CN110354072B - Preparation and application of near-infrared light-responsive graphene oxide/attapulgite composite supramolecular hydrogel - Google Patents
Preparation and application of near-infrared light-responsive graphene oxide/attapulgite composite supramolecular hydrogel Download PDFInfo
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Abstract
The invention discloses a preparation method of a near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel, which comprises the steps of preparing a graphene oxide/attapulgite composite nano material, modifying a camptothecin nano prodrug modified by polyethylene glycol to the surface of the graphene oxide/attapulgite composite nano material through intermolecular interaction, introducing alpha-cyclodextrin, and self-assembling and crosslinking to form the supramolecular hydrogel by utilizing host-guest recognition effect of alpha-CD and PEG chains. The supramolecular hydrogel has injectability and near-infrared light sensitive gel-sol conversion behaviors, and has application value in the field of antitumor drug release. In addition, the supermolecule hydrogel can further wrap water-soluble anticancer drugs while being formed, so that the aim of drug combination is fulfilled.
Description
Technical Field
The invention relates to a preparation method of a supramolecular hydrogel, in particular to a preparation method of a near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel, which can be used as an anti-tumor drug slow-release carrier to be applied to a drug delivery system, and belongs to the technical field of composite materials and the field of biological medicines.
Background
Attapulgite is a natural one-dimensional nanometer material mineral, and has a special rigid rod-like crystal structure. The attapulgite has excellent performances of adsorptivity, rheological property, filling property, antibacterial property and the like, so that the attapulgite has great research value and development potential in the field of polymer composite materials. At present, the attapulgite is widely applied in the fields of rubber, plastics, paint, water-absorbent resin and the like and shows good effect. In addition, the attapulgite has excellent biocompatibility and can be used as a food additive, but the basic and application research of the attapulgite in the aspect of biomedical composite materials is less concerned. When alpha-cyclodextrin (alpha-CD) is mixed with a certain concentration of high molecular weight polyethylene glycol (PEG), supramolecular hydrogel can be formed due to strong hydrogen bonding between pseudopolyrotaxane (PPR) formed by partial inclusion of alpha-CD and PEG. The supramolecular hydrogel has reversible shear thinning property, and simultaneously, PEG and alpha-CD both have excellent biocompatibility, so the supramolecular hydrogel can be used as an injectable gel and has very good application prospect in a drug delivery system. The surface of the attapulgite shows electronegativity due to a large amount of hydroxyl, which is very beneficial to the modification of PEG, after the alpha-CD is introduced, the rod-shaped and rigid structure which is the characteristic of the attapulgite can effectively induce the directional aggregation between the adjacent PPRs, so that the inner part of the supermolecular hydrogel forms a regular porous structure, and the mechanical strength of the hydrogel can be greatly improved. (Koyangshan et al, Polymer-inorganic nanocomposite, Beijing: chemical Industrial Press, 2002, 21-22; J. Li, et al,Polym. J., 1994, 26, 1019-1026; J. Li, NPG Asia Mater., 2010, 2, 112-118）。
the PPR hydrogel has unique temperature-sensitive gel-sol transition behavior, alpha-CD on a PEG chain can slide off the chain after the temperature is increased, so that the collapse of the supermolecule hydrogel is triggered and the supermolecule hydrogel is converted into sol, and the unique property can be used for designing a temperature-sensitive controlled-release drug carrier. However, as an injectable hydrogel, it is a great challenge how to effectively control the temperature at the local injection site. The graphene oxide has excellent biocompatibility and near-infrared photosensitive highlight-heat conversion performance, and the local temperature of the part containing the graphene oxide can be effectively increased under the irradiation of near-infrared light. In addition, near-infrared light has a strong tissue penetration ability and little damage to normal tissues, and is widely applied in the field of photothermal therapy in recent years. Therefore, the graphene oxide/attapulgite composite material is constructed and further applied to preparation of the composite PPR supermolecule hydrogel, so that the near-infrared light-sensitive gel-sol conversion performance is endowed on the basis of effectively improving the mechanical strength of the PPR supermolecule hydrogel, and the graphene oxide/attapulgite composite material has a wide application prospect in the field of light-controlled injectable antitumor drug delivery.
Disclosure of Invention
The invention aims to provide a preparation method of a near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel;
the invention also aims to provide the application of the supramolecular hydrogel as a slow-release carrier of the anticancer drug.
Preparation of graphene oxide/attapulgite composite supramolecular hydrogel
The invention relates to a preparation method of near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel, which comprises the following steps:
(1) preparation of the chitosan modified attapulgite: dispersing attapulgite into water to obtain attapulgite water dispersion, adding diluted solution of carboxymethyl chitosan, magnetically stirring at room temperature for 12-36 h, centrifuging, and washing to remove unadsorbed chitosan to obtain chitosan-modified attapulgite.
The diameter of the attapulgite is 20-70 nm; in the attapulgite water dispersion liquid, the concentration of attapulgite is 0.02-0.2 wt%; the deacetylation degree of the carboxymethyl chitosan is 80-95%, and the substitution degree of the carboxymethyl is 60-90%; in the dispersion, the concentration of the carboxymethyl chitosan is 0.05-0.5%.
(2) Preparing a graphene oxide/attapulgite composite nano material: and (2) dispersing graphene oxide in water to prepare a graphene oxide aqueous dispersion, adding the chitosan modified attapulgite prepared in the step (1), magnetically stirring at room temperature for 8-24 h, centrifuging, and washing to remove unadsorbed graphene oxide, thus obtaining the graphene oxide/attapulgite composite nanomaterial.
In the aqueous dispersion, the concentration of the graphene oxide is 0.04-0.4 wt%, and the concentration of the chitosan-modified attapulgite is 0.02-0.2 wt% (by the concentration of the attapulgite).
(3) Preparing a PEG modified graphene oxide/attapulgite composite nano material: and (3) dispersing the graphene oxide/attapulgite composite nano material prepared in the step (2) into water, adding the PEG modified camptothecin nano prodrug, magnetically stirring at room temperature for 8-24 h, centrifuging, and washing to remove the unadsorbed PEG modified camptothecin nano prodrug, so as to obtain the PEG modified graphene oxide/attapulgite composite nano material.
The concentration of the graphene oxide/attapulgite composite nano material is 0.02-0.2 wt%.
In the PEG-modified camptothecin nano prodrug, the connection mode between PEG and camptothecin is disulfide bond, and the synthesis of the PEG-camptothecin nano prodrug connected by the disulfide bond is described in literature methods (w. Ha, et al,ACS Appl. Mater. Interfaces2018, 10, 21149-21159.). The structural formula is as follows:
the molecular weight of mPEG is 500-10000 (corresponding to n = 10-225).
The connection mode between PEG and camptothecin is ester bond, and the synthesis of the nano prodrug with PEG and camptothecin connected by ester bond is described in literature methods (w.J. Mater. Chem. B, 2013, 1, 5532-5538). The structural formula is as follows:
the molecular weight of PEG is 500-10000 (corresponding to n = 10-225).
The concentration of the PEG modified camptothecin nano prodrug is 0.2-2 wt%, preferably 0.5-1.5 wt%.
(4) Preparing the graphene oxide/attapulgite composite supramolecular hydrogel: dispersing the PEG modified graphene oxide/attapulgite composite nano material in water to form a water dispersion, adding alpha-CD, performing ultrasonic dispersion for 5-10 min, standing for 48-72 h, and performing self-assembly crosslinking through the host-guest action of the alpha-CD and a PEG chain to form the supermolecule hydrogel.
In the aqueous dispersion, the concentration of the PEG modified graphene oxide/attapulgite composite nano material is 0.1-0.6 wt% (preferably 0.05-0.15 wt%), and the concentration of alpha-CD is 5-16 wt% (preferably 8-12 wt%).
Characterization of graphene oxide/attapulgite composite supramolecular hydrogel
Respectively taking 4mL of attapulgite, chitosan-modified attapulgite and graphene oxide/attapulgite composite Nano-material, wherein the concentration of the attapulgite, the chitosan-modified attapulgite and the graphene oxide/attapulgite composite Nano-material is 0.4 mg/mL, and testing the Zeta potential value of the solution by using a laser dynamic light scattering instrument (Zetasizer Nano 3600, UK). FIG. 1 is Zeta potential diagram of attapulgite, chitosan modified attapulgite and graphene oxide/attapulgite. FIG. 1 shows that the attapulgite has a potential value of-33.3 mV, which indicates that the surface of the attapulgite has strong electronegativity and can be further modified by electrostatic adsorption. After the attapulgite is modified by the carboxymethyl chitosan, the surface potential value of the attapulgite is changed to 4.48 mV, which shows that a large number of chitosan chains are successfully modified on the surface of the attapulgite, and a large number of amino groups on the chitosan chains ensure that the surface of the attapulgite is electropositive. After the graphene oxide is further modified, the surface potential value of the graphene oxide/attapulgite composite nano material is changed to-31.4 mV, which shows that a large amount of graphene oxide is successfully modified on the surface of attapulgite through electrostatic interaction, and a large amount of carboxyl and hydroxyl in the graphene oxide lamellar structure enable the surface of the material to present electronegativity. The information shows that the graphene oxide/attapulgite composite nano material is successfully prepared.
And further preparing 0.1 mg/mL graphene oxide/attapulgite composite nano material, and inspecting the morphology of the material by using a transmission electron microscope (FEITecnai, G2 TF20, USA). FIG. 2 is a transmission electron microscope image of graphene oxide/attapulgite. As can be seen from FIG. 2, a large amount of attapulgite is wrapped in the graphene oxide sheets, further illustrating the successful preparation of the graphene oxide/attapulgite composite nano material.
The PEG modified graphene oxide/attapulgite composite material can greatly improve the water solubility of attapulgite, can form a uniform aqueous solution in water, and can be converted into supramolecular hydrogel under an ultrasonic condition after alpha-CD is introduced. The forming speed and the strength of the gel depend on the concentration and the proportion of the PEG modified attapulgite and the alpha-CD. When the concentration of the PEG modified graphene oxide/attapulgite composite nano material is 0.4wt%, the PEG modified graphene oxide/attapulgite composite supramolecular hydrogel can be formed when the concentration of alpha-CD is 5wt% -12wt% (see figure 3).
Performance of graphene oxide/attapulgite composite supermolecule hydrogel
1. Rheological Properties
The rheological properties of the supramolecular hydrogels formed were measured using a rotational rheometer (HAAKE RS 6000), test conditions: 35 mm parallel disks, the test temperature is 20 ℃, the disk spacing is 1 mm, and the oscillation stress is 1 Pa; the gel was allowed to stand at room temperature for 72h before testing. As shown in fig. 4a, the storage modulus (G') of 4wt% PEG-modified graphene oxide attapulgite composite/10 wt% α -CD supramolecular hydrogel sample is much greater than its loss modulus (G ") throughout the measurement range, indicating that supramolecular hydrogel is formed and has a permanent crosslinked network. Compared with the traditional PPR supermolecule hydrogel, the storage modulus of the attapulgite hydrogel is improved by more than 60 times, which shows that the mechanical strength of the attapulgite hydrogel can be obviously improved by introducing the attapulgite composite material into the PPR supermolecule hydrogel. In addition, G' and G "vary little with angular frequency, indicating that the gel has the typical characteristics of a highly non-covalently crosslinked supramolecular hydrogel. As shown in fig. 4b, the supramolecular hydrogel also shows the typical shear-thinning properties of injectable hydrogels.
2. Near infrared light sensitive gel-sol transition behavior
A total of 1 mL of the mixed solution (4 wt% PEG-modified attapulgite composite/10 wt% alpha-CD) was injected into a 4mL glass vial, sonicated to form a gel, and allowed to stand for 72 h. The hydrogel in the vial was irradiated with a laser light source (808 nm), the temperature change of the irradiated site over time was recorded with a thermal imager, and the sol-gel transition behavior of the gel was recorded with a camera. Fig. 5 shows the temperature and the form change of the graphene oxide/attapulgite composite supramolecular hydrogel under near-infrared irradiation. The result shows that the temperature of the irradiated part in the gel gradually increases along with the increase of the irradiation time, and the temperature is increased from 30 ℃ to 53 ℃ within 20min, and the appearance of the gel-sol transition is obvious. This unique property is very advantageous for the controlled release of the loaded drug to be regulated by near infrared light.
3. Supramolecular hydrogel in vitro release capacity
The hydrogel has a highly hydrophilic internal structure, and can be further loaded with another anti-tumor drug, taking 5-fluorouracil as an example, 0.1-1% of 5-fluorouracil and PEG-modified graphene oxide/attapulgite composite material are jointly dissolved in water, 10wt% of alpha-CD is added, and the camptothecin and 5-fluorouracil loaded double-drug supramolecular hydrogel can be obtained under the ultrasonic condition. Subsequently, 5 mL of phosphate buffer (PBS, pH 7.4) was added as a release medium, and 0.2 mL of the supernatant was removed from the tube at a predetermined time point, followed by addition of 0.2 mL of fresh PBS to maintain the volume at 5 mL. For the release behavior after irradiation with near infrared light, the same hydrogel sample was irradiated with a laser light source (808 nm), and the release sample was collected by the same method. And (3) detecting the release behaviors of the camptothecin nano prodrug and the 5-fluorouracil by using HPLC.
Fig. 6 shows the in vitro drug release behavior of the camptothecin and 5-fluorouracil loaded double-drug loaded supramolecular hydrogel before and after near-infrared light irradiation. The result shows that the gel has good slow release effect on the 5-fluorouracil and camptothecin prodrug before near infrared irradiation, and only a small amount of drug is released from the gel. After near-infrared irradiation, the release of the 5-fluorouracil and camptothecin prodrug is remarkably accelerated, mainly because the temperature in the gel rises after the near-infrared irradiation, so that the gel generates gel-sol transition behavior, and the release of the drug is accelerated.
After the gel is injected to the tumor side or in the tumor, the gel generates gel-sol conversion under the irradiation of near infrared light, the loaded antitumor drug can be quickly released from the gel to the tumor side or in the tumor through the embedding effect, and the simultaneously released camptothecin nano prodrug can also release the camptothecin drug under the action of high-concentration glutathione or intratumoral esterase of tumor cells, thereby achieving the purpose of drug combination.
In conclusion, the graphene oxide/attapulgite composite nanomaterial is prepared, the polyethylene glycol (PEG) -modified camptothecin nano prodrug is modified on the surface of the graphene oxide/attapulgite composite nanomaterial through intermolecular interaction, then alpha-cyclodextrin (alpha-CD) is introduced, and self-assembly crosslinking is performed by utilizing host-guest recognition effects of the alpha-CD and a PEG chain to form the supramolecular hydrogel. According to the invention, by utilizing the easily-modified and special rod-shaped rigid structure of attapulgite and the excellent near infrared light-heat conversion performance of graphene oxide, the mechanical strength of the traditional PPR supermolecule hydrogel is effectively improved, and the material is endowed with excellent near infrared light-sensitive gel-conversion performance. And the supermolecule hydrogel has excellent biocompatibility and injectability, and can be used as a drug carrier to have a very good application prospect in a drug delivery system.
Drawings
FIG. 1 is Zeta potential diagram of attapulgite, chitosan modified attapulgite and graphene oxide/attapulgite.
FIG. 2 is a transmission electron microscope image of graphene oxide/attapulgite.
FIG. 3 is a diagram of the formation of composite supramolecular hydrogel and the formation of gel loaded with 5-fluorouracil when the concentration of the PEG modified graphene oxide/attapulgite is 0.4wt% and the concentration of alpha-CD is 5wt% -12 wt%.
FIG. 4 is a rheological dynamics test diagram of 4wt% PEG modified attapulgite composite material/10 wt% alpha-CD supramolecular hydrogel.
FIG. 5 is a diagram showing the near-infrared light-sensitive temperature change and gel-sol transition behavior of 4wt% PEG-modified attapulgite composite material/10 wt% alpha-CD supramolecular hydrogel.
FIG. 6 is a graph showing the release behavior of a 4wt% PEG-modified attapulgite composite material/10 wt% alpha-CD/0.5 wt% 5-fluorouracil supramolecular hydrogel near-infrared photosensitive drug.
Detailed Description
The preparation and application of the graphene oxide/attapulgite composite supramolecular hydrogel are further described by the following specific examples.
Example one
(1) Preparing the chitosan modified attapulgite: dispersing 50 mg of attapulgite into 50 mL of water, dropwise adding 50 mL of 0.1wt% carboxymethyl chitosan solution, magnetically stirring at room temperature for 24 h, centrifuging, washing to remove unadsorbed chitosan, and thus obtaining chitosan-modified attapulgite; (2) preparing a graphene oxide/attapulgite composite nano material: dispersing 4mg of graphene oxide into 4mL of water, dropwise adding 4mL of chitosan modified attapulgite solution (1 mg/mL), magnetically stirring at room temperature for 10 hours, centrifuging, and washing to remove unadsorbed graphene oxide, thereby obtaining the graphene oxide/attapulgite composite nano material;
(3) preparing the polyethylene glycol modified graphene oxide/attapulgite composite nano material: dispersing 4mg of graphene oxide/attapulgite composite nano material into 4mL of water, and adding 20mg of PEG connected by disulfide bonds2000(average molecular weight is 2000) modified camptothecin nano prodrug (PEG-S-S-CPT), magnetically stirring for 12 h at room temperature, centrifuging, washing to remove unadsorbed PEG modified camptothecin nano prodrug, and obtaining the PEG modified graphene oxide/attapulgite composite nano material;
(4) preparing near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel: alpha-CD (100 mg) was added to 1 mL PEG2000In the modified graphene oxide/attapulgite composite nano material dispersion liquid (0.4 wt%), performing ultrasonic dispersion for 10 min, standing for 72h, and performing self-assembly crosslinking through the host-guest action of alpha-CD and a PEG chain to form supramolecular hydrogel;
(5) preparing the near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel loaded with 5-fluorouracil and camptothecin: 10 mg 5-Fluorouracil was added to 1 mL PEG2000Modified graphene oxide/attapulgiteAnd (3) performing ultrasonic treatment on the composite nano material dispersion liquid (0.4 wt%) for 10 min, adding alpha-CD (100 mg), performing ultrasonic treatment for 5 min, and standing for 72h to obtain the graphene oxide/attapulgite composite supramolecular hydrogel loaded with 5-fluorouracil and camptothecin.
Example two
(1) (2), (4) and (5) are the same as in example 1;
(3) preparing the polyethylene glycol modified graphene oxide/attapulgite composite nano material: dispersing 4mg of graphene oxide/attapulgite composite nano material into 4mL of water, and adding 20mg of PEG connected by ester bonds2000And (average molecular weight is 2000) modifying the camptothecin nano prodrug (PEG-CPT), magnetically stirring for 24 hours at room temperature, centrifuging, washing and removing the unadsorbed PEG-CPT nano prodrug to obtain the PEG modified graphene oxide/attapulgite composite nano material.
EXAMPLE III
(1) And (2) same as example 1;
(3) preparing the polyethylene glycol modified graphene oxide/attapulgite composite nano material: dispersing 4mg of graphene oxide/attapulgite composite nano material into 4mL of water, and adding 15 mg of PEG connected by ester bonds5000(average molecular weight is 5000) modifying camptothecin nano prodrug (PEG-CPT), magnetically stirring for 24 h at room temperature, centrifuging, washing to remove unadsorbed PEG-CPT nano prodrug, and obtaining the PEG modified graphene oxide/attapulgite composite nano material;
(4) preparing near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel: alpha-CD (100 mg) was added to 1 mL PEG5000Carrying out ultrasonic treatment on the modified graphene oxide/attapulgite composite nano material dispersion liquid for 5 min and then standing for 48 h to obtain composite supramolecular hydrogel;
(5) preparing the 5-fluorouracil and camptothecin loaded near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel: 10 mg 5-Fluorouracil was added to 1 mL PEG5000Adding 0.4wt% of modified graphene oxide/attapulgite composite nano material dispersion liquid into alpha-CD (100 mg) after ultrasonic treatment for 10 min, and standing for 72h after ultrasonic treatment for 5 min to obtain the modified graphene oxide/attapulgite composite nano material dispersion liquid5-fluorouracil and camptothecin loaded graphene oxide/attapulgite composite supramolecular hydrogel.
Example four
(1) The procedures of (2) and (3) are the same as those in example 3;
(4) preparing near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel: alpha-CD (80 mg) was added to 1 mL PEG5000Modifying the graphene oxide/attapulgite composite nano material dispersion liquid (0.4 wt%), ultrasonically dispersing for 10 min, and standing for 72h to obtain the composite supramolecular hydrogel;
(5) preparing the 5-fluorouracil and camptothecin loaded near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel: 5 mg of 5-Fluorouracil was added to 1 mL of PEG5000And (3) adding alpha-CD 80 mg into the modified graphene oxide/attapulgite composite nano-material dispersion liquid (0.4 wt%), performing ultrasonic treatment for 10 min, and standing for 72h after performing ultrasonic treatment for 5 min to obtain the graphene oxide/attapulgite composite supramolecular hydrogel loaded with 5-fluorouracil and camptothecin.
Claims (4)
1. A preparation method of a near-infrared light response graphene oxide/attapulgite composite supramolecular hydrogel comprises the following steps:
(1) preparing the attapulgite modified by the carboxymethyl chitosan: dispersing attapulgite in water to obtain attapulgite water dispersion, adding dilute solution of carboxymethyl chitosan, magnetically stirring at room temperature for 12-36 h, centrifuging, washing to remove unadsorbed carboxymethyl chitosan, and obtaining carboxymethyl chitosan-modified attapulgite; the concentration of the attapulgite water dispersion liquid is 0.02-0.2 wt%, and the concentration of carboxymethyl chitosan in the dispersion liquid is 0.05-0.5 wt%;
(2) preparing a graphene oxide/attapulgite composite nano material: dispersing graphene oxide into water to prepare graphene oxide aqueous dispersion, adding the carboxymethyl chitosan modified attapulgite prepared in the step (1), magnetically stirring at room temperature for 8-24 h, centrifuging, washing to remove unadsorbed graphene oxide, and thus obtaining a graphene oxide/attapulgite composite nano material; in the dispersion liquid, the concentration of the graphene oxide is 0.04-0.4 wt%, and the concentration of the attapulgite modified by the carboxymethyl chitosan is 0.02-0.2 wt%;
(3) preparing a PEG modified graphene oxide/attapulgite composite nano material: dispersing the graphene oxide/attapulgite composite nano material prepared in the step (2) into water, adding the PEG modified camptothecin nano prodrug, magnetically stirring at room temperature for 8-24 h, centrifuging, washing to remove the unadsorbed PEG modified camptothecin nano prodrug, and thus obtaining the PEG modified graphene oxide/attapulgite composite nano material; the concentration of the graphene oxide/attapulgite composite nano material is 0.02-0.2 wt%, and the concentration of the PEG modified camptothecin nano prodrug is 0.2-2 wt%;
the structural formula of the PEG modified camptothecin nano prodrug is as follows:
(4) preparing the graphene oxide/attapulgite composite supramolecular hydrogel: dispersing the PEG modified graphene oxide/attapulgite composite nano material in water to form a water dispersion, adding alpha-CD, performing ultrasonic dispersion for 5-10 min, standing for 48-72 h, and performing self-assembly crosslinking through the main-object action of the alpha-CD and a PEG chain to form supramolecular hydrogel; in the aqueous dispersion, the concentration of the PEG modified graphene oxide/attapulgite composite nano material is 0.1-0.6 wt%, and the concentration of alpha-CD is 5-16 wt%.
2. The preparation method of the near-infrared light-responsive graphene oxide/attapulgite composite supramolecular hydrogel according to claim 1, which is characterized in that: in the step (1), the diameter of the attapulgite is 20-70 nm.
3. The preparation method of the near-infrared light-responsive graphene oxide/attapulgite composite supramolecular hydrogel according to claim 1, which is characterized in that: in the step (1), the deacetylation degree of carboxymethyl chitosan is 80-95%, and the substitution degree of carboxymethyl is 60-90%.
4. The application of the near-infrared light-responsive graphene oxide/attapulgite composite supramolecular hydrogel prepared by the method of claim 1 as a drug sustained-release carrier.
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