CN111499888A - Preparation and application method of hypoxic degradable phosphorylcholine polymer nanogel - Google Patents
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Abstract
A preparation method of hypoxic degradable phosphorylcholine polymer nanogel comprises the steps of firstly preparing a hypoxic degradable cross-linking agent containing azobenzene groups by using amide reaction, and secondly reacting a phosphorylcholine zwitterionic monomer and an azo type hypoxic degradable initiator in an organic solvent by using a reflux precipitation polymerization method to obtain the hypoxic degradable phosphorylcholine polymer nanogel; an application method of the hypoxia degradable phosphorylcholine polymer nanogel adopts a finished product of the hypoxia degradable phosphorylcholine polymer nanogel as a carrier and adopts the nanogel to load an anti-tumor drug to treat tumors. The finished product prepared by the invention is applied to tumor treatment, can keep high stability in the blood circulation process, has hiding capability, is not easy to be identified and phagocytized by an endothelial reticulum system, and can be quickly degraded and release loaded drugs after reaching a tumor hypoxia environment, thereby effectively killing tumor cells and providing powerful technical support for cancer treatment. The invention has good prospect.
Description
Technical Field
The invention belongs to the technical field of high-molecular drug carriers, and particularly relates to a preparation and application method of hypoxic degradable phosphorylcholine polymer nanogel.
Background
The hydrogel has good biocompatibility, high water content and high mechanical strength, and is widely applied to implantable tissue frames, surface coatings of implanted inductors, wound dressings, drug delivery carriers and the like in the medical field. Particularly, nano-sized hydrogel particles (nanogels) have received much attention from researchers due to their high drug loading, ability to concentrate into tumor tissues based on enhanced permeation and retention effects, and ability to respond to environmental factors such as temperature, pH, or redox.
For the drug-loaded nanogel, the drug is kept to be released less or zero in a physiological environment, and the drug is efficiently and rapidly released in a tumor microenvironment, so that the toxic and side effects of the drug-loaded nanogel on normal tissues can be reduced, and the killing effect on tumors can be greatly enhanced. To achieve controlled release of the drug, degradable cross-linking agents are often incorporated into the polymer network in the medical field. The degradable cross-linking agent is induced to break through the stimulation response of the tumor microenvironment, and the degradation of the nanogel is further caused, so that the full release of the medicine can be realized. In tumors, abnormal proliferation of cancer cells, as well as alterations in tumor vasculature and loss of function, results in an imbalance in the consumption and supply of oxygen molecules within the tumor. The diffusion distance of oxygen molecules in tumor tissues is about 100-200 μm, and a region in the tumor, which is far away from effective blood vessels, is usually subjected to a remarkable oxygen depletion condition. Generally, the oxygen partial pressure in the slightly hypoxic region in tumor tissue is below 3%, the oxygen partial pressure in the heavily hypoxic region is below 1%, and in some regions far from the blood vessels the oxygen partial pressure is close to 0%, significantly lower than in vascular arteries (> 13%) and veins (> 5%). Therefore, by utilizing the significant difference of the oxygen concentration between the tumor tissue and the normal tissue, the hypoxic degradable cross-linking agent which keeps the structure stable in the normal oxygen concentration and has a broken structure in the hypoxic environment of the tumor tissue is designed, and the low release of the nano gel in the normal tissue and the quick release of the tumor tissue medicament can be realized. However, in the prior art, no synthesized hypoxic degradable cross-linking agent exists, so that a nano gel based on the hypoxic degradable cross-linking agent cannot be prepared, and better support cannot be provided for treating tumors.
Disclosure of Invention
In order to overcome the defects that the prior art can not prepare nano gel based on the hypoxic degradable cross-linking agent and can not provide better support for the treatment of tumors because the hypoxic degradable cross-linking agent is not synthesized, the invention provides a hypoxic degradable cross-linking agent prepared by a simple and rapid method, and the hypoxic degradable phosphorylcholine polymer nanogel is prepared based on the hypoxic degradable cross-linking agent, and the prepared finished product is applied to tumor treatment after being loaded with drugs, can maintain high stability in the blood circulation process, has hiding capability, is not easy to be identified and phagocytized by an endothelial reticulum system, and after reaching the tumor hypoxia environment, the nanogel is rapidly degraded and releases the loaded drug, thereby effectively killing tumor cells and providing a powerful technical support for the treatment of cancers.
The technical scheme adopted by the invention for solving the technical problems is as follows:
the preparation method of the hypoxic degradable phosphorylcholine polymer nanogel is characterized in that firstly, an amide reaction is utilized to prepare a hypoxic degradable cross-linking agent containing azobenzene groups, and secondly, a reflux precipitation polymerization method is adopted to obtain the hypoxic degradable phosphorylcholine polymer nanogel by reacting a phosphorylcholine zwitter-ion monomer and an azo hypoxic degradable initiator in an organic solvent; the hypoxic degradable cross-linking agent comprises an azobenzene group and two carbon-carbon double bond groups, and adopts the following raw materials, wherein, one of azobenzene-4, 4-dicarboxylic acid, methacrylic acid or acrylic acid is taken as a raw material I, one of diaminoazobenzene, 2-aminoethyl methacrylate, 2-aminoethyl acrylate or allylamine hydrochloride is used as a raw material II, one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS) or 4-Dimethylaminopyridine (DMAP) is taken as a catalyst, taking one of N, N' -dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and the like as a solvent, and obtaining the hypoxic degradable cross-linking agent by the raw materials through an amide reaction preparation method; the preparation method of the hypoxic degradable phosphorylcholine polymer nanogel comprises the following steps of preparing phosphorylcholine zwitterion monomers, a cross-linking agent, an azo initiator and an organic solvent from the raw materials by adopting a reflux precipitation polymerization method.
Further, in the preparation of the anaerobic degradable cross-linking agent containing the azobenzene group, raw material one is preferably azobenzene-4, 4-dicarboxylic acid, raw material two is preferably 2-aminoethyl methacrylate, catalyst is preferably EDC and DMAP, and solvent is preferably N, N' -dimethylformamide.
Further, in the preparation of the azobenzene group-containing hypoxic degradable cross-linking agent, the concentration of the raw material I is 5mgm L-1～500mg mL-1The concentration of the second raw material is 5mg mL-1～500mg mL-1EDC concentration of 10mg m L-1～1000mgmL-1DMAP concentration of 0.5mg m L-1～50mg mL-1The volume of the N, N' -dimethylformamide is 10-1000 m L.
The method for preparing the anaerobic degradable cross-linking agent containing the azobenzene group by using the amide reaction comprises the following steps of (1) dissolving a raw material I, a raw material II, EDC and DMAP in an organic solvent, carrying out ultrasonic treatment for 3 minutes, uniformly dispersing, (2) adding the treated raw material I and the raw material II into a reaction bottle, replacing nitrogen in the reaction bottle, stirring at room temperature for 48 hours, concentrating an organic phase to 40m L, then placing the concentrated solution into 4 centrifuge tubes with the capacity of 50m L, adding water to 40m L, uniformly shaking, centrifuging, pouring out a supernatant, then washing and precipitating twice, and (3) dissolving the precipitate in tetrahydrofuran, drying with sodium sulfate, and then carrying out silica gel column chromatography (dichloromethane: tetrahydrofuran ═ 19:1) to obtain pure brown red brown powder, namely the anaerobic degradable cross-linking agent containing the azobenzene group.
Further, in the hypoxic degradable phosphorylcholine polymer nanogel prepared by adopting a reflux precipitation polymerization method, a phosphorylcholine zwitter-ion monomer is 2-methacryloyloxy ethoxy phosphorylcholine (MPC); the cross-linking agent is a synthesized hypoxic degradable cross-linking agent.
Further, in the hypoxic degradable phosphorylcholine polymer nanogel prepared by adopting a reflux precipitation polymerization method, azo initiators are azodiisobutyronitrile, azodiisoheptonitrile, dimethyl azodiisobutyrate and the like, preferably azodiisobutyronitrile;
further, in the hypoxic degradable phosphorylcholine polymer nanogel prepared by adopting the reflux precipitation polymerization method, the organic solvent is acetonitrile, ethanol, dimethyl sulfoxide and the like, or a mixture of the above, preferably acetonitrile.
Further, in the hypoxic degradable phosphorylcholine polymer nanogel prepared by adopting the reflux precipitation polymerization method, the concentration of MPC is 1mg m L-1～50mg mL-1The concentration of the hypoxic degradable cross-linking agent is 0.2mg m L-1～10mg mL-1Concentration of azo initiatorsDegree of 0.01mg m L-1～1.0mg mL-1。
Further, the method for preparing the hypoxic degradable phosphorylcholine polymer nanogel by adopting the reflux precipitation polymerization method comprises the following steps of (1) dissolving MPC, a hypoxic degradable cross-linking agent and an azo initiator in an organic solvent, and performing ultrasonic treatment for 3 minutes to uniformly disperse the MPC, the hypoxic degradable cross-linking agent and the azo initiator; (2) introducing nitrogen for 10 minutes, heating to 100 ℃, reacting for 1 hour at the temperature in the nitrogen atmosphere, cooling, centrifuging at a high speed, removing the organic solvent, adding water for dispersion, centrifuging again, repeating the water washing process for three times, and freeze-drying the obtained sample to obtain the finished product of the hypoxia degradable phosphorylcholine polymer nanogel.
An application method of hypoxic degradable phosphorylcholine polymer nanogel adopts a finished product of the hypoxic degradable phosphorylcholine polymer nanogel as a carrier, and adopts the nanogel to load an anti-tumor drug to treat tumors, wherein the anti-tumor drug is one or more of adriamycin, camptothecin, taxol, docetaxel and cisplatin.
Further, the drug loading of the finished hypoxic degradable phosphorylcholine polymer nanogel product is 3% -30%.
Further, the antitumor drug is loaded into the hypoxia degradable phosphorylcholine polymer nanogel finished product through a swelling adsorption or organic solvent volatilization method.
The invention has the beneficial effects that: the hypoxic degradable cross-linking agent is simple and convenient to synthesize, and is favorable for batch production. The hypoxic degradable nanogel prepared by the method has good biocompatibility, longer blood circulation time and good immune compatibility. The nano gel loaded with the anti-tumor drug releases less than 10 percent of the drug within 24 hours under the physiological environment, and releases more than 80 percent of the drug within 24 hours under the tumor hypoxia environment. The nanogel loaded with the anti-tumor drug has remarkably enhanced killing effect on cells (smmc-7721) such as human liver cancer tumor and the like under hypoxic condition compared with physiological condition. The nanogel loaded with the anti-tumor drug can be effectively enriched in tumor tissues after being injected into tail veins of a human body. The loaded nanogel of chemotherapeutic drugs such as adriamycin and the like keeps stable in normal physiological tissues and hardly releases the drugs; the nanogel is rapidly disintegrated after reaching a hypoxic tumor area, and the drug is rapidly released, so that the drug-loaded nanogel can selectively kill tumor tissues without toxic and side effects on normal tissues, and has good application value in the field of antitumor drugs. The invention provides powerful technical support for the treatment of cancer. Based on the above, the invention has good application prospect.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the hypoxic degradable cross-linking agent of the invention.
FIG. 2 is a mass spectrum of the hypoxic degradable cross-linking agent of the invention.
FIG. 3 is a transmission electron microscope image of the hypoxic degradable phosphorylcholine polymer nanogel of the invention, with a scale bar of-200 (unit: nanometer, nm).
FIG. 4 is a hydrated particle size distribution diagram of the hypoxic degradable phosphorylcholine polymer nanogel.
FIG. 5 is a diagram showing the degradation of hypoxic degradable phosphorylcholine polymer nanogel.
Fig. 6 is a drug release diagram of the hypoxic degradable phosphorylcholine polymer nanogel of the invention.
FIG. 7 is a graph of toxicity test of hypoxic degradable phosphorylcholine polymer nanogel on 293T cells.
FIG. 8 is a graph of the toxicity test of the hypoxic degradable phosphorylcholine polymer nanogel carrying the medicine of the invention to smmc-7721 cells.
Figure 9 schematic enrichment of drug loaded nanogels in HepG 2-loaded tumor mice.
Figure 10 inhibition effect of drug loaded nanogels on HepG2 tumor-loaded mice.
FIG. 11 is a flow chart of a preparation method of hypoxic degradable phosphorylcholine polymer nanogel.
Detailed Description
Fig. 11 shows a preparation method of a hypoxic degradable phosphorylcholine polymer nanogel, which comprises the steps of firstly preparing a hypoxic degradable cross-linking agent containing an azobenzene group by using an amide reaction, and secondly obtaining the hypoxic degradable phosphorylcholine polymer nanogel by using a phosphorylcholine zwitterionic monomer and an azo hypoxic degradable initiator in an organic solvent reaction by using a reflux precipitation polymerization method; the hypoxic degradable cross-linking agent comprises an azobenzene group and two carbon-carbon double bond groups, and adopts the following raw materials, wherein, one of azobenzene-4, 4-dicarboxylic acid, methacrylic acid or acrylic acid is taken as a raw material I, one of diaminoazobenzene, 2-aminoethyl methacrylate, 2-aminoethyl acrylate or allylamine hydrochloride is used as a raw material II, one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS) or 4-Dimethylaminopyridine (DMAP) is taken as a catalyst, taking one of N, N' -dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and the like as a solvent, and obtaining the hypoxic degradable cross-linking agent by the raw materials through an amide reaction preparation method; the preparation method of the hypoxic degradable phosphorylcholine polymer nanogel comprises the following steps of preparing phosphorylcholine zwitterion monomers, a cross-linking agent, an azo initiator and an organic solvent from the raw materials by adopting a reflux precipitation polymerization method.
As shown in FIG. 11, in the preparation of the anaerobic degradable cross-linking agent containing azobenzene groups, raw material one is preferably azobenzene-4, 4-dicarboxylic acid, raw material two is preferably 2-aminoethyl methacrylate, catalyst is preferably EDC and DMAP, and solvent is preferably N, N' -dimethylformamide, in the preparation of the anaerobic degradable cross-linking agent containing azobenzene groups, the concentration of raw material one is 5mg m L-1～500mg mL-1The concentration of the second raw material is 5mg m L-1～500mg mL-1EDC concentration of 10mg m L-1～1000mg mL-1DMAP concentration of 0.5mg m L-1～50mg mL-1The volume of the N, N' -dimethylformamide is 10-1000 m L. the method for preparing the anaerobic degradable cross-linking agent containing the azobenzene group by using the amide reaction comprises the following steps of (1) dissolving the raw material I, the raw material II, EDC and DMAP in an organic solvent, performing ultrasonic treatment for 3 minutes, uniformly dispersing, (2) adding the treated raw material I and the raw material II into a reaction bottle, replacing nitrogen in the reaction bottle, stirring and reacting at room temperature for 48 hours, concentrating the organic phase to 40m L, and then placing the concentrated solution into 4 containersAdding water 40m L into a centrifuge tube with the capacity of 50m L, uniformly shaking and centrifuging, pouring out supernate, then adding water to wash and precipitate twice, (3) dissolving the precipitate in tetrahydrofuran, drying by using sodium sulfate, and then carrying out silica gel column chromatography (dichloromethane: tetrahydrofuran: 19:1) to obtain pure brown red powder, namely the hypoxia degradable cross-linking agent containing the azobenzene group.
FIG. 11 shows that in the method of reflux precipitation polymerization for preparing the degradable phosphorylcholine spent polymer nanogel, the phosphorylcholine zwitterionic monomer is 2-methacryloyloxy ethoxy phosphorylcholine (MPC), the cross-linking agent is a synthesized degradable cross-linking agent, the method of reflux precipitation polymerization for preparing the degradable phosphorylcholine spent polymer nanogel is performed, the azo initiators are azobisisobutyronitrile, azobisisoheptonitrile, dimethyl azobisisobutyrate and the like, preferably azobisisobutyronitrile, the method of reflux precipitation polymerization for preparing the degradable phosphorylcholine spent polymer nanogel is performed, the organic solvent is acetonitrile, ethanol, dimethyl sulfoxide and the like, or the mixture of the two, preferably acetonitrile, the method of reflux precipitation polymerization for preparing the degradable phosphorylcholine spent polymer nanogel is performed, and the concentration of MPC is 1mg m L-1～50mg mL-1The concentration of the hypoxic degradable cross-linking agent is 0.2mg m L-1～10mg mL-1The azo initiator concentration was 0.01mg m L-1～1.0mg mL-1. The preparation method of the hypoxic degradable phosphorylcholine polymer nanogel by adopting a reflux precipitation polymerization method comprises the following steps of (1) dissolving MPC, a hypoxic degradable cross-linking agent and an azo initiator in an organic solvent, and performing ultrasonic treatment for 3 minutes to uniformly disperse; (2) introducing nitrogen for 10 minutes, heating to 100 ℃, reacting for 1 hour at the temperature in the nitrogen atmosphere, cooling, centrifuging at a high speed, removing the organic solvent, adding water for dispersion, centrifuging again, repeating the water washing process for three times, and freeze-drying the obtained sample to obtain the finished product of the hypoxia degradable phosphorylcholine polymer nanogel.
An application method of hypoxic degradable phosphorylcholine polymer nanogel adopts a finished product of the hypoxic degradable phosphorylcholine polymer nanogel as a carrier, and adopts the nanogel to load an anti-tumor drug to treat tumors, wherein the anti-tumor drug is one or more of adriamycin, camptothecin, taxol, docetaxel and cisplatin. The drug-loading rate of the finished product of the hypoxia degradable phosphorylcholine polymer nanogel is 3-30%. The antitumor drug is loaded into the hypoxic degradable phosphorylcholine polymer nanogel finished product through a swelling adsorption or organic solvent volatilization method.
Referring to fig. 11, in the preparation of the hypoxic degradable cross-linking agent containing azobenzene group, the actual operation process is as follows, firstly, azobenzene-4, 4-dicarboxylic acid (11.4mmol,3.07g), ethylamine methacrylate hydrochloride (27.3mmol,5.00g), EDC (27.3mmol,5.24g), DMAP (2.85mmol,0.35g) and anhydrous N, N' -dimethylformamide (100m L) are added into a reaction bottle, nitrogen is replaced in the reaction bottle, then the reaction is stirred at room temperature for 48h, then the raw materials after the stirring reaction are concentrated into an organic phase of 40m L, then the concentrated solution is distributed into 4 centrifuge tubes with the capacity of 50m L, water is added into the centrifuge tubes, the centrifuge tubes are evenly shaken for centrifugation is carried out after 40m L is added, supernatant is poured out, precipitate is washed twice by water to obtain precipitate, the precipitate is dried by sodium sulfate, the precipitate is dyed back to obtain a finished product of pure hypoxic cross-linking agent by silica gel column chromatography (dichloromethane mass spectrum: THF 19:1), the yield of the degradable oxygen-deficient cross-linking agent is shown as 18%, the magnetic cross-linking agent, the core hydrogen is prepared, and the degradable cross-hydrogen cross-linking agent is shown in the graph, and the core hydrogen-hydrogen cross.
FIG. 11 shows that in the preparation of the hypoxic degradable phosphorylcholine polymer nanogel by the reflux precipitation polymerization method, the actual operation process is as follows, 600mg MPC and 120mg of the prepared hypoxic degradable cross-linking agent are taken firstly, 8mg AIBN (azo initiator) is dissolved in 80m L acetonitrile, the mixture is poured into a three-neck flask after being subjected to ultrasonic dispersion for 3 minutes, the mixture is heated to 100 ℃ under the nitrogen atmosphere, the heating is stopped after the reaction is carried out for 2 hours, then the nanogel is obtained by centrifugal dispersion separation at 12000rpm, water washing is carried out for three times, and freeze drying is carried out, thus obtaining the finished product of the hypoxic degradable phosphorylcholine polymer nanogel, FIG. 3 is a transmission electron microscope picture of the prepared nanogel, the diameter of the nanogel is 115 +/-5 nm, FIG. 4 is the hydrated particle size distribution of the prepared nanogel, the hydrated particle size of the nanogel is 168nm, and the number of the0.06. Shown in figure 5 (figure 5 is a degradation behavior diagram of the nanogel in a normal environment and a hypoxic environment), the finished product of the hypoxic degradable phosphorylcholine polymer nanogel (1mg m L)-1) The nano-gel degradation degree and the relative turbidity of the nano-gel are in positive correlation, and the nano-gel is shown to be highly stable under normal oxygen concentration and be rapidly degraded in the hypoxic environment.
The application method of the hypoxic degradable phosphorylcholine polymer nanogel comprises the following steps of weighing 3mg of adriamycin, dispersing 10mg of nanogel into 3M L deionized water, dropwise adding 0.01M of sodium hydroxide solution until the pH value of the system is 8-9, wrapping the nanogel with tinfoil paper in a dark place, rotating and shaking up for 24 hours, centrifugally separating the nanogel, washing the nanogel with water for three times to remove the adriamycin attached to the surface of the nanogel, obtaining the nanogel loaded with the adriamycin, weighing 0.8mg of paclitaxel, dissolving the paclitaxel in 2M L chloroform, and dissolving the nanogel in 3mg M L of chloroform-1Swelling the gel in deionized water, ultrasonically mixing the gel for 15 minutes, removing chloroform by rotary evaporation, putting the drug-loaded gel into an ultrafiltration tube after 48 hours, centrifugally washing the gel for three times at 12000rpm for 20 minutes, and collecting supernatant to obtain the taxol-loaded nanogel.
Taking 1mg of adriamycin-loaded nanogel to disperse in 1m of L corresponding buffer solution, transferring the nanogel into a dialysis bag with the cutoff molecular weight of 14000Da, then fastening the dialysis bag, placing the dialysis bag into 100m of L corresponding buffer solution, setting the temperature to be 37 ℃ and stirring the solution by slight magnetic force, taking 2m of L solution from the release medium at a specific time interval, simultaneously supplementing fresh buffer solution corresponding to 2m of L, measuring the content of the adriamycin in the release medium by ultraviolet spectrum, and fig. 6 shows the drug release behavior of the drug-loaded nanogel in normal environment and oxygen environment, which shows that the drug-loaded nanogel hardly releases the drug in normal oxygen environment and quickly releases the drug in oxygen-poor environment.
The toxicity test of the blank nanogel without the loaded drug is carried out by taking HepG2 cells (HepG2 cells are from liver cancer tissues of 15-year-old white people) with the growth state in logarithmic phase and respectively taking 1 × 104Inoculating into 96-well culture plate, adding 200 μ L culture solution, standing at 37 deg.C and 5% CO2Humidity and humidity>Culturing in 95% incubator for 24h, discarding the culture solution, adding culture solution containing nanogel (0, 10, 50, 100, 200, 500 and 1000 μ g/m L) of different concentrations 100 μ L into the wells, setting 4 wells for each concentration, culturing in incubator for 24h, discarding the culture solution, washing with PBS (buffer solution), and adding MTT (thiazole blue) solution (5mg m L) of 20 μ L into each well-1Dissolving in PBS 7.4), continuing to culture for 4h, carefully removing the supernatant in each well, adding 150 mu L DMSO (dimethyl sulfoxide) to dissolve purple formazan, keeping out of the sun and shaking for 15min gently, and then measuring the absorbance at 490nm of each well by using a microplate reader, taking cells without nanogel culture medium as a negative control, and defining the ratio of the absorbance measured by an experimental group to the absorbance of a control group as the cell survival rate, wherein fig. 7 is a toxicity diagram of blank nanogels to HepG2 cells, which shows that the blank nanogels are almost nontoxic to HepG2 cells within the concentration range of 0-1000 mu g/m L.
The toxicity experiment operation of the drug-loaded nanogel is as follows, HepG2 cells with the growth state in logarithmic phase are taken and respectively treated with 1 × 104Inoculating into 96-well culture plate, adding 200 μ L culture solution, standing at 37 deg.C and humidity of 5% CO2>Culturing in 95% incubator for 24h, discarding culture solution, adding drug-loaded nanogel into the wells, setting 4 wells for each concentration, placing into incubator, culturing in normal environment and hypoxic environment for 24h, discarding culture solution, washing with PBS, and adding 20 μ L MTT solution (5mg m L) into each well-1Dissolved in PBS 7.4), the supernatant in each well is carefully removed, 150 mu L DMSO is added to dissolve purple formazan, the absorbance at 490nm of each well is measured by a microplate reader after gentle shaking in the dark for 15min, and nanogel is not contained or the supernatant is continuously cultured for 4hThe cells loaded with the drug medium served as negative control, and the ratio of the absorbance measured in the experimental group to the absorbance in the control group was defined as the cell survival rate. Fig. 8 is a toxicity evaluation of the drug-loaded nanogel on HepG2 cells, and the result shows that the drug-loaded nanogel has a stronger killing effect on HepG2 cells in an hypoxic environment.
In a further experiment of the invention, Balb/c (white-variant laboratory mice) nude mice (5-6 weeks, about 20g) were selected and injected subcutaneously to contain about 2 × 106The physiological saline of the HepG2 cells is injected into the hind leg position of a nude mouse until the tumor volume of the mouse is about 100mm3In size, tail vein is injected with near infrared fluorescent molecule Cy5 marked hypoxic degradation nano gel, the change of near infrared fluorescence intensity of mouse tumor part is shot by the living body fluorescence imaging of the small animal at different time, figure 9 is the enrichment graph of the drug-loaded nano gel in HepG2 tumor-loaded mouse, in the further experiment of the invention, Balb/c nude mouse (5-6 weeks, about 20g) is selected, and the drug-loaded nano gel is injected subcutaneously to contain about 2 × 106The physiological saline of the HepG2 cells is injected into the hind leg position of a nude mouse until the tumor volume of the mouse is about 100mm3Randomly dividing the tumor-bearing nude mice into 4 groups in size, wherein each group comprises 5 mice, namely a normal saline group, an adriamycin group, a drug-loaded reduction degradation nano-gel group and a drug-loaded hypoxia degradation nano-gel group, the injection dosage of tail vein of each group is 2mgDOX/kg, the control group is injected with normal saline with the same volume, the mice are killed after 14 days, and the mice are photographed after the tumors are stripped; FIG. 10 is a graph of the inhibitory effect of drug loaded nanogels on HepG2 tumor-loaded mice. From fig. 10, it is clear that the tumor inhibition effect of the drug-loaded reductive degradation nanogel group is far lower than that of the drug-loaded hypoxic degradation nanogel group, the effect of the normal saline group is lower than that of the adriamycin group, and the adriamycin group is lower than that of the drug-loaded reductive degradation nanogel group, which fully shows that the drug-loaded hypoxic degradable phosphorylcholine polymer nanogel-based nano-gel of the invention can achieve effective tumor inhibition and treatment effects.
In the invention, the molecular weight of the hypoxic degradable cross-linking agent is 100-1000 g mol-1. The hydrated particle size of the nanogel is 10-1000 nm, and the potential of a Zeta (potential meter) is-5 mV. The nanometer gel is degraded rapidly in tumor hypoxia environment, and the degradation products are separatedA molar mass of 500g mol-1-10000g mol-1The nano gel loaded with the anti-tumor drug releases less than 10 percent of the drug within 24 hours in a physiological environment and releases more than 80 percent of the drug within 24 hours in a tumor hypoxia environment, and the nano gel not loaded with the anti-tumor drug is 1000 mu g m L-1Is almost non-toxic (survival rate) to human renal epithelial cells (293T) at the concentration of (1)>90%). The nanogel loaded with the anti-tumor drug has remarkably enhanced killing effect on human liver cancer tumor cells (smmc-7721) under hypoxic conditions compared with physiological conditions. Compared with the prior art, the hypoxic degradable cross-linking agent and the hypoxic degradable phosphorylcholine polymer nanogel have the following advantages: the hypoxic degradable cross-linking agent keeps stable in physiological environment and can be rapidly degraded under tumor hypoxic condition; the hypoxic degradable cross-linking agent is simple and quick to prepare; the hypoxic degradable phosphorylcholine polymer nanogel has uniform size, is stable in physiological environment and is rapidly degraded under tumor hypoxic conditions; the drug-loaded nanogel hardly releases the loaded drug in a physiological environment and quickly releases the loaded drug under the condition of tumor hypoxia; the nanogel can be specifically enriched in tumor tissues. The hypoxic degradable cross-linking agent is simple and convenient to synthesize, and is favorable for batch production. The hypoxic degradable nanogel prepared by the method has good biocompatibility, longer blood circulation time and good immune compatibility. The nanogel loaded with the anti-tumor drug can be effectively enriched in tumor tissues after being injected into tail veins of a human body. The loaded nanogel of chemotherapeutic drugs such as adriamycin and the like keeps stable in normal physiological tissues and hardly releases the drugs; the nanogel is rapidly disintegrated after reaching a hypoxic tumor area, and the drug is rapidly released, so that the drug-loaded nanogel can selectively kill tumor tissues without toxic and side effects on normal tissues, and has good application value in the field of antitumor drugs. The invention provides powerful technical support for the treatment of cancer.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention, together with the advantages thereof, it will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (10)
1. The preparation method of the hypoxic degradable phosphorylcholine polymer nanogel is characterized in that firstly, an amide reaction is utilized to prepare a hypoxic degradable cross-linking agent containing azobenzene groups, and secondly, a reflux precipitation polymerization method is adopted to obtain the hypoxic degradable phosphorylcholine polymer nanogel by reacting a phosphorylcholine zwitter-ion monomer and an azo hypoxic degradable initiator in an organic solvent; the hypoxic degradable cross-linking agent comprises an azobenzene group and two carbon-carbon double bond groups, and adopts the following raw materials, wherein one of azobenzene-4, 4-dicarboxylic acid, methacrylic acid or acrylic acid is taken as a raw material I, one of p-diaminoazobenzene, 2-aminoethyl methacrylate, 2-aminoethyl acrylate or allylamine hydrochloride is taken as a raw material II, one of EDC, NHS or DMAP is taken as a catalyst, one of N, N' -dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone and the like is taken as a solvent, and the hypoxic degradable cross-linking agent is prepared by an amide reaction preparation method from the raw materials; the preparation method of the hypoxic degradable phosphorylcholine polymer nanogel comprises the following steps of preparing phosphorylcholine zwitterion monomers, a cross-linking agent, an azo initiator and an organic solvent from the raw materials by adopting a reflux precipitation polymerization method.
2. The method for preparing the hypoxic degradable phosphorylcholine polymer nanogel according to claim 1, wherein in the preparation of the hypoxic degradable cross-linking agent containing the azobenzene group, a raw material, preferably azobenzene-4, 4-dicarboxylic acid, a raw material, preferably 2-aminoethyl methacrylate, a catalyst, preferably EDC and DMAP, and a solvent, preferably N, N' -dimethylformamide are adopted.
3. The method for preparing the hypoxic degradable phosphorylcholine polymer nanogel according to claim 1, wherein in the preparation of the hypoxic degradable cross-linking agent containing azobenzene groups, the concentration of the first raw material is 5mg m L-1～500mg mL-1The concentration of the second raw material is 5mg m L-1～500mg mL-1EDC concentration of 10mg m L-1～1000mg mL-1DMAP concentration of 0.5mg m L-1～50mg mL-1The volume of the N, N' -dimethylformamide is 10-1000 m L.
4. The preparation method of the hypoxic degradable phosphorylcholine polymer nanogel as claimed in claim 1, wherein the preparation method of the hypoxic degradable cross-linking agent containing the azobenzene group by using the amide reaction comprises the following steps of (1) dissolving a raw material I, a raw material II, EDC and DMAP in an organic solvent, performing ultrasonic treatment for 3 minutes, and uniformly dispersing, (2) adding the treated raw material I and raw material II into a reaction bottle, replacing nitrogen in the reaction bottle, stirring and reacting at room temperature for 48 hours, concentrating an organic phase to 40m L, then dividing the concentrated solution into 4 centrifuge tubes with the capacity of 50m L, adding water to 40m L, uniformly shaking and centrifuging, pouring out supernatant, then adding water to wash and precipitate twice, and (3) dissolving the precipitate in tetrahydrofuran, drying with sodium sulfate, and then performing silica gel column chromatography to obtain brownish red powder, namely the hypoxic degradable azobenzene group-containing cross-linking agent.
5. The method for preparing the hypoxic degradable phosphorylcholine polymer nanogel according to claim 1, wherein in the hypoxic degradable phosphorylcholine polymer nanogel prepared by the reflux precipitation polymerization method, the phosphorylcholine zwitterionic monomer is MPC; the cross-linking agent is a synthesized hypoxic degradable cross-linking agent.
6. The preparation method of the hypoxic degradable phosphorylcholine polymer nanogel according to claim 1, wherein in the hypoxic degradable phosphorylcholine polymer nanogel prepared by the reflux precipitation polymerization method, the azo initiators are azobisisobutyronitrile, azobisisoheptonitrile, dimethyl azobisisobutyrate and the like, preferably azobisisobutyronitrile.
7. The method for preparing the hypoxic degradable phosphorylcholine polymer nanogel according to claim 1, wherein in the hypoxic degradable phosphorylcholine polymer nanogel prepared by the reflux precipitation polymerization method, the organic solvent is acetonitrile, ethanol, dimethyl sulfoxide and the like, or a mixture of the organic solvent and the organic solvent, preferably acetonitrile.
8. The method for preparing the hypoxic degradable phosphorylcholine polymer nanogel as claimed in claim 5, wherein the concentration of MPC in the hypoxic degradable phosphorylcholine polymer nanogel prepared by the reflux precipitation polymerization method is 1mg m L-1～50mg mL-1The concentration of the hypoxic degradable cross-linking agent is 0.2mg m L-1～10mg mL-1The azo initiator concentration was 0.01mg m L-1～1.0mg mL-1。
9. The method for preparing the hypoxic degradable phosphorylcholine polymer nanogel according to claim 588, wherein the method for preparing the hypoxic degradable phosphorylcholine polymer nanogel by adopting the reflux precipitation polymerization method comprises the following steps of (1) dissolving MPC, a hypoxic degradable cross-linking agent and an azo initiator in an organic solvent, and performing ultrasonic treatment for 3 minutes to uniformly disperse the solution; (2) introducing nitrogen for 10 minutes, heating to 100 ℃, reacting for 1 hour at the temperature in the nitrogen atmosphere, cooling, centrifuging at a high speed, removing the organic solvent, adding water for dispersion, centrifuging again, repeating the water washing process for three times, and freeze-drying the obtained sample to obtain the hypoxic degradable phosphorylcholine polymer nanogel.
10. The application method of the hypoxic degradable phosphorylcholine polymer nanogel according to claim 1, characterized in that the hypoxic degradable phosphorylcholine polymer nanogel is used as a carrier, and the nanogel is used for loading an anti-tumor drug to treat tumors, wherein the anti-tumor drug is one or more of adriamycin, camptothecin, paclitaxel, docetaxel and cisplatin; the drug-loading rate of the hypoxic degradable phosphorylcholine polymer nanogel is 3-30 percent; the antitumor drug is loaded into the hypoxic degradable phosphorylcholine polymer nanogel by a swelling adsorption or organic solvent volatilization method.
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