CN106822916B - Preparation method of pH-sensitive nano Bcl-2 selective inhibitor, product and application - Google Patents
Preparation method of pH-sensitive nano Bcl-2 selective inhibitor, product and application Download PDFInfo
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Abstract
The invention relates to a preparation method of a pH-sensitive nano Bcl-2 selective inhibitor, which comprises the following steps: 1) dissolving amphiphilic polymer in a good solvent, adding a modifier with a pH responsive group, stirring for reaction, and dialyzing to obtain a pH-sensitive amphiphilic polymer; 2) dissolving the pH-sensitive amphiphilic polymer obtained in the step 1) and the Bcl-2 selective inhibitor in a good solvent, and stirring for reaction to obtain a mixed solution; 3) and (3) carrying out rotary evaporation, dialysis and centrifugation on the mixed solution in the step 2) to obtain the pH-sensitive nano Bcl-2 selective inhibitor. The invention also relates to the prepared pH-sensitive nano Bcl-2 selective inhibitor and application thereof. The preparation reaction system is mild, the conditions are controllable, and the prepared material has good biocompatibility and good clinical transformation possibility.
Description
Technical Field
The invention relates to the field of preparation of Bcl-2 selective inhibitors, in particular to a preparation method of a pH-sensitive nano Bcl-2 selective inhibitor, a product and application thereof.
Background
Asthma is a serious respiratory disease that affects the health of millions of people worldwide, and the number of patients shows a rising trend. Asthma is an inflammatory disease of the respiratory tract with multiple subtypes, and innate and adaptive immune system interactions can cause recruitment of inflammatory cells, airway hyperreactivity, mucus hypersecretion, and airway remodeling.
Glucocorticoid or combination of long-term short-acting β -agonist bronchodilators (LABA or SABA) and leukotriene antagonists (LTRAs) are currently used as first line agents for the treatment of asthma, with good therapeutic results in most asthmatics, however, a subset of asthmatics are not under effective control.
Studies have shown that the anti-apoptotic protein Bcl-2 is significantly expressed in both eosinophilic and neutrophilic asthma types. At present, overexpression of Bcl-2 protein on mitochondria has been reported. The invention discovers that the selective inhibitor of Bcl-2 can cause apoptosis of inflammatory cells and effectively relieve asthma symptoms. However, Bcl-2 selective inhibitors are poorly water soluble and lack intracellular targeting. Therefore, clinical treatment of Bcl-2 selective inhibitors is greatly limited and the efficacy of the inhibitors cannot be exerted to a great extent.
Disclosure of Invention
The invention aims to provide a preparation method, a product and an application of a pH-sensitive nano Bcl-2 selective inhibitor aiming at the defects of the prior art, wherein the pH-sensitive nano Bcl-2 selective inhibitor has a good asthma inhibition effect and can overcome the defects of the prior art.
The technical scheme provided by the invention is as follows:
a method for preparing a pH-sensitive nano Bcl-2 selective inhibitor comprises the following steps:
1) dissolving amphiphilic polymer in a good solvent, adding a modifier with a pH responsive group, stirring for reaction, and dialyzing to obtain a pH-sensitive amphiphilic polymer;
2) dissolving the pH-sensitive amphiphilic polymer obtained in the step 1) and the Bcl-2 selective inhibitor in a good solvent, and stirring for reaction to obtain a mixed solution;
3) and (3) carrying out rotary evaporation, dialysis and centrifugation on the mixed solution in the step 2) to obtain the pH-sensitive nano Bcl-2 selective inhibitor.
The pH-sensitive nano Bcl-2 selective inhibitor obtained by the preparation method contains a Bcl-2 selective inhibitor with an asthma treatment effect, and meanwhile, micelles are formed by self-assembling pH-sensitive amphiphilic polymers, so that the intracellular microenvironment targeting of the Bcl-2 selective inhibitor is improved, and the asthma inhibition effect is improved.
The pH-sensitive nano Bcl-2 selective inhibitor (hereinafter referred to as inhibitor) improves the diffusion efficiency of nano drugs in the lung by virtue of the unique nano-scale size, realizes the mitochondrial targeting by enhancing the potential after entering cells by utilizing the pH responsiveness, exerts the effect of the Bcl-2 selective inhibitor and realizes the killing of inflammatory cells. Firstly, nano-level drugs can be better dispersed in the lung by instilling the drugs in the air passage; secondly, positive charges on the surface of the inhibitor can be more effectively taken up by cells, positive potentials on the surface of the inhibitor are increased along with the reduction of the pH value of a lysosome, and the carried Bcl-2 selective inhibitor can be more combined with over-expressed Bcl-2 protein on mitochondria due to the electrostatic interaction with the mitochondria, so that the drug effect is improved.
The modifier with pH responsive group is small molecule compound with imidazole, piperidine and other groups.
The pH-responsive group is an imidazole group or a piperidine group. The pH-sensitive amphiphilic polymer needs to be effectively connected with a group with pH responsiveness, so that the performance of the functional nano Bcl-2 selective inhibitor with mitochondrion targeting is ensured.
The amphiphilic polymer is selected from a commercial amphiphilic auxiliary material or a synthetic high molecular polymer.
The commercially available amphiphilic auxiliary material is selected from one or more of poloxamer, polyvinylpyrrolidone, polyvinyl alcohol, tween, vitamin E polyethylene glycol succinate, span, phospholipid, polyethylene glycol, lauryl sodium sulfate, cetyl trimethyl ammonium bromide, albumin, lipoprotein, castor oil polyoxyethylene ether, fatty acid polyoxyethylene ester, fatty acid polyoxyethylene ether, alkylphenol polyoxyethylene ether and polyol ester.
The synthetic high molecular polymer is a polymer modified by using high molecules such as polyethylene glycol, chitosan, poly benzyl aspartate, polyetherimide, polydopamine and the like as a framework.
Preferably, the good solvent in step 1) is one or more selected from dimethyl sulfoxide, N-dimethylformamide, methyl pyrrolidone and N, N-dimethylacetamide.
Preferably, the amphiphilic polymer in step 1) is selected from one or more of ethylene glycol benzyl aspartate copolymer, ethylene glycol glutamic acid copolymer, poloxamer, polyvinylpyrrolidone, polyvinyl alcohol, tween, vitamin E polyethylene glycol succinate, polylactic acid-glycolic acid copolymer, albumin and lipoprotein.
Preferably, the modifying agent in step 1) is selected from 1- (3-aminopropyl) imidazole or 1- (3-aminopropyl) piperidine.
Preferably, the mass ratio of the amphiphilic polymer to the modifier in the step 1) is 1: 5-10.
Preferably, the Bcl-2 selective inhibitor in step 2) is selected from ABT-737, ABT-263, GX15-070, TW-37, ABT-199, GDC-0199, BDA-366, A-1155463, AT101 or HA 14-1.
Preferably, the mass ratio of the Bcl-2 selective inhibitor to the pH-sensitive amphiphilic polymer in the step 2) is 1: 2-20. More preferably 1:2 to 3, and the ratio of the pH-sensitive amphiphilic polymer to the Bcl-2-selective inhibitor needs to be controlled in order to incorporate the Bcl-2-selective inhibitor into the micelle more preferably.
Preferably, the good solvent in step 2) is one or more selected from dimethyl sulfoxide, N-dimethylformamide, methyl pyrrolidone, N-dimethylacetamide and methanol.
The invention also provides a pH-sensitive nano Bcl-2 selective inhibitor prepared by the preparation method. The nano inhibitor can realize excellent distribution in the lung by virtue of the nano size; but also can respond to the microenvironment in the inflammatory cells by virtue of the pH sensitivity of the composition, so as to improve the targeting of the medicament to the mitochondria of the inflammatory cells and promote the apoptosis of the inflammatory cells. Preferably, the particle size of the pH-sensitive nano Bcl-2 selective inhibitor is 1-600 nm.
The invention also provides application of the pH-sensitive nano Bcl-2 selective inhibitor in preparing a medicament for treating asthma.
Compared with the prior art, the invention has the beneficial effects that:
(1) the preparation method provided by the invention is mild in system and controllable in conditions, and the prepared materials have good biocompatibility and good clinical transformation possibility.
(2) The pH-sensitive nano Bcl-2 selective inhibitor can effectively reduce the number of inflammatory cells and inflammatory related factors, and inhibit recruitment of inflammatory cells beside a bronchus, mucus production and airway hyperreactivity.
Drawings
FIG. 1 is the NMR spectrum of imidazole-modified benzyl aspartate glycol copolymer of example 1;
FIG. 2 is a TEM photograph of a pH sensitive nanosized Bcl-2 selective inhibitor of example 1;
FIG. 3 is a schematic diagram of modeling of an asthma mouse model in an application example;
FIG. 4 is a graph showing the analysis of the number change in total inflammatory cells in lung lavage fluid after treatment with different agents of the application examples;
FIG. 5 is a graph showing the analysis of the change in the number of eosinophils in lung lavage fluid following treatment with the various formulations of the present application;
FIG. 6 is a graph showing the quantitative change in the number of neutrophils in lung lavage fluid after treatment with different agents of this application;
FIG. 7 is a graph showing the analysis of the changes in the inflammatory factor IL-4 in lung lavage fluid after treatment with different agents in this application;
FIG. 8 is a graph showing the analysis of the change of the inflammatory factor IL-5 in lung lavage fluid after treatment with different agents of this application.
Detailed Description
The invention is further illustrated by the following examples and figures.
Example 1
1) Synthesis of pH sensitive amphiphilic polymer: 0.2g of ethylene glycol benzyl aspartate copolymer was dissolved in 5ml of N, N-dimethylformamide, and 1g of 1- (3-aminopropyl) imidazole was added dropwise. Stirring is carried out for 12 hours at room temperature under the protection of argon. After the reaction is finished, the solution is dripped into 0.1N hydrochloric acid solution at 4 ℃, and then dialyzed in 0.01N hydrochloric acid solution, and freeze-dried to obtain the imidazole modified ethylene glycol benzyl aspartate copolymer. The prepared pH-sensitive amphiphilic polymer was subjected to NMR structural characterization as shown in fig. 1.
2) preparation of pH-sensitive nanocrystallized Bcl-2 selective inhibitors: bcl-2 selective inhibitor ABT-1995mg and imidazole modified ethylene glycol benzyl aspartate copolymer 10mg obtained in step 1) were dissolved in 3ml of dimethyl sulfoxide and 1ml of methanol, stirred, and the methanol was removed by rotary evaporation. The solution was then dialyzed for two days and centrifuged to remove excess polymer and to obtain a pH sensitive nanosized Bcl-2 selective inhibitor.
The prepared pH-sensitive nanocrystallized Bcl-2 selective inhibitor was subjected to TEM characterization, as shown in FIG. 2.
Example 2
1) Synthesis of pH sensitive amphiphilic polymer: 0.2g of the octadecylamine benzyl aspartate copolymer was dissolved in 5ml of dimethyl sulfoxide, and 1g of 1- (3-aminopropyl) piperidine was added dropwise. Stirring is carried out for 12 hours at room temperature under the protection of argon. After the reaction is finished, the solution is dripped into 0.1N hydrochloric acid solution at 4 ℃, and then dialyzed in 0.01N hydrochloric acid solution, and freeze-dried to obtain the piperidine modified octadecylamine benzyl aspartate copolymer.
2) preparation of pH-sensitive nanocrystallized Bcl-2 selective inhibitors: bcl-2 selective inhibitor ABT-1995mg and 15mg of piperidine modified benzyl aspartate copolymer obtained in step 1) were dissolved in 3ml of dimethyl sulfoxide and 1ml of methanol, stirred, and the methanol was removed by rotary evaporation. The solution was then dialyzed for two days and centrifuged to remove excess polymer and to obtain a pH sensitive nanosized Bcl-2 selective inhibitor.
Example 3
1) Synthesis of pH sensitive amphiphilic polymer: 0.2g of ethylene glycol benzyl glutamate copolymer was dissolved in 5ml of dimethyl sulfoxide, and 1g of 1- (3-aminopropyl) imidazole was added dropwise. Stirring is carried out for 12 hours at room temperature under the protection of argon. After the reaction is finished, the solution is dripped into 0.1N hydrochloric acid solution at 4 ℃, and then dialyzed in 0.01N hydrochloric acid solution, and freeze-dried to obtain the imidazole modified ethylene glycol benzyl glutamate copolymer.
2) preparation of pH-sensitive nanocrystallized Bcl-2 selective inhibitors: bcl-2 selective inhibitor ABT-1995mg and imidazole modified benzyl ethylene glycol glutamate copolymer 15mg obtained in step 1) were dissolved in 3ml of dimethylformamide and 1ml of methanol, stirred, and the methanol was removed by rotary evaporation. The solution was then dialyzed for two days and centrifuged to remove excess polymer and to obtain a pH sensitive nanosized Bcl-2 selective inhibitor.
Application example: a pH sensitive nano Bcl-2 selective inhibitor is used for relieving inflammatory cells and inflammatory factors in the airway of an asthmatic mouse.
Establishment and result analysis of mouse allergic asthma model: male C57BL/6 mice were molded and nebulized with 1% ovalbumin/alum for 40 minutes on days 0 to 14. Then, the Bcl-2 selective inhibitor and the pH-sensitive nano-sized Bcl-2 selective inhibitor (prepared by the method of example 1) were continuously atomized and molded, and the molding process is shown in FIG. 3. 24 hours after the last ovalbumin/alum molding, the mice were sacrificed and lung lavage fluid was collected. Then, the amount of various inflammatory cells and inflammatory factors in the lavage fluid was analyzed by statistical analysis, as shown in FIGS. 4 to 8.
Figure 4 is a graph showing the analysis of the number change in total inflammatory cells in lung lavage fluid after treatment with different agents. It can be seen that the Bcl-2 selective inhibitor and the pH-sensitive nano Bcl-2 selective inhibitor both show good inhibition effect, and the pH-sensitive nano Bcl-2 selective inhibitor has better effect under the same concentration.
FIG. 5 is a graph showing the analysis of the change in the number of eosinophils in lung lavage fluid after treatment with different agents. It can be seen that the Bcl-2 selective inhibitor and the pH-sensitive nano Bcl-2 selective inhibitor both show good inhibition effect, and the pH-sensitive nano Bcl-2 selective inhibitor has better effect under the same concentration.
FIG. 6 is a graph showing the quantitative change in the number of neutrophils in lung lavage fluid after treatment with different agents. It can be seen that the Bcl-2 selective inhibitor and the pH-sensitive nano Bcl-2 selective inhibitor both show good inhibition effect, and the pH-sensitive nano Bcl-2 selective inhibitor has better effect under the same concentration.
FIG. 7 is a graph showing the analysis of changes in IL-4, an inflammatory factor associated with asthma, in lung lavage fluid after treatment with various agents. It can be seen that the Bcl-2 selective inhibitor and the pH-sensitive nano Bcl-2 selective inhibitor both show good inhibition effect, and the pH-sensitive nano Bcl-2 selective inhibitor has better effect under the same concentration.
FIG. 8 is a graph showing the analysis of changes in IL-5, an inflammatory factor associated with asthma, in lung lavage fluid after treatment with various agents. It can be seen that the Bcl-2 selective inhibitor and the pH-sensitive nano Bcl-2 selective inhibitor both show good inhibition effect, and the pH-sensitive nano Bcl-2 selective inhibitor has better effect under the same concentration.
The above embodiments are described in detail to explain the technical solutions and advantages of the present invention, and it should be understood that the above embodiments are only specific examples of the present invention and are not intended to limit the present invention, and any modifications, additions, equivalents, etc. made within the scope of the principles of the present invention should be included in the scope of the present invention.
Claims (6)
1. A preparation method of a pH-sensitive nano Bcl-2 selective inhibitor is characterized by comprising the following steps:
1) dissolving amphiphilic polymer in a good solvent, adding a modifier with a pH responsive group, stirring for reaction, and dialyzing to obtain a pH-sensitive amphiphilic polymer;
2) dissolving the pH-sensitive amphiphilic polymer obtained in the step 1) and the Bcl-2 selective inhibitor in a good solvent, and stirring for reaction to obtain a mixed solution;
3) carrying out rotary evaporation, dialysis and centrifugation on the mixed solution in the step 2) to obtain a pH-sensitive nano Bcl-2 selective inhibitor;
the good solvent in the step 1) is one or more selected from dimethyl sulfoxide, N-dimethylformamide, methyl pyrrolidone and N, N-dimethylacetamide;
the amphiphilic polymer in the step 1) is selected from ethylene glycol benzyl aspartate copolymer, octadecylamine benzyl aspartate copolymer or ethylene glycol benzyl glutamate copolymer;
the modifier in the step 1) is selected from 1- (3-aminopropyl) imidazole or 1- (3-aminopropyl) piperidine;
the Bcl-2 selective inhibitor in the step 2) is ABT-199.
2. The method for preparing the pH-sensitive nano Bcl-2 selective inhibitor according to claim 1, wherein the mass ratio of the amphiphilic polymer to the modifier in the step 1) is 1: 5-10.
3. The method for preparing the pH-sensitive nanocrystallized Bcl-2 selective inhibitor according to claim 1, wherein the mass ratio of the Bcl-2 selective inhibitor to the pH-sensitive amphiphilic polymer in the step 2) is 1: 2-20.
4. The method for preparing the pH-sensitive nano Bcl-2 selective inhibitor according to claim 1, wherein the good solvent in the step 2) is one or more selected from dimethyl sulfoxide, N-dimethylformamide, methyl pyrrolidone, N-dimethylacetamide and methanol.
5. A pH-sensitive nanocrystallized Bcl-2 selective inhibitor prepared by the preparation method of any one of claims 1 to 4.
6. Use of a pH sensitive, nanosized Bcl-2 selective inhibitor according to claim 5 for the preparation of a medicament for the treatment of asthma.
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