CN108478779B - Tumor-targeted nano-drug, preparation method and application thereof - Google Patents
Tumor-targeted nano-drug, preparation method and application thereof Download PDFInfo
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- CN108478779B CN108478779B CN201810324584.6A CN201810324584A CN108478779B CN 108478779 B CN108478779 B CN 108478779B CN 201810324584 A CN201810324584 A CN 201810324584A CN 108478779 B CN108478779 B CN 108478779B
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Abstract
The invention relates to a tumor-targeted nano-drug and a preparation method and application thereof, wherein the nano-drug comprises a mannose polymer with perylene bisimide as a terminal group, an anticancer drug bortezomib and a poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half-ester random copolymer, and the mannose polymer and the bortezomib are loaded by forming a dynamic covalent bond; the poly (ethylene glycol) acrylate-3-acrylamide-co-o-hydroxymethyl phenylboronic acid half ester random copolymer is combined with a mannose polymer through a dynamic covalent bond, so that the stability of the nano-drug is improved; the nano-drug can realize targeted dissociation and release of bortezomib at tumor sites. The nano-drug can be used for chemotherapy through bortezomib, photo-thermal therapy and photoacoustic imaging, and provides guidance for real-time diagnosis in the process of tumor therapy.
Description
Technical Field
The invention belongs to the technical field of nano-drug diagnosis and treatment preparations, and particularly relates to a tumor targeting nano-drug, a preparation method and application thereof, aiming at improving the water solubility and fluorescence quantum efficiency of the tumor targeting nano-drug and having the effect of photo-thermal tumor treatment.
Background
Cancer is now a serious disease threatening human health, and is currently treated mainly by chemical drugs, however, this method has great side effects on human body. Scientists have developed new technologies for cancer therapy, such as photodynamic therapy and photothermal therapy, and the combination of various therapeutic approaches has become a hot spot in the current cancer therapy research. In addition, with the deep understanding of the pathogenesis of cancer, various cancer treatment drugs, such as inhibitors for the tumor microenvironment, are rapidly developed.
Nano-drugs are widely concerned by researchers and medical workers, and mainly load chemical drugs, light therapeutic drugs and the like in a polymer or inorganic carrier, so that the safe transportation of the drugs in vivo is realized, and the problems of leakage and rapid release of the drugs in vivo are solved. However, most of nano-drugs also achieve enrichment at tumor sites mainly through a passive targeting mode, and in order to improve the enrichment degree of the drugs in tumors, biomolecules with targeting characteristics on the tumors need to be modified on the surfaces of the nano-drugs. In addition, the introduction of chemical groups with environmental responsiveness into the polymer also can realize high stability and controllable drug release of the nano-drug. Therefore, the multifunctional nano-medicament with high stability is expected to be prepared in the technical field of novel nano-medicament diagnosis and treatment preparations.
Disclosure of Invention
The purpose is as follows: the invention provides a tumor-targeted nano-drug, a preparation method and application thereof.
The technical scheme is as follows: in order to solve the technical problems, the technical scheme adopted by the invention is as follows:
the nano-drug is characterized by consisting of a mannose polymer with perylene imide as an end group, an anticancer drug bortezomib and a poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half-ester random copolymer, and the preparation method comprises the following steps:
1) adding bortezomib to the mannose polymer aqueous solution under ultrasonic conditions; the mannose polymer and the bortezomib are loaded by forming a dynamic covalent bond;
2) adding the poly (ethylene glycol) acrylate-co-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, and dialyzing to obtain the poly (ethylene glycol) acrylate-co-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution. The poly (ethylene glycol) acrylate-3-acrylamide-co-o-hydroxymethyl phenylboronic acid half ester random copolymer is combined with a mannose polymer through a dynamic covalent bond, and is used for improving the stability of the nano-drug. The dynamic covalent bond between the sugar and the half ester of phenylboronic acid is sensitive to hydrogen peroxide and acid in a tumor microenvironment, and the nano medicament can realize targeted dissociation and release of bortezomib at a tumor part.
The structural formula of the mannose polymer with the end group of perylene bisimide is as follows:
wherein the number n of the repeating units of the mannose-containing structural unit in the mannose polymer is 10 to 100.
The structural formula of the poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half-ester random copolymer is as follows:
wherein the number p of the repeating units of the structural unit of the poly (ethylene glycol) acrylate is 10-100, and the number q of the repeating units of the structural unit of the half ester of the o-hydroxymethylphenylboronic acid is 50-100.
As a preferred scheme, the nano-drug is characterized in that: in the preparation process, the mass ratio of the added mannose polymer with the end group of perylene bisimide to the added bortezomib is 10:1 to 2: 1. The mass ratio of the added mannose polymer to the poly (ethylene glycol) acrylate-co-o-hydroxymethylphenylboronic acid half-ester random copolymer is 3:1 to 1: 3.
In the preparation process, bortezomib is firstly dissolved in a polar organic solvent, wherein the organic solvent is one or more of dimethyl sulfoxide, ethanol, N-dimethylformamide and acetonitrile.
As a preferred scheme, the nano-drug is characterized in that: the concentration of the mannose polymer aqueous solution is 0.5 mg-2 mg/mL.
As a preferred scheme, the nano-drug is characterized in that: the concentration of the poly (ethylene glycol) acrylate-co-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution is 0.5 mg-2 mg/mL.
The invention also provides application of the nano-drug as a photothermal therapeutic agent and a photoacoustic imaging contrast agent.
The invention also provides the application of the nano-drug in preparing drugs for treating tumor diseases.
Has the advantages that: the invention designs and synthesizes a tumor-targeted nano-drug, which has the following advantages: 1. the preparation method of the nano-drug is simple, the number of the repeating units can be controlled through polymerization, the dosage ratio and the concentration of the two polymers can be adjusted, and the loading capacity of the bortezomib drug can be conveniently adjusted. 2. The bortezomib and poly (ethylene glycol) acrylate-co-o-hydroxymethyl phenylboronic acid half ester random copolymer and the sugar polymer are combined in a dynamic covalent bond mode, so that the stability of the nano-drug is greatly improved. (1) The mannose polymer and the bortezomib are loaded by forming a dynamic covalent bond, and compared with a common method for loading medicine through hydrophobicity, the medicine loading mode can effectively reduce the risk of medicine leakage; (2) the poly (ethylene glycol) acrylate-3-acrylamide-co-o-hydroxymethyl phenylboronic acid half ester random copolymer can also be combined with a sugar polymer through a dynamic covalent bond, so that the stability of the nano-drug can be improved; (3) the dynamic covalent bond between the sugar and the half ester of phenylboronic acid is sensitive to hydrogen peroxide and acid in a tumor microenvironment, and the nano medicament can realize targeted dissociation and release of bortezomib at a tumor part. 3. The polymer has perylene bisimide functional segments which can perform photoacoustic imaging, photothermal therapy and tumor targeting, so that the nano-drug is multifunctional. The nano-drug can be used for chemotherapy through bortezomib, photo-thermal therapy and photoacoustic imaging, and all parts have synergistic effect, so that guidance is provided for real-time diagnosis in the tumor treatment process.
Drawings
FIG. 1 is a transmission electron micrograph of the nano-drug obtained in example 1 of the present invention;
FIG. 2 is the hydrodynamic particle size of the nano-drug obtained in example 1 of the present invention measured by dynamic light scattering;
FIG. 3 is a diagram of a sample of the nano-drug obtained in example 1 of the present invention;
FIG. 4 is a diagram showing the UV absorption of the nano-drug obtained in example 2 of the present invention;
FIG. 5 is a diagram showing the photothermal conversion effect of the nano-drug obtained in example 2 of the present invention;
FIG. 6 shows the results of the treatment of human breast cancer cells with the nano-drug obtained in example 3 of the present invention;
FIG. 7 shows the results of the treatment of the nano-drug for human breast cancer tumor-bearing mice obtained in example 3 of the present invention.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
Example 1:
dissolving 9 mg of sugar polymer with 20 perylene bisimide mannose polymer block repeating units in 4.5 ml of water; the number of the repeating units of the phenylboronic acid half-ester polymer block is 50, and 3 mg of the polymer with the number of the repeating units of the polyethylene glycol block being 60 is dissolved in 1.5 ml of water; bortezomib 1 mg was dissolved in 0.5 ml dimethyl sulfoxide.
(1) Adding bortezomib into the perylene imide mannose polymer aqueous solution under ultrasonic conditions.
(2) Adding the poly (ethylene glycol) acrylate-co-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, and dialyzing for one day to obtain the nano-drug.
Fig. 1 is a transmission electron microscope photograph of the nano-drug obtained in example 1 of the present invention, and it can be seen from fig. 1 that nano-drug particles with a particle size in the range of 10 to 50 nm are obtained under the above compounding ratio.
Fig. 2 shows the hydrodynamic particle size of the nano-drug obtained in example 1 of the present invention measured by dynamic light scattering, and the obtained result is consistent with the result of transmission electron microscopy.
Fig. 3 is a diagram of a substance of the nano-drug obtained in example 1 of the present invention.
Example 2:
5mg of sugar polymer with 20 perylene bisimide mannose polymer block repeating units is dissolved in 2.5 ml of water; 5mg of polymer with the number of repeating units of the phenylboronic acid polymer block being 50 and the number of repeating units of the polyethylene glycol block being 60 was dissolved in 2.5 ml of water; bortezomib 2mg was dissolved in 1 ml dimethyl sulfoxide.
(1) Adding bortezomib into the perylene imide mannose polymer aqueous solution under ultrasonic conditions.
(2) Adding the poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, and dialyzing for one day to obtain the nano-drug.
FIG. 4 is a diagram showing the UV absorption of the nano-drug obtained in example 2 of the present invention, so that a light source with a certain wavelength band can be selected for photothermal therapy.
FIG. 5 is a graph showing the photothermal conversion effect of the nano-drug obtained in example 2 of the present invention, and it can be seen that the temperature can be raised by about 30 ℃ at most, indicating that the photothermal therapy can be performed well.
Example 3:
dissolving 3 mg of sugar polymer with 20 perylene bisimide mannose polymer block repeating units in 1.5 ml of water; 9 mg of polymer with the number of repeating units of the phenylboronic acid polymer block being 50 and the number of repeating units of the polyethylene glycol block being 60 was dissolved in 4.5 ml of water; 0.6 mg of bortezomib was dissolved in 0.3 ml of dimethyl sulfoxide.
(1) Adding bortezomib into the perylene imide mannose polymer aqueous solution under ultrasonic conditions.
(2) Adding the poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, and dialyzing for one day to obtain the nano-drug.
FIG. 6 shows the therapeutic results of the nano-drug obtained in example 3 of the present invention on human breast cancer cells, and the nano-drug can achieve a strong killing effect on cancer cells at a lower concentration.
FIG. 7 shows the therapeutic results of the nano-drug for human breast cancer tumor-bearing mice obtained in example 3 of the present invention, showing that the tumor is significantly reduced.
Example 4:
dissolving 9 mg of sugar polymer with 50 repeated units of perylene bisimide mannose polymer block in 4.5 ml of water; the number of repeating units of the phenylboronic acid polymer block was 80, and 3 mg of the polymer having the number of repeating units of the polyethylene glycol block of 60 was dissolved in 1.5 ml of water; bortezomib 1 mg was dissolved in 0.5 ml dimethyl sulfoxide.
(1) Adding bortezomib into a perylene bisimide mannose polymer aqueous solution under an ultrasonic condition;
(2) adding the poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, and dialyzing for one day to obtain the nano-drug.
Example 5:
5mg of sugar polymer with 50 of perylene bisimide mannose polymer block repeating units is dissolved in 2.5 ml of water; 5mg of polymer with the number of the repeating units of the phenylboronic acid polymer block being 80 and the number of the repeating units of the polyethylene glycol block being 60 was dissolved in 2.5 ml of water; bortezomib 2mg was dissolved in 1 ml dimethyl sulfoxide.
(1) Adding bortezomib into a perylene bisimide mannose polymer aqueous solution under an ultrasonic condition;
(2) adding the poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, and dialyzing for one day to obtain the nano-drug.
Example 6:
dissolving 3 mg of sugar polymer with 50 repeated units of perylene bisimide mannose polymer block in 1.5 ml of water; 9 mg of the polymer having a phenylboronic acid polymer block repeating unit number of 80 and a polyethylene glycol block repeating unit number of 60 was dissolved in 4.5 ml of water; 0.6 mg of bortezomib was dissolved in 0.3 ml of dimethyl sulfoxide.
(1) Adding bortezomib into a perylene bisimide mannose polymer aqueous solution under an ultrasonic condition;
(2) adding the poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, and dialyzing for one day to obtain the nano-drug.
Example 7:
dissolving 9 mg of sugar polymer with 50-number of perylene bisimide mannose polymer block repeating units in 9 ml of water; 3 mg of polymer with the number of repeating units of the phenylboronic acid polymer block being 80 and the number of repeating units of the polyethylene glycol block being 60 was dissolved in 3 ml of water; bortezomib 1 mg was dissolved in 1 ml dimethyl sulfoxide.
(1) Adding bortezomib into a perylene bisimide mannose polymer aqueous solution under an ultrasonic condition;
(2) adding the poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, and dialyzing for one day to obtain the nano-drug.
Example 8:
dissolving 3 mg of sugar polymer with 50 repeated units of perylene bisimide mannose polymer block in 6 ml of water; 9 mg of polymer with the number of the repeating units of the phenylboronic acid polymer block being 80 and the number of the repeating units of the polyethylene glycol block being 60 was dissolved in 18 ml of water; bortezomib 0.6 mg was dissolved in 1.2 ml dimethyl sulfoxide.
(1) Adding bortezomib into a perylene bisimide mannose polymer aqueous solution under an ultrasonic condition;
(2) adding the poly (ethylene glycol) acrylate-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, and dialyzing for one day to obtain the nano-drug.
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.
Claims (8)
1. The nano-drug is characterized by consisting of a mannose polymer with perylene imide as an end group, an anticancer drug bortezomib and a polyethylene glycol acrylate-o-hydroxymethylphenylboronic acid half-ester random copolymer, wherein the structure formula of the mannose polymer with perylene imide as an end group is as follows:
wherein the number n of the repeating units of the mannose-containing structural unit in the mannose polymer is 10 to 100;
the structural formula of the polyethylene glycol acrylate-o-hydroxymethylphenylboronic acid half-ester random copolymer is as follows:
wherein the number p of the repeating units of the polyethylene glycol acrylate structural unit is 10-100, and the number q of the repeating units of the o-hydroxymethylphenylboronic acid half-ester structural unit is 50-100;
the preparation method comprises the following steps:
1) adding bortezomib into a mannose polymer aqueous solution under an ultrasonic condition, and realizing the loading of the bortezomib by forming a dynamic covalent bond between the mannose polymer and the bortezomib;
2) adding the polyethylene glycol acrylate-co-o-hydroxymethylphenylboronic acid half ester random copolymer aqueous solution into the solution obtained in the first step under the ultrasonic condition, combining the polyethylene glycol acrylate-3-acrylamide-co-o-hydroxymethylphenylboronic acid half ester random copolymer with a mannose polymer through a dynamic covalent bond, and dialyzing to obtain the product.
2. The nano-drug of claim 1, wherein: in the preparation process, the mass ratio of the added mannose polymer with the end group of perylene bisimide to the added bortezomib is 10:1 to 2: 1.
3. The nano-drug of claim 1, wherein: in the preparation process, the mass ratio of the added mannose polymer to the polyethylene glycol acrylate-co-o-hydroxymethylphenylboronic acid half-ester random copolymer is 3:1 to 1: 3.
4. The nano-drug of claim 1, wherein: in the preparation process, bortezomib is firstly dissolved in a polar organic solvent, wherein the organic solvent is one or more of dimethyl sulfoxide, ethanol, N-dimethylformamide and acetonitrile.
5. The nano-drug of claim 1, wherein: the concentration of the mannose polymer water solution is 0.5 mg-2 mg/mL; the concentration of the polyethylene glycol acrylate-co-o-hydroxymethyl phenylboronic acid half ester random copolymer aqueous solution is 0.5 mg-2 mg/mL.
6. Use of the nano-drug as claimed in any one of claims 1 to 5 for the preparation of a medicament for photothermal therapy against tumors.
7. Use of a nano-drug as defined in any of claims 1-5 for the preparation of a contrast agent for photoacoustic imaging.
8. Use of a nano-drug according to any of claims 1-5 for the preparation of a medicament for the treatment of a tumor disease.
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| CN105030795A (en) * | 2015-06-17 | 2015-11-11 | 国家纳米科学中心 | Nanometer drug-loading system as well as preparation method and application thereof |
| CN105924685A (en) * | 2016-05-03 | 2016-09-07 | 南京邮电大学 | Double-component high-strength hydrogel and preparation method thereof |
| CN107875385A (en) * | 2017-09-18 | 2018-04-06 | 南京邮电大学 | A kind of ASGPR targeting proteins diagnosis and treatment agent and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105030795A (en) * | 2015-06-17 | 2015-11-11 | 国家纳米科学中心 | Nanometer drug-loading system as well as preparation method and application thereof |
| CN105924685A (en) * | 2016-05-03 | 2016-09-07 | 南京邮电大学 | Double-component high-strength hydrogel and preparation method thereof |
| CN107875385A (en) * | 2017-09-18 | 2018-04-06 | 南京邮电大学 | A kind of ASGPR targeting proteins diagnosis and treatment agent and application |
Non-Patent Citations (3)
| Title |
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| Spatiotemporal Control of Synergistic Gel Disintegration Consisting of Boroxole- and Glyco-Based Polymers via Photoinduced Proton Transfer;Yohei Kotsuchibashi et al.;《J. Phys. Chem. B》;20140911;第119卷;2323-2329 * |
| The glyco-regioismerism effect on dynamic interactions between glycopolymers with galactose pendants and benzoxaborole-containing polymer;Pengfei Sun et al.;《Sci. China Chem.》;20171016;第61卷(第1期);71-75 * |
| The glyco-stereoismerism effect on hydrogelation of polymers interacting via dynamic covalent bonds;Mingchang Lin et al.;《Chem. Comm.》;20140709;第50卷;9779-9782 * |
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