CN112570725B - Preparation method of functionalized ligand modified gold nanoparticles - Google Patents
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Abstract
The invention provides a preparation method of gold nanoparticles modified by functional ligands, belonging to the technical field of biological materials. The method comprises the following steps: 1) adding a carboxyl activating agent into a functional ligand with a carboxyl group or aqueous solution of a reductive micromolecule with the carboxyl group to activate the carboxyl group; 2) respectively adding the activated functional ligand with carboxyl groups or the activated reductive micromolecules with carboxyl groups into the reductive micromolecules with amino groups or the functional ligands with hydroxyl groups, adjusting the pH of the mixed solution, and reacting for a period of time to obtain the functional ligand with sulfhydryl groups; 3) and mixing and dissolving the functionalized ligand with the mercapto group and chloroauric acid, heating to boiling, and reacting for a period of time to obtain the gold nanoparticle modified by the functionalized ligand. The preparation method of the invention directly prepares the reducing agent by reacting the functional ligand with the reductive micromolecule, and has the advantages of simple preparation steps, environment-friendly and nontoxic reagent, stable product, good water dispersibility and high surface functionalization efficiency.
Description
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to a preparation method of gold nanoparticles modified by functional ligands.
Background
The nano-scale gold shows unique physical and chemical properties, such as surface plasmon resonance absorption (SPR), Raman Scattering (RS) and the like, and is widely applied to the field of medical biology, mainly comprising biosensing, imaging, thermal treatment, targeted drug delivery and the like. In order to ensure the stability, biocompatibility, cell target recognition, endocytosis efficiency and drug loading rate, various ligands such as hyaluronic acid, chitosan, dextran, polyethylene glycol, cyclodextrin and the like are commonly used on the surface of the gold nanoparticleAnd (5) functionalizing the noodles. The traditional gold nanoparticle preparation mostly uses small molecules with reduction function such as sodium citrate, sodium borohydride, ascorbic acid, sodium thiocyanate or potassium thiocyanate and the like to reduce chloroauric acid (HAuCl)4) So as to form a colloidal gold nano-composite, and the surface functionalized ligand modification of the nano-particles is carried out through a ligand exchange mode after centrifugal enrichment. However, these traditional functional ligand modification methods have the following disadvantages: 1. the preparation method has complicated steps; 2. residual small molecule reducing agents are biologically toxic; 3. after the nanoparticles are enriched in a centrifugal mode, the nanoparticles are easy to aggregate and not easy to redisperse; 4. the low efficiency of ligand exchange results in a low number of surface-attached ligands.
Disclosure of Invention
The invention aims to provide an economical, safe, reliable and effective preparation method of gold nanoparticles directly modified by taking a functionalized ligand as a reducing agent and a stabilizing agent, aiming at the defects of low efficiency, poor safety, high synthesis cost, difficulty in realizing large-scale preparation and production and the like of the existing ligand exchange method for modifying the gold nanoparticles.
The purpose of the invention is realized by the following technical scheme:
a preparation method of gold nanoparticles modified by functionalized ligands comprises the steps of reacting functionalized ligands with reductive micromolecules, introducing reductive sulfydryl groups to obtain the reductive functionalized ligands with the sulfydryl groups, and finally reacting the functionalized ligands with the sulfydryl groups with chloroauric acid to obtain the gold nanoparticles modified by the functionalized ligands.
Further, the functional ligand and the reducing small molecule are introduced into a reducing sulfhydryl group through dehydration condensation reaction or esterification reaction.
Further, the functionalized ligand is a functionalized ligand with a carboxyl group or a functionalized ligand with a hydroxyl group.
Further, the functionalized ligand with carboxyl groups is hyaluronic acid; the functional ligand with hydroxyl groups is one of chitosan, polyethylene glycol, dextran and poly-beta-cyclodextrin.
Further, the reducing small molecule is a reducing small molecule with an amino group or a reducing small molecule with a carboxyl group.
Further, the reductive micromolecule with amino group is cysteine; the reducing micromolecules with carboxyl groups are one or more of glutathione, lipoic acid and L-cystine.
A method for preparing functionalized ligand modified gold nanoparticles comprises the following steps:
1) adding a carboxyl activating agent into a functional ligand with a carboxyl group or an aqueous solution of a reductive micromolecule with the carboxyl group, adjusting the pH value, and reacting for a period of time to activate the carboxyl group;
2) respectively adding the activated functional ligand with carboxyl groups or the activated reductive micromolecules with carboxyl groups into the reductive micromolecules with amino groups or the functional ligands with hydroxyl groups, adjusting the pH of the mixed solution, and reacting for a period of time to obtain the functional ligand with sulfhydryl groups;
3) and mixing and dissolving the functionalized ligand with the mercapto group and chloroauric acid, heating to boiling, and reacting for a period of time to obtain the gold nanoparticle modified by the functionalized ligand.
In the preparation process of the functionalized ligand modified gold nanoparticle, reductive micromolecules with different groups are adopted according to different types of groups carried by the functionalized ligand, and the reaction is different. When the functionalized ligand is a functionalized ligand with a carboxyl group, the functionalized ligand with the carboxyl group is subjected to carboxyl activation, then a reductive micromolecule with an amino group is added, and the amino group and the carboxyl group of the functionalized ligand are subjected to dehydration condensation reaction to generate the functionalized ligand with a sulfhydryl group; when the functional ligand is provided with a hydroxyl group, adding the activated reductive micromolecules with a carboxyl group, and carrying out esterification reaction on the carboxyl group of the reductive micromolecules and the hydroxyl group of the functional ligand to generate the functional ligand with a sulfhydryl group.
Further, in the step 1), the carboxyl activating agent is one or more of EDC-1-ethyl-3- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDC) and N-hydroxysuccinimide (NHS); adjusting the pH value to 4.0-6.0 by using dilute hydrochloric acid, and reacting for more than 15min to activate carboxyl.
Further, in the step 2), after the pH value of the mixed solution is adjusted to 4.0-6.0, the reaction is carried out for more than 12 hours to obtain the functionalized ligand with the mercapto group.
Further, in the step 3), the functionalized ligand with the mercapto group is mixed with chloroauric acid for dissolving, and the mixture is heated to boiling at the temperature of 80-1000 ℃ for reaction for 30-300s to obtain the gold nanoparticles modified by the functionalized ligand.
Compared with the prior art, the invention has the following beneficial effects:
compared with the traditional ligand exchange method for preparing the surface functionalized gold nanoparticles, the preparation method disclosed by the invention has the advantages that the functionalized ligand is firstly reacted with the reductive micromolecules to directly prepare the reducing agent, and the traditional method of taking the micromolecules as the reducing agent and then carrying out ligand exchange is replaced. The method has the characteristics of simple preparation steps, environment-friendly and nontoxic preparation reagents, stable prepared products, good water dispersibility and high surface functionalization efficiency. The preparation method of the invention reduces the synthesis cost and improves the safety, and is easy to realize large-scale preparation and production.
Drawings
FIG. 1 is a transmission electron microscope image of gold nanoparticles (HA/AuNP) prepared by ligand exchange of nano-reduced hyaluronic acid citrate in comparative example 1;
FIG. 2 is a transmission electron micrograph of gold nanoparticles (HA-SH @ AuNP) prepared from thiolated hyaluronic acid of example 1;
FIG. 3 is a comparison of the inflammatory response of gold nanoparticles prepared by the ligand exchange of sodium citrate reduced hyaluronic acid (HA/AuNP) of comparative example 1 and gold nanoparticles prepared by the thiolated hyaluronic acid (HA-SH @ AuNP) of example 1 to inhibit LPS-induced macrophage cell line (RAW264.7) in mice.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
1. Hyaluronic acid modification with different sulfydryl grafting rates
Hyaluronic Acid (HA), EDC-1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) are sequentially added into water, magnetic stirring is assisted, and the next raw material is added after the previous raw materials are completely dissolved. After all the raw materials are completely dissolved, dilute hydrochloric acid is added to adjust the pH of the mixed solution to 4.5, and the reaction is carried out for 30 minutes to activate carboxyl. Cysteine (C) was added after the activation3H7NO2S), and the pH of the mixed solution was adjusted to 4.5, followed by reaction for 14 hours. The resulting solution was transferred to a dialysis bag and dialyzed in deionized water for 48 hours (Mr. 1000 to 5000, pH 4.5). After dialysis, the samples were freeze-dried for use. Modified hyaluronic acid with different mercapto grafting rates is obtained by regulating and controlling the molar ratio of the raw materials, and the grafting rates of the products obtained by different feeding ratios are shown in table 1.
TABLE 1 HA/C in different ratios3H7NO2Grafting ratio of hyaluronic acid obtained from S/EDC/NHS
| HA(mg) | C3H7NO2S(mg) | EDC(mg) | NHS(mg) | Graft ratio of mercapto group |
| 300 | 600 | 1000 | 350 | 3％-5％ |
| 300 | 600 | 100 | 35 | 9％-14％ |
| 300 | 600 | 2000 | 700 | 20％-23％ |
| 300 | 600 | 5000 | 3500 | 35％-40％ |
2. Preparation of hyaluronic acid functionalized gold nanoparticles
Mixing and dissolving the modified sulfhydryl hyaluronic acid (HA-SH) and chloroauric acid (HAuCl4) in deionized water, and heating to boil. The solution changes from colorless to wine red within 90s, and after the solution color is stabilized at wine red, the boiling reaction is continued for 2 minutes. Stopping heating, and cooling the solution to room temperature to obtain the gold nanoparticle dispersion liquid wrapped by hyaluronic acid with different mercapto grafting rates. Hyaluronic acid functionalized gold nanoparticles (HA-SH @ AuNP) with different particle sizes are obtained by regulating the feed ratio of mercaptohyaluronic acid and chloroauric acid, and are shown in Table 2.
TABLE 2 particle size and potential of HA-SH @ AuNP from 9% -14% HA-SH/HAuCl4 in different proportions
Comparative example 1
The following detailed procedure of the prior art nano-gold particles (HA/AuNP) prepared by the sodium citrate reduction hyaluronic acid ligand exchange method was supplemented as a comparative example.
Ligand exchange method: taking 5mg of HAuCl4Dissolving the sodium citrate in 50mL of deionized water, transferring the solution into a round-bottom flask, adding a condensing reflux device, heating the solution to boiling by using a heating sleeve, then dropwise adding 0.5mL of 10mg/mL sodium citrate solution, continuously heating until the solution turns into wine red, and continuously heating and keeping boiling for 2min to finish the reaction to obtain 30-40 nm AuNPs with the surface of sodium citrate. And centrifuging the solution at the rotating speed of 12000rpm (rounds per minute) for 15min, repeating the centrifuging for three times, removing the supernatant, adding 50mL of deionized water for redispersion, immediately adding 500mg of HA-SH (9 percent of grafting rate) after the redispersion, and continuously stirring for 24h at the rotating speed of 500rpm by using a mechanical stirrer to obtain the ligand-exchanged HA/AuNP.
FIG. 1 is a transmission electron microscope image of gold nanoparticles (HA/AuNP) prepared by ligand exchange of nano-reduced hyaluronic acid citrate in comparative example 1; FIG. 2 is a transmission electron micrograph of gold nanoparticles (HA-SH @ AuNP) prepared from thiolated hyaluronic acid of example 1. When hyaluronic acid and chloroauric acid with the same content are added, the hyaluronic acid functionalized gold nanoparticles obtained in example 1 have more hyaluronic acid content coated on the surface compared with the hyaluronic acid functionalized gold nanoparticles obtained in the conventional ligand exchange method in comparative example 1.
FIG. 3 is a comparison of the inflammatory response of gold nanoparticles prepared by the ligand exchange of sodium citrate reduced hyaluronic acid (HA/AuNP) of comparative example 1 and gold nanoparticles prepared by the thiolated hyaluronic acid (HA-SH @ AuNP) of example 1 to inhibit LPS-induced macrophage cell line (RAW264.7) in mice. As can be seen from FIG. 3, the effect of the gold nanoparticles (HA-SH @ AuNP) prepared in example 1 on inhibiting inflammatory reaction is more obvious.
Example 2
1. Chitosan modification with different sulfydryl grafting rates
Glutathione (C)10H17N3O6S), EDC-1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) are sequentially added into water, magnetic stirring is assisted, and the next raw material is added after the previously added raw materials are completely dissolved. After all the raw materials are completely dissolved, dilute hydrochloric acid is added to adjust the pH of the mixed solution to 5.0, and the reaction is carried out for 40 minutes to activate carboxyl. After the activation, analytically pure Chitosan (Chitosan) with the molecular weight of 5000-50000 was added, and after the pH of the mixed solution was adjusted to 5.0, the reaction was carried out for 20 hours. Transferring the obtained solution into a dialysis bag, and dialyzing in deionized water for 48-72 hours (Mr is 1000-5000, pH 5.0). After dialysis, the samples were freeze-dried for use. Modified chitosan with different mercapto grafting rates is obtained by regulating and controlling the molar ratio of the raw materials, and the grafting rates of the products obtained by different feeding ratios are shown in table 3.
TABLE 3 different proportions of Chitosan/C10H17N3O6Grafting ratio of hyaluronic acid obtained from S/EDC/NHS
| Chitosan(mg) | C10H17N3O6S(mg) | EDC(mg) | NHS(mg) | Graft ratio of mercapto group |
| 160 | 1500 | 1000 | 350 | 3％-5％ |
| 160 | 1500 | 100 | 35 | 9％-14％ |
| 160 | 1500 | 2000 | 700 | 20％-23％ |
| 160 | 1500 | 5000 | 3500 | 35％-40％ |
2. Preparation of chitosan functionalized gold nanoparticles
Mixing and dissolving the modified sulfhydryl Chitosan (Chitosan-SH) and chloroauric acid (HAuCl4) in deionized water, and heating to boil. The solution changes from colorless to wine red within 10min, and boiling reaction is continued for 2min after the solution color is stabilized at wine red. Stopping heating, and cooling the solution to room temperature to obtain the gold nanoparticle dispersion liquid wrapped by chitosan with different sulfydryl grafting rates. Chitosan-SH @ Au nanoparticles with different particle sizes are obtained by regulating the feed ratio of sulfhydryl Chitosan to chloroauric acid, and are shown in Table 4.
TABLE 4 different proportions of 3% -5% Chitosan-SH/HAuCl4Particle size and potential of obtained Chitosan-SH @ Au
Example 3
1. Glucan modification with different sulfhydryl grafting rates
Lipoic acid (C)8H14O2S2) EDC-1-ethyl-3- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDC) and N-hydroxysuccinimide (NHS) are sequentially added into water, and magnetic stirring is assisted to ensure that the previously added raw materials are completely dissolved and then the next raw material is added. After all the raw materials are completely dissolved, dilute hydrochloric acid is added to adjust the pH of the mixed solution to 3.5, and the reaction is carried out for 50 minutes to activate carboxyl. Adding Dextran (Dextran) with molecular weight of 5000-4) The disulfide bond of lipoic acid is broken to form two sulfydryl groups, and the obtained solution is transferred into a dialysis bag and dialyzed in deionized water for 72 hours (Mr is 1000-5000, pH 3.5). After dialysis, the samples were freeze-dried for use. Modified glucan with different sulfydryl grafting rates is obtained by regulating and controlling the feeding molar ratio of raw materials, and the grafting rates of products obtained by different feeding ratios are shown in table 5.
TABLE 5 Dextran/C in different ratios8H14O2S2Grafting ratio of hyaluronic acid/EDC/NHS
| Dextran(mg) | C8H14O2S2(mg) | EDC(mg) | NHS(mg) | Graft ratio of mercapto group |
| 160 | 1000 | 1000 | 350 | 8％-10％ |
| 160 | 1000 | 100 | 35 | 15％-18％ |
| 160 | 1000 | 2000 | 700 | 22％-25％ |
| 160 | 1000 | 5000 | 3500 | 30％-35％ |
2. Preparation of dextran functionalized gold nanoparticles
Mixing the modified mercaptodextran (Dextran-SH) and chloroauric acid (HAuCl4) in deionized water, and heating to boil. The solution changes from colorless to wine red within 15min, and boiling reaction is continued for 2min after the solution color is stabilized at wine red. Stopping heating, and cooling the solution to room temperature to obtain gold nanoparticle dispersion liquid coated by glucan with different sulfydryl grafting rates. Dextran functionalized gold nanoparticles (Dextran-SH @ Au) with different particle sizes are obtained by regulating the feed ratio of mercaptodextran to chloroauric acid, and are shown in Table 6.
TABLE 6 different proportions of 22% -25% Dextran-SH/HAuCl4The particle size and potential of the obtained Dextran-SH @ Au
Example 4
1. Modification of poly-beta-cyclodextrin with different mercapto grafting rate
Adding L-cystine (C)6H12N2O4S2) EDC-1-ethyl-3- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDC) and N-hydroxysuccinimide (NHS) are sequentially added into water, and magnetic stirring is assisted to ensure that the previously added raw materials are completely dissolved and then the next raw material is added. After all the raw materials are completely dissolved, dilute hydrochloric acid is added to adjust the pH value of the mixed solution to 5.8, and the reaction is carried out for 40 minutes. Adding Poly-beta-cyclodextrin (Poly-beta-cyclodextrin) with molecular weight of 3000-20000 for analytical purification after activation, using concentrated sulfuric acid as catalyst and water absorbent, adjusting pH of the mixed solution to 5.8, heating in oil bath to 60-80 deg.C for reflux reaction for more than 10 hours, and adding 1mg of sodium borohydride (NaBH)4) The disulfide bond of L-cystine is broken to form two sulfydryl groups, the obtained solution is transferred into a dialysis bag and dialyzed in an aqueous solution for 72 hours (Mr is 1000-5000, pH 5.8). After dialysis, the samples were freeze-dried for use. Modified poly-beta-cyclodextrin with different mercapto grafting rates is obtained by regulating and controlling the molar ratio of the raw materials, and the grafting rates of the products obtained by different feeding ratios are shown in table 7.
TABLE 7 different ratios Poly-beta-cyclodextrin/C6H12N2O4S2Grafting ratio of hyaluronic acid/EDC/NHS
2. Preparation of poly-beta-cyclodextrin functionalized gold nanoparticles
Mixing and dissolving the sulfhydrylation Poly-beta-cyclodextrin (Poly-beta-cyclodextrin-COOH) and chloroauric acid (HAuCl4) modified in the steps in deionized water, and heating to boil. The solution changes from colorless to wine red within 5min, and boiling reaction is continued for 2min after the solution color is stabilized at wine red. Stopping heating, and cooling the solution to room temperature to obtain the gold nanoparticle dispersion liquid wrapped by different sulfhydrylation poly-beta-cyclodextrin. Cyclodextrin functionalized gold nanoparticles (Poly-beta-cyclodextrin-SH @ Au) with different particle sizes are obtained by regulating the feed ratio of thiolated Poly-beta-cyclodextrin and chloroauric acid, and are shown in Table 8.
TABLE 8 different proportions of 6% -9% Poly-beta-cyclodextrin-SH/HAuCl4The particle size and potential of the obtained Poly-beta-cyclodextrin-SH @ Au
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (7)
1. A preparation method of gold nanoparticles modified by functionalized ligands is characterized in that the method comprises the steps of introducing a functionalized ligand and a reductive micromolecule into a reductive sulfydryl group through amidation reaction or esterification reaction, further obtaining the functionalized ligand with the reductive sulfydryl group, and finally reacting the functionalized ligand with the sulfydryl group with chloroauric acid to obtain the gold nanoparticles modified by the functionalized ligand;
the functionalized ligand is a functionalized ligand with carboxyl groups or a functionalized ligand with hydroxyl groups;
the reducing small molecule is a reducing small molecule with an amino group or a reducing small molecule with a carboxyl group.
2. The method for preparing functionalized ligand-modified gold nanoparticles according to claim 1, wherein the functionalized ligand with carboxyl groups is hyaluronic acid; the functional ligand with hydroxyl groups is one of chitosan, polyethylene glycol, dextran and poly-beta-cyclodextrin.
3. The method for preparing functionalized ligand modified gold nanoparticles according to claim 2, wherein the reductive small molecule with amino group is cysteine; the reducing micromolecules with carboxyl groups are one or more of lipoic acid and L-cystine.
4. A preparation method of functionalized ligand modified gold nanoparticles is characterized by comprising the following steps:
1) adding a carboxyl activating agent into a functional ligand with a carboxyl group or an aqueous solution of a reductive micromolecule with the carboxyl group, adjusting the pH value, and reacting for a period of time to activate the carboxyl group;
2) adding a reductive micromolecule with an amino group into the activated functional ligand with a carboxyl group, or adding a functional ligand with a hydroxyl group into the activated reductive micromolecule with the carboxyl group, adjusting the pH of the mixed solution, and reacting for a period of time to obtain a functional ligand with a sulfhydryl group;
3) and mixing and dissolving the functionalized ligand with the mercapto group and chloroauric acid, heating to boiling, and reacting for a period of time to obtain the gold nanoparticle modified by the functionalized ligand.
5. The method for preparing functionalized ligand modified gold nanoparticles according to claim 4, wherein in the step 1), the carboxyl activating agent is one or more of EDC-1-ethyl-3- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDC) and N-hydroxysuccinimide (NHS); adjusting the pH value to 4.0-6.0 by using dilute hydrochloric acid, and reacting for more than 15min to activate carboxyl.
6. The method for preparing gold nanoparticles modified by the functionalized ligand according to claim 4, wherein in the step 2), the pH of the mixed solution is adjusted to 4.0-6.0, and then the reaction is carried out for more than 12 hours to obtain the functionalized ligand with the mercapto group.
7. The method for preparing gold nanoparticles modified by the functionalized ligand according to claim 4, wherein in the step 3), the functionalized ligand with the mercapto group is mixed with chloroauric acid for dissolution, and the mixture is heated to boiling for reaction for 30-300s to obtain the gold nanoparticles modified by the functionalized ligand.
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| CN109986090A (en) * | 2019-03-22 | 2019-07-09 | 华南理工大学 | A kind of double ligand gold nanoparticle aqueous solutions and its preparation method and application |
| CN110669506A (en) * | 2019-09-25 | 2020-01-10 | 福建医科大学 | Preparation method of water-soluble gold nanocluster fluorescent material jointly protected by cysteamine and N-acetyl L-cysteine |
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