CN112390962B - Enzyme-responsive polysaccharide supramolecular assembly for plasmid DNA controlled release and preparation method thereof - Google Patents

Enzyme-responsive polysaccharide supramolecular assembly for plasmid DNA controlled release and preparation method thereof Download PDF

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CN112390962B
CN112390962B CN202011222091.5A CN202011222091A CN112390962B CN 112390962 B CN112390962 B CN 112390962B CN 202011222091 A CN202011222091 A CN 202011222091A CN 112390962 B CN112390962 B CN 112390962B
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张玉辉
王李娟
王杰
盛显良
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Inner Mongolia Agricultural University
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Abstract

An enzyme response polysaccharide supermolecule assembly for plasmid DNA controlled release and a preparation method thereof. The assembly construction unit is adamantane modified hyaluronic acid and tetraethylenepentamine modified cyclodextrin, a polysaccharide supramolecular assembly with hyaluronidase responsiveness is constructed through the host-guest action between the cyclodextrin and adamantane, and the particle size of the assembly is about 100 nm. The invention has the advantages that: 1) the water solubility and the biocompatibility of the assembly can be effectively improved by introducing hyaluronic acid and beta-cyclodextrin; 2) the assembly can gather polyamine chains together to enhance the action of the assembly on plasmid DNA, so that the wrapping capacity of the assembly on the plasmid DNA is improved; 3) the pair of response systems of hyaluronic acid-hyaluronidase is successfully applied to the construction of an enzymatic response nano assembly, and controllable wrapping and release of plasmid DNA can be realized; 4) the assembly body has simple construction method, easy implementation and low cost of raw materials, and has good application prospect in the field of gene delivery.

Description

Enzyme-responsive polysaccharide supramolecular assembly for plasmid DNA controlled release and preparation method thereof
Technical Field
The invention relates to the technical field of biological gene delivery, in particular to an enzyme-responsive polysaccharide supramolecular nano-assembly and a preparation method and application thereof.
Background
The key to the success of gene therapy is the preparation of efficient and low-toxicity gene vectors. At present, there are two main types of gene vectors, viral vectors and non-viral vectors. Although the transfection efficiency of viral vectors is high, clinical applications are limited due to a number of safety issues. For non-viral vectors, achieving therapeutic efficacy requires overcoming various obstacles, such as complexation of nucleic acids with the vector, efficiency of uptake of the vector by the cell, endosomal escape, and the like. Although some non-viral gene delivery systems based on polymeric nanoparticles, dendrimers, mesoporous silica nanoparticles, liposomes and nucleocapsid nanoparticles have shown potential to replace viral vectors in recent years, there are still some challenges to constructing these systems: (1) the complex synthetic procedures make vectors and DNA-vector complexes difficult to manufacture repeatedly and mass-produce; (2) poor water solubility results in difficulty in maintaining stability during blood circulation; (3) the toxicity is high, and the damage to normal cells is large; (4) lack of specificity; (5) insufficient gene release. Specific bonding sites, such as macrocyclic molecules with cavities and ions with complex structures, are coded in simple monomer structures in the synthesis process by utilizing supramolecular chemistry, and the monomers can spontaneously form assemblies by means of recognition among the bonding sites, so that the complex synthesis process can be avoided.
Disclosure of Invention
Aiming at the technical analysis and problems, the invention constructs an enzyme-responsive polysaccharide supermolecule nano-assembly for plasmid DNA controlled release by utilizing the host-guest interaction between cyclodextrin and adamantane, wherein the assembly takes adamantane modified hyaluronic acid (HA-ADA) and tetraethylenepentamine modified cyclodextrin (TEPA-CD) as construction units, and the gene can be released by enzymatic degradation due to the benefit of a biocompatible HA skeleton; the preparation method of the assembly is simple, has low toxic and side effects, and is suitable for amplification synthesis and practical production application.
The technical scheme of the invention is as follows:
an enzyme response polysaccharide supramolecular assembly for plasmid DNA controlled release takes tetraethylenepentamine modified cyclodextrin TEPA-CD as a main body and adamantane modified hyaluronic acid HA-ADA as an object, the polysaccharide supramolecular assembly with hyaluronidase responsiveness constructed by the action of the supramolecular main body and the object can effectively load plasmid DNA and realize controllable release, and the particle size of the assembly is about 100 nm; wherein the molecular formula of the tetraethylenepentamine modified cyclodextrin TEPA-CD is C46H81N3O34The average high molecular chain of the adamantane modified hyaluronic acid HA-ADA is connected with 178.17 adamantane units, and the structure of the assembly building unit is as follows:
Figure GDA0003515881410000021
the invention also provides a preparation method of the enzyme response polysaccharide supramolecular assembly for plasmid DNA controlled release, which comprises the steps of mixing the adamantane modified hyaluronic acid HA-ADA and the tetraethylenepentamine modified cyclodextrin TEPA-CD according to the molar ratio of 1:178.17, and dissolving the mixture by ultrapure water to obtain the enzyme response polysaccharide supramolecular assembly for plasmid DNA controlled release. Wherein the concentrations of the adamantane modified hyaluronic acid HA-ADA and the tetraethylenepentamine modified cyclodextrin TEPA-CD are 0.0768mM and 13.6696mM respectively.
The application of the enzyme response polysaccharide supramolecular assembly for DNA controlled release is used for loading plasmid DNA, realizing the controllable release of the plasmid DNA by utilizing hyaluronidase, and conveying the green fluorescent protein plasmid DNA to 293T cells as a carrier for gene transportation. The specific implementation method comprises the following steps: the prepared assembly and plasmid DNA were dissolved in water to obtain an assembly solution with a concentration of 0.0768mmol/L and a plasmid DNA solution with a concentration of 0.12. mu.g/. mu.L, 20. mu.L of the assembly solution was mixed with 20. mu.L of the plasmid DNA solution, the nitrogen/phosphorus ratio in the mixed solution was 80, and after shaking for 5 seconds, the mixture was allowed to stand at room temperature for 30min to obtain an assembly solution carrying plasmid DNA. Then, 2429IU of hyaluronidase is added into the assembly solution loaded with the plasmid DNA, and the assembly solution is stirred and incubated for 2.5 hours in a water bath environment at 37 ℃, so that the release of the plasmid DNA can be realized.
The invention has the advantages and beneficial effects that:
1) the introduction of HA and beta-CD can effectively improve the water solubility and the biocompatibility; 2) the nano assembly can gather polyamine chains together and promote the interaction with DNA, thereby improving the wrapping property of the DNA; 3) the HA-HAase pair is successfully applied to the construction of an enzyme response nano assembly, and controllable pDNA combination and release can be realized; 4) the assembly body has simple construction method, easy implementation and low cost of raw materials, and has good application prospect in the field of gene delivery.
Drawings
FIG. 1 is a schematic diagram of the synthetic route of adamantane-modified hyaluronic acid.
FIG. 2 is a schematic diagram of a construction route of an enzyme-responsive polysaccharide supramolecular nano-assembly.
FIG. 3 is a scanning electron microscope image of enzyme-responsive polysaccharidic supramolecular nano-assemblies before (a) and after (b) DNA aggregation.
Fig. 4 is an agarose gel electrophoresis of the enzyme-responsive polysaccharide supramolecular nano-assembly before and after enzymatic degradation.
Fig. 5 shows the result of cytotoxicity test of enzyme-responsive polysaccharide supramolecular nano-assembly.
FIG. 6 shows the results of in vitro transfection assay of enzyme-responsive supramolecular polysacharide nanoassemblies, wherein (a) TEPA-CD (b) HA-ADA/TEPA-CD (N/P ═ 80) (c) bPEI25k(N/P＝10)。
Detailed Description
The invention will now be further described, by way of example, with reference to the accompanying drawings, in which:
example 1:
preparation of enzyme response polysaccharide supermolecular assembly for plasmid DNA controlled release,
the method is characterized in that tetraethylenepentamine modified cyclodextrin TEPA-CD is used as a main body, adamantane modified hyaluronic acid HA-ADA is used as an object, a polysaccharide supermolecule assembly with hyaluronidase responsiveness is constructed through the action of the supermolecule main body and the object, plasmid DNA can be effectively loaded, controllable release can be realized, and the particle size of the assembly is about 100 nm; wherein the molecular formula of the tetraethylenepentamine modified cyclodextrin TEPA-CD is C46H81N3O34The average high molecular chain of the adamantane modified hyaluronic acid HA-ADA is connected with 178.17 adamantane units, and the structure of the assembly building unit is as follows:
Figure GDA0003515881410000031
the preparation method comprises the steps of mixing the adamantane modified hyaluronic acid HA-ADA and the tetraethylenepentamine modified cyclodextrin TEPA-CD according to the molar ratio of 1:178.17, and dissolving the mixture by using ultrapure water to obtain the enzyme response polysaccharide supramolecular assembly for controlling the plasmid DNA release, wherein the concentrations of the adamantane modified hyaluronic acid HA-ADA and the tetraethylenepentamine modified cyclodextrin TEPA-CD are 0.0768mM and 13.6696mM respectively.
The application of enzyme-responsive polysaccharide supramolecular assemblies for controlled DNA release,
the vector is used for loading plasmid DNA, realizes the controllable release of the plasmid DNA by utilizing hyaluronidase, and can be used as a vector for gene transportation to convey the green fluorescent protein plasmid DNA to 293T cells. The specific implementation method comprises the following steps: the prepared assembly and plasmid DNA are respectively dissolved in water to obtain an assembly solution with the concentration of 0.0768mmol/L and a plasmid DNA solution with the concentration of 0.12 mu g/mu L, 20 mu L of aggregate solution is mixed with 20 mu L of plasmid DNA solution, the nitrogen/phosphorus ratio in the mixed solution is 80, the mixture is shaken for 5 seconds and then is kept stand for 30min at room temperature, and the assembly solution loaded with the plasmid DNA can be prepared. Then, 2429IU of hyaluronidase is added into the assembly solution loaded with the plasmid DNA, and the assembly solution is stirred and incubated for 2.5 hours in a water bath environment at 37 ℃, so that the release of the plasmid DNA can be realized.
FIG. 1 is a schematic diagram of the synthetic route of adamantane-modified hyaluronic acid.
FIG. 2 is a schematic diagram of a construction route of an enzyme-responsive polysaccharide supramolecular nano-assembly.
FIG. 3 is a scanning electron microscope image of enzyme-responsive polysaccharidic supramolecular nano-assemblies before (a) and after (b) DNA aggregation.
Example 2:
the enzymatic degradation reaction experiment of the assembly verifies that:
2429IU of hyaluronidase is added into the assembly solution loaded with the pDNA, and the solution is stirred and incubated for 2.5 hours in a water bath environment at 37 ℃, and then the obtained solution is subjected to agarose gel electrophoresis experiment. As shown in FIG. 4, the left band is pDNA, the middle band is HA-ADA @ pDNA, and the right band is HA-ADA @ pDNA + HAase, it can be seen that the assembly completely coagulated the pDNA before the enzyme was added, and after the enzyme was added, the pDNA migrated, indicating that hyaluronidase promotes the degradation of hyaluronic acid, resulting in a decrease in the charge density of tetraethylenepentamine, thereby releasing the pDNA. The assembly was demonstrated to be responsive to enzymatic degradation.
Example 3:
the cytotoxicity experiment of the assembly verifies that:
293T cells were plated at 5X 104The cells/well were plated evenly in 96-well plates at 37 ℃ with 5% CO2After incubation in the incubator of (1) for 24h, HA-ADA, TEPA-CD, HA-ADA/TEPA-CD, and bPEI were added at different concentrations25kAfter incubation of the solution for another 48h, the relative viability of the cells was determined by the MTT method.
FIG. 5 shows the results of cytotoxicity test. The relative viability of the cells treated with the assemblies is still greater than 80% at a concentration of 1mM, much higher than that of the cells treated with bPEI25kThe treated cells indicate that the assemblies have good biocompatibility. Furthermore, as can be seen from the figure, the cytotoxicity of the assembly was less than that of the host and guest, indicating that the hyaluronic acid shell can improve biocompatibility.
Example 4:
the gene transfection capacity experiment of the assembly body verifies that:
293T cells were plated at 5X 104cells/mL were plated evenly in 6-well plates at 37 ℃ with 5% CO2After incubation for 24h in the incubator, HA-ADA/TEPA-CD @ pEGFP, TEPA-CD @ pEGFP and bPEI are added respectively25k@ pEGFP solution, incubation was continued for 48 h. Then, the cells were washed 3 times with PBS and fixed with paraformaldehyde, and the gene expression of EGFP was observed by CLSM.
FIG. 6 shows the results of in vitro transfection assays of assemblies, wherein (a) TEPA-CD (b) HA-ADA/TEPA-CD (N/P ═ 80) (c) bPEI25k(N/P ═ 10). As shown, the assembly has a bPEI25kThe equivalent transfection capability indicates that the assembly has potential application value in the field of gene delivery.

Claims (6)

1. An enzyme response polysaccharide supramolecular assembly for plasmid DNA controlled release is characterized in that tetraethylenepentamine modified cyclodextrin TEPA-CD is used as a main body, adamantane modified hyaluronic acid HA-ADA is used as an object, and the polysaccharide supramolecular assembly with hyaluronidase response is constructed by the action of the supramolecular main body and the object and can effectively load plasmid DNA and realize controllable release; wherein the molecular formula of the tetraethylenepentamine modified cyclodextrin TEPA-CD is C46H81N3O34Adamantane modified transparent178.17 adamantane units are connected on an average polymer chain of the hyaluronic acid HA-ADA, and the structure of the assembly building unit is as follows:
Figure FDA0003533902490000011
2. the enzyme-responsive polyanhydride supramolecular assembly for controlled release of plasmid DNA as claimed in claim 1, wherein the particle size of the assembly is 100 nm.
3. The method for preparing the enzyme-responsive polysaccharide supramolecular assembly for the controlled release of the plasmid DNA, as claimed in claim 1, is characterized in that the enzyme-responsive polysaccharide supramolecular assembly for the controlled release of the plasmid DNA is obtained by mixing adamantane-modified hyaluronic acid HA-ADA and tetraethylenepentamine-modified cyclodextrin TEPA-CD according to a molar ratio of 1:178.17 and dissolving the mixture with ultrapure water.
4. The method of preparing the enzyme-responsive polyase supramolecular assembly for controlled DNA release of claim 3, wherein the concentration of adamantane-modified hyaluronic acid HA-ADA and tetraethylenepentamine-modified cyclodextrin TEPA-CD is 0.0768mM and 13.6696mM, respectively.
5. Use of the enzyme-responsive polysaccharidic supramolecular assemblies for controlled DNA release of claim 1, wherein the loaded plasmid DNA for non-disease diagnostic and therapeutic purposes transports it into cells and uses hyaluronidase to achieve controlled release of plasmid DNA.
6. The application of claim 5, wherein the specific application method is as follows: respectively dissolving the prepared assembly and plasmid DNA in water to obtain an assembly solution with the concentration of 0.0768mmol/L and a plasmid DNA solution with the concentration of 0.12 mu g/mu L, mixing 20 mu L of the assembly solution with 20 mu L of the plasmid DNA solution, oscillating for 5 seconds, and standing for 30min at room temperature to prepare an assembly solution loaded with the plasmid DNA; then, 2429IU of hyaluronidase was added to the assembly solution loaded with plasmid DNA, and incubated for 2.5 hours with stirring in a water bath environment at 37 ℃, that is, the release of plasmid DNA could be achieved.
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