM of F3 polypeptide guiding is the preparation and application of the tumour medicine nano-carrier of core |
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