CN113244165A - Stimulus-response-type size-adjustable nano hydrogel drug delivery system and preparation method thereof - Google Patents
Stimulus-response-type size-adjustable nano hydrogel drug delivery system and preparation method thereof Download PDFInfo
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Abstract
The invention provides a stimulus-response size-adjustable nano hydrogel drug delivery system and a preparation method thereof, aiming at the requirements that single drug treatment is easy to generate drug resistance, drugs are difficult to enter the interior of a tumor and the like, the drug delivery system synthesizes nano hydrogel by using monomer acrylic acid and monomer N-isopropylacrylamide through a reflux precipitation method, then promotes tetra-polyaniline to be connected to the nano hydrogel through EDC/NHS, and then loads anticancer drugs through electrostatic adsorption to form the nano hydrogel drug delivery system. The temperature-sensitive material N-isopropylacrylamide enables the nano-hydrogel to have the property of adjustable temperature control size, and the stimulation response type size-adjustable nano-hydrogel drug delivery system can realize image-guided photothermal/chemotherapy/deep treatment combined treatment by combining the excellent photothermal photoacoustic imaging property of the tetraphenylamine.
Description
Technical Field
The invention relates to a stimulus-response type size-adjustable nano hydrogel drug delivery system and a preparation method thereof, belonging to the technical field of synthesis of drug carrier base materials.
Background
In recent years, with the attention of researchers to drug-loaded delivery systems, more and more nano-drug delivery systems are designed to improve the drug delivery rate, however, most of the drug delivery systems, whether nano-drug delivery systems or hydrogel-based in situ injection delivery systems, have their own disadvantages, such as difficulty in reaching the inside of tumor and difficulty in achieving deep treatment. Therefore, it would be of great importance to design a drug delivery system that can facilitate the drug to enter the interior of the tumor for deep treatment.
When designing a drug delivery system capable of realizing deep treatment, the process that the nano material enters a tumor microenvironment is researched, the nano material mainly enters the tumor microenvironment through an EPR effect, the arrangement of tumor cells is more and more compact along with the increase of the depth of tumor tissues, intercellular gaps are also smaller and smaller, and the size of the common nano material is certain, so that the material is difficult to continue to permeate after reaching a certain depth. Therefore, designing a nanoparticle size-variable material as a drug delivery system is an effective way to improve the effect of deep therapy.
The nano hydrogel is a microscopic hydrogel, and has the advantages of both hydrogel and nano particle systems. Compared with the common nano-particles, the nano-hydrogel serving as a drug carrier can achieve higher loading capacity, and the preparation method is simpler compared with the common nano-particles; the nano hydrogel also has the hydrophilicity, flexibility, biocompatibility, high water absorbability and the like of the hydrogel, and can control the release of the drug through stimulus response. These excellent properties of nano-hydrogels make them extremely potential drug delivery systems. Polyaniline can be used as a deep treatment tracking agent due to good photoacoustic imaging effect, can generate a large amount of stable heat energy under the irradiation of near infrared light when in an oxidation state, and can be used as a photo-thermal conversion material.
Disclosure of Invention
The invention aims to provide a stimulation response type size-adjustable nano hydrogel drug delivery system loaded with tetrapolyaniline, aiming at the defects of the prior art, and the system tracks drugs to reach the specific position of a tumor in real time by utilizing the good photo-thermal and photo-acoustic imaging properties of the tetrapolyaniline so as to realize image-guided chemotherapy/thermal therapy/deep therapy combined treatment.
The technical scheme of the invention is as follows: a stimulation-response-type size-adjustable nano-hydrogel drug delivery system is composed of a polymer nano-hydrogel (DOX @ AT-PAN NG) loaded with an anticancer drug Doxorubicin (DOX), and the loading is completed through electrostatic adsorption.
Further, the polymer nanogel is formed by preparing a size-adjustable nanogel (PAN NG) from Acrylic Acid (AA) and N-isopropyl acrylamide (NIPAAm) through a reflux precipitation method, and promoting the connection of the tetrapolyaniline (AT) to the nanogel (AT-PAN NG) through 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS). The drug delivery system is that the anticancer drug DOX is loaded on the polymer nano hydrogel through electrostatic adsorption. The size of the stimulus response type size-adjustable nano hydrogel drug delivery system is small, the drug delivery system can enter a tumor part through a tumor high penetration and retention effect (EPR effect) when the drug delivery system circulates to the tumor part through a tail vein, the drug delivery system can gradually release anticancer drugs DOX in a slightly acidic environment, meanwhile, due to the fact that the polyaniline on the surface of the polymer nano hydrogel has good photo-thermal photo-acoustic properties, photo-acoustic imaging tracking is carried out on the tumor part of a mouse, the drug enrichment amount of the tumor part is monitored in real time, when the drug enrichment amount reaches the maximum, near-infrared light irradiation is carried out on the tumor, the size of the polymer nano hydrogel is reduced under the irradiation of near-infrared light, the polymer nano hydrogel can penetrate into the tumor, and image-guided chemotherapy/thermal therapy/depth treatment combined treatment is achieved. The products of the polymer nano hydrogel drug delivery system after degradation have no obvious biotoxicity.
Furthermore, the polymer nano hydrogel has uniform size of 200-300 nm, and has good hydrophilicity and variable temperature control size.
Furthermore, the polymer nano hydrogel has the property of stimulus response type size adjustability, namely the size of the nano hydrogel can be adjusted through temperature change, and the size of the nano hydrogel is reduced when the temperature is increased. The polymer nano hydrogel connected with AT through EDC/NHS has good photo-thermal and photo-acoustic properties.
The invention also provides a preparation method of the stimulus-responsive size-adjustable nano hydrogel drug delivery system, which comprises the following steps:
and 4, dispersing 1 mg of tetrapolyaniline in a mixed solution of N, N-dimethylformamide and water, dropwise adding the mixed solution into an overnight reaction device, putting the overnight reaction device into a shaking table, continuing to react for 24 hours, centrifugally washing the mixture for 3 times by adopting ultrapure water after the reaction is finished, removing unreacted substances, and freeze-drying and storing the product.
and 6, after the reaction is finished, centrifuging and collecting the precipitate, and repeatedly washing the precipitate for 3 times by using ultrapure water to remove unreacted adriamycin to obtain the nano hydrogel drug delivery system.
Further, in the step 1, the mass ratio of the monomer acrylic acid to the N-isopropylacrylamide is 7: 3.
Further, in the step 2, the temperature of the heating reaction is 95 ℃.
Further, in the step 4, the volume of the mixed solution is 1mL, and the volume ratio of the N, N-dimethylformamide to the water is 1: 9.
Further, the preparation of the tetra-polyaniline in the step 4 comprises the following steps:
step 4.1, adding 0.02 mmol of monomer N-phenyl-p-phenylenediamine into a single-neck round-bottom flask filled with a mixed solution of 160 mL of acetone and 1 mol/mL of hydrochloric acid in a volume ratio of 1:1, and then placing the device in an ice bath at 0 ℃ to stir uniformly;
step 4.2, dissolving 0.02 mmol of ammonium persulfate in a mixed solution of 160 mL of acetone and 1 mol/mL of hydrochloric acid in a volume ratio of 1:1 in advance, dropwise adding the solution into the single-neck round-bottom flask in the reaction in the step 3 for about 30 min, and continuously stirring and reacting for 2 h in an ice bath environment after dropwise adding;
and 4.3, filtering the reaction solution after the reaction is finished, repeatedly washing the reaction solution for 3 times by using 1 mol/mL hydrochloric acid and deionized water to obtain a crude product of the tetraphenylamine, dispersing the crude product in 1 mol/mL ammonia water, stirring for reacting for 2 hours, filtering and cleaning the reaction solution until the filtrate is neutral by using a pH test paper to obtain the purified tetraphenylamine, and freeze-drying and storing.
Compared with the prior art, the invention has the beneficial effects that:
1. the drug delivery system has reasonable structural design, wide raw material source and low cost;
2. the release efficiency of the nano hydrogel drug delivery system is 81.9% in 56 h under the conditions of pH 5.0 and 10 mM glutathione GSH;
3. the material used in the invention has the characteristics of low toxicity and good biocompatibility, and has wide application prospect in the field of biological application.
Drawings
FIG. 1 is a schematic diagram of the synthesis of a stimuli-responsive, size-adjustable nanohydrogel drug delivery system DOX @ AT-PAN NG according to the present invention;
FIG. 2 is a TEM test of a nano-hydrogel PAN NG and a polymer nano-hydrogel AT-PAN NG synthesized in an example of the present invention;
FIG. 3 is a graphical representation of DLS particle size distribution and solution temperature versus hydrodynamic size effects of PAN NG synthesized in accordance with an embodiment of the present invention;
FIG. 4 is a graph showing photothermal effects of the synthesized tetrapolyaniline AT and AT-PAN NG according to the example of the present invention;
FIG. 5 is a graph representing photoacoustic signals of an AT and an AT-PAN NG synthesized in an embodiment of the present invention;
FIG. 6 is a graph showing the release profile of the anticancer drug doxorubicin DOX under different pH, GSH and laser conditions in the examples of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples.
As shown in fig. 1, the present embodiment provides a stimulus-responsive size-tunable nano-hydrogel drug delivery system, which is a nano-hydrogel loaded with an anticancer drug DOX. The load of the anticancer drug DOX is mainly through electrostatic adsorption, and the preparation of the nano hydrogel is divided into two parts. Firstly, preparing stimulus-responsive size-adjustable nano hydrogel from monomer acrylic acid and N-isopropyl acrylamide by a reflux precipitation method, and connecting the nano hydrogel with AT through EDC/NHS to form the polymer nano hydrogel.
FIG. 2 is a TEM test chart of the synthesized nano-hydrogels PAN NG (left) and AT-PAN NG (right) in the example of the invention, and the test results show that the prepared nano-hydrogels have uniform particle size and average size of about 250 nm; FIG. 3 is a DLS particle size distribution diagram of PAN NG and a variation diagram of influence of solution temperature on hydrodynamic size of PAN NG, and test results show that PAN NG has a particle size distribution of about 230 nm at normal temperature, the particle size has no obvious change when the solution temperature rises from 20 ℃ to 30 ℃, and the size of PAN NG is continuously reduced when the solution temperature rises to 47 ℃, and the size is reduced from 230 nm to 170 nm; FIG. 3 is an infrared analysis spectrum observed at 1483 cm-1And 1584 cm-1Has stretching vibration peak of benzene ring and quinone ring on AT and AT-PAN NG, 1735 cm-1The peak of stretching vibration of carboxyl groups of PAN NG and AT-PAN NG is shown. FIG. 4 is a graph showing the photothermal temperature rise of AT and AT-PAN NG synthesized in the example of the present invention, as seen from the test results, AT 1 m/cm2Under the irradiation of the power, the temperature of the solutions of AT and AT-PAN NG is continuously increased along with the time extension, and the temperature rise effect of the material is better and better along with the increase of the concentration; fig. 5 is a graph representing photoacoustic signals of AT and AT-PAN NG synthesized in the embodiment of the present invention, and it can be seen from the test results that both AT and AT-PAN NG have significant photoacoustic signals, and the photoacoustic signals become stronger as the material concentration increases. The Polymer Nanogel AT in this exampleThe specific preparation method of PAN NG comprises the following steps:
and 9, dispersing 1 mg of AT prepared in the step 6 in 1mL of mixed solution with the volume ratio of DMF to water being 1:9, dropwise adding the mixed solution into an overnight reaction device, putting the overnight reaction device into a shaking table, continuing to react for 24 hours, centrifugally washing the mixture for 3 times by using ultrapure water after the reaction is finished, and removing unreacted substances to obtain the AT-PAN NG.
Fig. 6 is a drug release profile of a stimulus-responsive, size-tunable nanohydrogel drug delivery system in an embodiment of the invention. Compared with other experimental groups, the nano hydrogel drug delivery system prepared by the embodiment of the invention has good stimulation response effect in GSH and acidic stimulation environment and under the laser irradiation condition, and compared with other control groups, the release efficiency of the adriamycin DOX drug-loaded system under the release liquid of 10 mM GSH and the laser irradiation condition has more obvious release effect, and 80% of the drug can be released in 56 h.
All test results show that the stimulus-response size-adjustable nano hydrogel drug delivery system provided by the invention adopts the combination of the tetraphenylamine and the size-adjustable nano hydrogel, so that the physical and chemical properties of the nano hydrogel are improved, the nano hydrogel drug delivery system has the advantages of both the hydrogel and the nanoparticle delivery system, the drug release efficiency of the nano hydrogel is obviously improved under the photo-thermal condition, and the chemo-thermal therapy combined treatment is realized. Meanwhile, the system also has the characteristics of hydrophilicity, flexibility, biocompatibility, high water absorption and the like of hydrogel, and can control the release of the medicine through stimulation response. The polyaniline on the surface of the polymer nano hydrogel has good photo-thermal property and photo-acoustic property, and the nano hydrogel has the characteristic of adjustable temperature control size, so that chemotherapy/thermotherapy/deep therapy combined treatment can be realized under the guidance of images. The method has simple synthetic process, and can reach higher loading capacity when being used as a drug carrier. In addition, the materials used in the invention have good biocompatibility and low toxicity, and the synthesis process is simple, so the material has good biological application prospect, and has important research significance for researching the preparation field of the drug delivery system material.
Claims (9)
1. A stimuli-responsive, dimensionally-tunable nanohydrogel drug delivery system, comprising: the polymer nano hydrogel loaded with anticancer drug adriamycin is formed, and the loading is completed through electrostatic adsorption.
2. The stimuli-responsive, dimensionally-tunable nanohydrogel drug delivery system of claim 1, wherein: the polymer nano gel is formed by preparing nano hydrogel with adjustable size by monomer acrylic acid and N-isopropyl acrylamide through a reflux precipitation method and promoting the connection of the tetra-polyaniline to the nano hydrogel through 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride and N-hydroxysuccinimide.
3. The stimuli-responsive, dimensionally-tunable nanohydrogel drug delivery system of claim 1, wherein: the polymer nano hydrogel is uniform in size, and the size is 200-300 nm.
4. The stimuli-responsive, dimensionally-tunable nanohydrogel drug delivery system of claim 1, wherein: the polymer nano hydrogel has the property of stimulus response type size adjustability, namely the size of the nano hydrogel can be adjusted through temperature change.
5. The method of preparing a stimuli-responsive, size-tunable nanohydrogel drug delivery system of claim 1, wherein: the method comprises the following steps:
step 1, adding monomer acrylic acid and N-isopropylacrylamide into a 100 mL double-neck flask according to a certain mass ratio, simultaneously adding a cross-linking agent with the component of bis (2-methyl propylene) ethoxy disulfide and an initiator with the component of 2, 2-azobisisobutyronitrile, mixing and dissolving in 40mL acetonitrile solution, and performing ultrasonic treatment for 10 min to uniformly disperse;
step 2, placing the double-mouth flask obtained in the step 1 in a reflux precipitation device, heating for oil bath reaction, continuing to react for 1 h after the solution is heated until white turbidity appears, separating out the precipitate in a centrifugal mode after the reaction is finished, repeatedly washing the precipitate for three times by adopting an acetonitrile solution, and freeze-drying and storing the precipitate;
step 3, dissolving 0.2 mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.4 mmol of N-hydroxysuccinimide in 0.1M 2- (N-morpholine) ethanesulfonic acid buffer solution, adding 1 mg of the nano hydrogel prepared in the step 2, and putting the nano hydrogel and the nano hydrogel into a shaker together at room temperature for overnight reaction;
step 4, dispersing 1 mg of tetrapolyaniline in a mixed solution of N, N-dimethylformamide and water, dropwise adding the mixed solution into an overnight reaction device, putting the overnight reaction device into a shaking table, continuing to react for 24 hours, centrifugally washing the mixture for 3 times by adopting ultrapure water after the reaction is finished, removing unreacted substances, and freeze-drying and storing the product;
step 5, taking 1 mg of the polymer nano hydrogel prepared in the step 4 to dissolve in PBS (phosphate buffer solution) with pH of 7.4, then adding 1mL of doxorubicin solution with the concentration of 1 mg/mL into the PBS solution, carrying out ultrasonic treatment to fully dissolve the doxorubicin solution, and stirring the mixture at room temperature overnight;
and 6, after the reaction is finished, centrifuging and collecting the precipitate, and repeatedly washing the precipitate for 3 times by using ultrapure water to remove unreacted adriamycin to obtain the nano hydrogel drug delivery system.
6. The method of making a stimuli-responsive, dimensionally-tunable nanohydrogel drug delivery system of claim 5, wherein: in the step 1, the mass ratio of the monomer acrylic acid to the N-isopropylacrylamide is 7: 3.
7. The method of preparing a stimuli-responsive, size-tunable nanohydrogel drug delivery system of claim 5, wherein: in the step 2, the temperature of the heating reaction is 95 ℃.
8. The method of making a stimuli-responsive, size-tunable nanohydrogel drug delivery system of claim 5, wherein: in the step 4, the volume of the mixed solution is 1mL, and the volume ratio of the N, N-dimethylformamide to the water is 1: 9.
9. The method of making a stimuli-responsive, size-tunable nanohydrogel drug delivery system of claim 5, wherein: the preparation method of the tetrapolyaniline in the step 4 comprises the following steps:
step 4.1, adding 0.02 mmol of monomer N-phenyl-p-phenylenediamine into a single-neck round-bottom flask filled with a mixed solution of 160 mL of acetone and 1 mol/mL of hydrochloric acid in a volume ratio of 1:1, and then placing the device in an ice bath at 0 ℃ to stir uniformly;
step 4.2, dissolving 0.02 mmol of ammonium persulfate in a mixed solution of 160 mL of acetone and 1 mol/mL of hydrochloric acid in a volume ratio of 1:1 in advance, dropwise adding the solution into the single-neck round-bottom flask in the reaction in the step 3 for about 30 min, and continuously stirring and reacting for 2 h in an ice bath environment after dropwise adding;
and 4.3, filtering the reaction solution after the reaction is finished, repeatedly washing the reaction solution for 3 times by using 1 mol/mL hydrochloric acid and deionized water to obtain a crude product of the tetraphenylamine, dispersing the crude product in 1 mol/mL ammonia water, stirring for reacting for 2 hours, filtering and cleaning the reaction solution until the filtrate is neutral by using a pH test paper to obtain the purified tetraphenylamine, and freeze-drying and storing.
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