CN111632152A - PH-GSH dual-responsiveness nano curcumin prodrug drug loading system - Google Patents
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Abstract
The invention discloses a pH-GSH double-responsiveness nano curcumin prodrug drug carrying system, which adopts water-soluble column [5] arene with pH responsiveness as a host molecule, adopts disulfide bond with GSH responsiveness and pyridine salt modified phenylboronic acid derivatives as guest molecules, modifies curcumin on the guest molecules through forming a boroester bond with pH stimulation response with the phenylboronic acid derivatives, forms amphiphilic curcumin prodrug molecules after host-guest complexation, and further enables the amphiphilic curcumin prodrug molecules to be self-assembled in aqueous solution to form nano particles by utilizing hydrophilic and hydrophobic effects, thereby obtaining the pH-GSH double-responsiveness nano curcumin prodrug system. Can be used for the transportation of anti-cancer drugs, and achieves the purpose of drug combination. Solves the problems of single medicine application and single stimulation response in a nano medicine carrying system, meets the development requirements of the current society, and has good application and development prospects.
Description
Technical Field
The invention belongs to the field of nano biomedical materials, relates to a drug loading system and preparation thereof, and particularly relates to a pH-GSH (glutathione-glutathione) double-responsiveness nano curcumin prodrug drug loading system.
Background
Research shows that in cancer treatment, most anticancer drugs have poor water solubility, low utilization rate and toxic and side effects on normal cells, which are always difficult problems in the chemotherapy process. Therefore, the structure design and modification are carried out on the micromolecule anticancer drug with poor water solubility, and the active group of the micromolecule anticancer drug is protected to form a prodrug molecule, so that the water solubility of the hydrophobic drug can be improved; differences between the microenvironment inside cancer cells and normal cells, such as lower pH, higher concentration of Glutathione (GSH), etc., can stimulate prodrug molecules to release active drugs, but not or less in normal cells, thereby reducing the toxic and side effects of the drugs on normal cells.
Curcumin (Curcumin, Cur) is a yellow polyphenol compound, and has wide pharmacological activity in the aspects of tumor resistance, inflammation resistance, oxidation resistance, blood pressure reduction, cholesterol reduction and the like, but the poor water solubility limits the clinical application of Curcumin. A nano prodrug system is a drug delivery system which can be self-assembled in aqueous solution to form a nano structure by designing and modifying the structure of the traditional anticancer drug. The drug delivery system has a high-permeability long-retention effect (EPR effect), can improve the water solubility of the drug, can be preferentially enriched in tumor tissues, releases an active drug after the current drug system is stimulated in cancer cells, and shows excellent anti-tumor performance in vitro and in vivo experiments. In 2017, gingerrin and the like modify phenylboronic acid on a polyethylene glycol-polyacrylic acid polymer (PEG-PPH), Cur and phenylboronic acid form a boroester bond to be modified on the polymer, the polymer is self-assembled in an aqueous solution to form a nano structure, the dispersibility and the stability are good, and the Cur is released under the stimulation response of a tumor microenvironment, so that the efficient drug delivery and the effective cancer treatment are realized.
However, the prodrug delivery system constructed by using a polymer mode has the defects of complex system structure, low drug loading rate, single stimulation response and low drug release rate, so that the construction of the nano prodrug system with easy synthesis, high loading rate and multiple stimulation responses has great significance.
Disclosure of Invention
Aiming at the defects or shortcomings in the prior art, the invention mainly aims to provide a multifunctional nano prodrug drug carrier system with good biocompatibility and double responsiveness.
In order to realize the task, the invention adopts the following technical solution:
a pH-GSH double-responsiveness nano curcumin prodrug drug carrying system is characterized in that water-soluble column [5] arene with pH responsiveness is used as a host molecule, disulfide bond with GSH responsiveness and pyridinium modified phenylboronic acid derivatives are used as guest molecules, curcumin is modified on the guest molecules through a boroester bond with pH stimulation response formed by the curcumin and the phenylboronic acid derivatives, amphiphilic curcumin prodrug molecules are formed after host-guest complexation, and the amphiphilic curcumin prodrug molecules are self-assembled in an aqueous solution to form nanoparticles by using hydrophilic and hydrophobic effects, so that the pH-GSH double-responsiveness nano curcumin prodrug system is obtained.
According to the invention, the pH responsiveness of the water-soluble column [5] arene comes from water-soluble carboxylate therein; the disulfide bond and pyridinium-modified phenylboronic acid derivative having a disulfide bond from which GSH responsiveness is derived; the curcumin prodrug is curcumin and phenylboronic acid derivatives which are connected through a boron ester bond, and the pH responsiveness of the curcumin prodrug comes from the boron ester bond.
The preparation method of the pH-GSH double-responsiveness nano curcumin prodrug drug-loading system is characterized by comprising the following steps:
1) modifying carboxylate with pH responsiveness on the column [5] arene macrocyclic molecule to obtain water-soluble column [5] arene as a main molecule;
2) carrying out host-guest complexation on a guest molecule disulfide bond and a pyridine salt modified phenylboronic acid derivative and a host molecule water-soluble column [5] arene to prepare a compound with a pH-GSH dual response;
3) connecting a pH-GSH double-response compound with curcumin in an aqueous solution through a boron ester bond to form an amphiphilic curcumin prodrug molecule and construct a nano curcumin prodrug system;
4) the amphiphilic curcumin prodrug molecule forms nano particles by utilizing the hydrophilic and hydrophobic effects to form a pH-GSH dual-responsiveness nano curcumin prodrug drug-carrying system.
Experiments of the applicant show that the pH-GSH double-response nano curcumin prodrug drug-carrying system
The experiment result shows that the pH-GSH double-responsiveness nano curcumin prodrug drug-loading system not only has good biocompatibility, but also can effectively reduce the toxic and side effects of the anticancer drug on normal cells; compared with a single anti-cancer drug such as curcumin or adriamycin, the nano curcumin prodrug system can enhance the killing capacity of the anti-cancer drug to cancer cells, realizes the effect of jointly treating cancer by the two anti-cancer drugs, and provides a new way for constructing a pH-GSH dual-responsiveness nano curcumin prodrug drug loading system.
The pH-GSH double-responsiveness nano curcumin prodrug drug carrying system provided by the invention enables an anticancer drug curcumin with poor water solubility to form prodrug molecules through structural modification, so that the water solubility of the prodrug molecules is improved. The breaking of nano prodrug particles in a system is promoted by utilizing the GSH with lower pH and higher concentration in the cancer cells, so that the loaded anticancer drug is quickly released in the cancer cells, and the curcumin prodrug molecules can be stimulated to release the active drug curcumin. Compared with the prior art. Has the following technical innovation:
(1) solves the problems of single medicine application and single stimulation response in a nano medicine carrying system, meets the development requirements of the current society, and has good application and development prospects.
(2) Compared with small molecular drugs, the nano curcumin prodrug drug carrying system has higher drug carrying capacity and can avoid the leakage of drugs wrapped by nano carriers in the transportation process.
(3) The nano curcumin prodrug system with double-load anticancer drugs can accelerate the nanoparticles to break and release curcumin and other anticancer drugs under the stimulation of lower pH and higher-concentration GSH in cancer cells, so that the purpose of drug combination is achieved, and the killing power on the cancer cells is improved.
Drawings
Fig. 1 is a schematic diagram of the preparation of the pH-GSH dual-responsive nanocurchin prodrug drug delivery system of the present invention and the release of anticancer drugs in cancer cells;
figure 2 is a scanning electron micrograph of a pH-GSH dual-responsive nanocurcumin prodrug system;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the compound WP5 obtained in example 5;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of Compound G obtained in example 7;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of WP5G obtained in example 8;
FIG. 6 is the ultraviolet absorption spectrum of amphipathic curcumin prodrug molecule WP5G-Cur obtained in example 9;
figure 7 is the cytotoxicity experimental results of the obtained pH-GSH dual-responsive nanocrystallized curcumin prodrug drug-loaded system;
figure 8 is an in vitro simulated release curve of the resulting pH-GSH dual-responsive nanocrystallized curcumin prodrug drug-loaded system;
fig. 9 is the results of laser confocal experiments of the resulting pH-GSH dual-responsive nanocrystallized curcumin prodrug drug carrier system, wherein panel a is the DAPI channel (blue fluorescence), panel b is the DOX-HCl channel (red fluorescence), panel c is the Cur channel (green fluorescence), and panel d is the combination of panels a, b, and c.
The present invention will be described in further detail with reference to the following drawings and examples.
Detailed Description
In order to make the objects, technical schemes and advantages of the present invention more clearly understood, the pH-GSH dual-responsive curcumin nano prodrug drug-carrying system and the preparation process thereof are given in the following examples, which should be understood as merely illustrative and not limiting of the present invention.
Referring to fig. 3, fig. 4, fig. 5 and fig. 6, in this embodiment, a pH-GSH dual-responsiveness nano curcumin prodrug drug delivery system is provided, which adopts water-soluble carboxylate functionalized column [5] arene with pH responsiveness as a host molecule, pyridine salt and a bisulphide bond modified phenylboronic acid derivative as a guest molecule, and prepares a pH-GSH dual-responsiveness compound through host-guest complexation, and an anticancer drug curcumin is connected with the compound through a boronate bond to form an amphiphilic curcumin prodrug molecule; the amphiphilic curcumin prodrug molecule forms a multifunctional nanoparticle through hydrophilic and hydrophobic effects, and an anticancer drug is loaded in pores of the nanoparticle, so that a pH-GSH dual-responsiveness nano curcumin prodrug drug loading system is formed.
The pH-GSH dual responsiveness is derived from column [5] arene functionalized by carboxylate in amphiphilic curcumin prodrug molecules, and disulfide bonds and boroester bonds in guest molecules.
The curcumin prodrug molecules can obviously improve the solubility of curcumin in an aqueous solution, and the nano curcumin prodrug particles not only have higher drug loading capacity, realize the active protection of the curcumin serving as an anti-cancer drug, but also can avoid the leakage of the curcumin in the transportation process.
The selectivity of the pH-GSH double-response group is derived from:
1) the main molecule is water-soluble carboxylate functionalized column [5] arene, and the pH responsiveness of the water-soluble carboxylate is derived from water-soluble sodium carboxylate;
2) the guest molecule is a phenylboronic acid derivative containing a disulfide bond and a pyridinium, and the GSH responsiveness of the phenylboronic acid derivative is the disulfide bond in the phenylboronic acid derivative;
3) the curcumin prodrug is an anticancer drug curcumin and phenylboronic acid derivative which are connected through a boron ester bond, and the pH responsiveness of the curcumin prodrug is derived from the boron ester bond in the curcumin and the phenylboronic acid derivative.
The pH-GSH double-responsiveness nano curcumin prodrug drug loading system can be used for the application of anticancer drug transportation, and the drug loading system promotes the break of a boron ester bond and the enhancement of the hydrophobicity of water-soluble carboxylate in the system by utilizing the lower pH environment of lysosomes, inclusion bodies and the like in cancer cells, so that the anticancer drug curcumin is released; and meanwhile, the GSH with higher concentration in the cancer cells promotes the disulfide bonds in the system to be rapidly broken, and the breaking of the nano particles is accelerated, so that the loaded anti-cancer drugs are rapidly released in the cancer cells, the purpose of drug combination is achieved, and the killing power to the cancer cells is improved.
The specific implementation is as follows.
Referring to fig. 1, the preparation method of the pH-GSH dual-responsiveness nano curcumin prodrug drug-loading system comprises the following steps:
1) modifying carboxylate at two ends of column [5] arene to obtain a main molecule WP 5;
2) synthesizing a phenylboronic acid derivative guest molecule G containing a disulfide bond and a pyridinium;
3) the preparation method comprises the steps of enabling phenylboronic acid derivative guest molecules containing disulfide bonds and pyridinium and column [5] arene functionalized by water-soluble carboxylate to form WP5G with pH-GSH double response through host-guest action, enabling an anticancer drug curcumin and WP5G to be connected through a boron ester bond in a solution to form amphiphilic curcumin prodrug molecules WP5G-Cur, enabling the amphiphilic curcumin prodrug molecules to be self-assembled through hydrophilic and hydrophobic effects to form multifunctional nanoparticles, and loading the anticancer drug in pores of the nanoparticles, so that a pH-GSH double response nano curcumin prodrug drug carrying system is constructed.
Synthesis of (mono) Water soluble carboxylate functionalized column [5] arene host molecule WP5
Example 1: synthesis of Compound 2
The synthetic route for compound 2 is as follows:
1, 4-Dimethoxybenzene (0.691g, 5mmol) and paraformaldehyde (0.450g, 15mmol) were weighed out accurately into a 100mL round-bottomed flask, and dissolved in 60mL of 1, 2-dichloroethane. Then, boron trifluoride ethyl ether (0.75ml, 6mmol) is added into the solution, stirred for 2 hours at normal temperature under the protection of nitrogen, and then ice water is added to quench the reaction after the reaction is finished. Filtration was carried out at atmospheric pressure, and then the solvent was removed using a rotary evaporator. Dissolving the residue in Dichloromethane (DCM), washing with deionized water, saturated NaHCO3 solution and saturated NaCl solution for 3 times, respectively, collecting the organic phase, drying with anhydrous MgSO4 for 2h, filtering, distilling under reduced pressure to remove the organic solvent to obtain crude product, and separating by column chromatography (petroleum ether/dichloromethane, v/v ═ 2: 1) to obtain white solid, i.e. compound 2.
Example 2: synthesis of Compound 3
The synthetic route for compound 3 is as follows:
compound 2(0.660g,0.88mmol) was weighed accurately into a 50mL round-bottom flask, dissolved by adding 20mL dry DCM, boron tribromide (4mL, 43mmol) was added dropwise, and stirred at room temperature under nitrogen for 24 h. After the reaction was completed, ice water was added to quench the reaction. Adding ice water, stirring for 30min, filtering to obtain a white solid, and washing with 1mmol/L hydrochloric acid and chloroform to obtain a compound 3. (this compound was unstable and, after selection, was directly used as the next step).
Example 3: synthesis of Compound 4
The synthetic route for compound 4 is as follows:
compound 3(0.610g, 1mmol) was dispersed in 30mL acetonitrile and K was added to the suspension2CO3(1.658g, 12mmol) was stirred at room temperature for 30 min. Ethyl bromoacetate (2mL, 18mmol) and KI (0.166g, 1mmol) were then added and refluxed for 24h under nitrogen. After the reaction is finished and the solution is naturally cooled, filtering to remove excessive K2CO3, and then removing the solvent using a rotary evaporator. The residue was redissolved in DCM, washed 3 times with deionized water, saturated NaCl solution, respectively, the organic phase was collected and washed with anhydrous Na2SO4 was dried for 2 h. After filtration at normal pressure and distillation under reduced pressure to remove the organic solvent, the crude product was obtained and separated by column chromatography (dichloromethane/methanol, v/v 50:1) to give orange solid 4.
Example 4: synthesis of Compound 5
The synthetic route for compound 5 is as follows:
compound 4(0.294g, 0.2mmol) was weighed accurately into a 50mL round-bottomed flask, dissolved by adding 12mL Tetrahydrofuran (THF), and heated under reflux for 18h by adding 6mL of 20% NaOH solution into the round-bottomed flask. After the reaction solution was cooled to room temperature, the mixture was distilled under reduced pressure to remove the solvent. The residue was dissolved in 20mL of deionized water and then acidified by dropwise addition of 1mmol/L hydrochloric acid until no more precipitate formed in the solution. Centrifuging the above solution at 8000rpm for 5min, removing supernatant to obtain white solid, washing with water for 3 times, and vacuum drying to obtain compound 5.
Example 5: synthesis of Compound WP5
The synthetic route for compound WP5 is as follows:
compound 5(0.240g, 0.2mmol) was weighed accurately into a 25mL round bottom flask and 4mL deionized water was added. NaOH (0.080mg,0.2mmol) is accurately weighed and dissolved in 1mL of deionized water, and then dropwise added into the solution and continuously shaken until the mixed solution is just completely clear. By vacuum drying, compound WP5 was obtained as a light yellow solid. The nuclear magnetic resonance hydrogen spectrum of the compound WP5 is shown in FIG. 3.
Synthesis of (di) pyridine salt-containing phenylboronic acid derivative guest molecule G with disulfide bond
Example 6: synthesis of Compound 8
The synthetic route for compound 8 is as follows:
compound 7(0.772g, 5mmol) was weighed accurately into a 50mL round-bottomed flask, 15mL acetonitrile was added as a solvent, dicyclohexylcarbodiimide (DCC, 1.236g, 6mmol) and 4-dimethylaminopyridine (DMAP, 0.061g, 0.5mmol) were added, and the mixture was stirred at room temperature for 30 min. 6-Bromohexanoic acid (0.975g, 5mmol) was dissolved in 5mL acetonitrile and added dropwise to a round bottom flask and stirred at room temperature for 72 h. After the reaction was complete, the reaction was filtered, the solvent was removed using a rotary evaporator, the residue was redissolved with DCM, washed 3 times with deionized water and saturated NaCl solution, respectively, the organic phase was collected and dried for 2h over anhydrous MgSO 4. Filtering under normal pressure to remove the drying agent, and removing the solvent by using a rotary evaporator to obtain a crude product. Compound 8 was obtained by column chromatography (petroleum ether/ethyl acetate, v/v 6: 1).
Example 7: synthesis of Compound G
The synthetic route for compound G is as follows:
compound 9(0.830g, 5mmol) was weighed accurately into a 50mL round-bottomed flask, dried THF (15mL) was added as solvent followed by thionyl chloride (5.950g, 50mmol) and stirred at room temperature for 12 h. After the reaction, the solvent was removed using a rotary evaporator. Dry pyridine was added to a round bottom flask, compound 8(0.662g, 2mmol) was added and heated to 80 ℃ under nitrogen for 24 h. After the solution is naturally cooled, the compound G can be obtained by column chromatography (dichloromethane/methanol, v/v ═ 10:1), and the nuclear magnetic resonance hydrogen spectrum of the compound G is shown in fig. 4.
(III) preparation of WP5G formed by complexing host and guest with pH-GSH dual stimulus responsiveness
Example 8:
WP5G preparation route is as follows:
accurately weigh 7.1mg WP5 and 2.5mg G, respectively in CD3OD：D2O is 1: 1 in the mixed solvent, and performing nuclear magnetic resonance hydrogen spectrum characterization. FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the amphipathic molecule WP 5G. (IV) preparation of pH-GSH dual-stimulus responsive amphiphilic curcumin prodrug molecule WP5G-Cur
Example 9:
the amphiphilic curcumin prodrug molecule WP5G-Cur with pH-GSH dual stimulus responsiveness is prepared by the following steps:
cur was weighed accurately and prepared into a 33 μ M Cur solution (with 5% methanol added to aid dissolution), while WP5G was weighed accurately and prepared into a WP5G solution of the same concentration. Mixing the two solutions in equal proportion, and stirring at normal temperature for 12h in a dark condition. Furthermore, 1mL of deionized water was added to 1mL of each of the above Cur solution and WP5G solution, and the mixture was stirred uniformly. And (3) performing ultraviolet-visible absorption spectrum measurement on the solution by using an ultraviolet-visible spectrophotometer. Figure 6 is an ultraviolet absorption spectrum of curcumin prodrug drug-loaded system with pH-GSH dual responsiveness.
(V) preparation of pH-GSH dual-stimulus responsive amphiphilic curcumin prodrug molecule WP5G-Cur
Example 10:
the amphiphilic curcumin prodrug molecule WP5G-Cur with pH-GSH dual stimulus responsiveness is prepared by the following steps:
quantitatively weighing an anticancer drug DOX & HCl, dissolving in deionized water to prepare a standard solution of 500 mu M, adding an equivalent amount of prepared WP5G-Cur solution, carrying out ultrasonic treatment for 2h in a dark condition, and standing for 24h to encapsulate the drug. And (3) dripping a small amount of the prepared solution on the surface of a copper mesh, dyeing, naturally airing, and observing by using a scanning electron microscope. Figure 2 shows a scanning electron microscope picture of a pH-GSH double-responsiveness nano curcumin prodrug drug-loading system.
In addition, the applicant also carried out cytotoxicity experiments on the pH-GSH dual-responsive nano curcumin prodrug drug-loading system (figure 7); in vitro simulated release curve of pH-GSH dual-responsive nanocurcated curcumin prodrug drug-loaded system (fig. 8); and laser confocal experiments of cancer cell uptake of pH-GSH dual-responsive nanocrystallized curcumin prodrug drug carrier (fig. 9), in fig. 9, panel a is DAPI channel (blue fluorescence), panel b is DOX-HCl channel (red fluorescence), panel c is Cur channel (green fluorescence), and panel d is a combination of panels a, b and c.
The nanometer medicine carrying system is successfully absorbed by cancer cells and releases antitumor drugs of adriamycin hydrochloride and curcumin through laser confocal experiments, and meanwhile, the pH-GSH double-responsiveness nanometer curcumin prodrug medicine carrying system is proved to have pH-GSH double-stimulation responsiveness; the pH-GSH double responsiveness of the drug-loaded system is verified through an in-vitro simulated release experiment; the cytotoxicity experiment proves that the medicine carrying system has better biocompatibility and improves the killing power of the medicine to cancer cells. The prodrug drug-loaded system of the multifunctional nanoparticles has the advantages of simple preparation process, short preparation period and good biocompatibility, and shows good application and development prospects in the nanometer drug-loaded system.
The above-described embodiments are preferred embodiments in order to facilitate a person of ordinary skill in the art to clearly understand and apply the present invention, and the present invention is not limited to the above-described embodiments. It will be apparent to those skilled in the art that various additions and substitutions can be easily made without undue inventive effort to these embodiments. Therefore, those skilled in the art should also make additions and substitutions to the technical solution of the present invention.
Claims (5)
1. A pH-GSH double-responsiveness nano curcumin prodrug drug carrying system is characterized in that water-soluble column [5] arene with pH responsiveness is used as a host molecule, disulfide bond with GSH responsiveness and pyridinium modified phenylboronic acid derivatives are used as guest molecules, curcumin is modified on the guest molecules through a boroester bond with pH stimulation response formed by the curcumin and the phenylboronic acid derivatives, amphiphilic curcumin prodrug molecules are formed after host-guest complexation, and the amphiphilic curcumin prodrug molecules are self-assembled in an aqueous solution to form nanoparticles by using hydrophilic and hydrophobic effects, so that the pH-GSH double-responsiveness nano curcumin prodrug system is obtained.
2. The pH-GSH dual-responsive nanocurcated curcumin prodrug drug delivery system of claim 1, wherein the pH-responsiveness of said water-soluble column [5] arene is derived from a water-soluble carboxylate salt thereof; the disulfide bond and pyridinium-modified phenylboronic acid derivative having a disulfide bond from which GSH responsiveness is derived; the curcumin prodrug is curcumin and phenylboronic acid derivatives which are connected through a boron ester bond, and the pH responsiveness of the curcumin prodrug comes from the boron ester bond.
3. The preparation method of the pH-GSH dual-responsive nanocurchin prodrug drug carrier system of claim 1 or 2, which is characterized by comprising the following steps:
1) modifying carboxylate with pH responsiveness on the column [5] arene macrocyclic molecule to obtain water-soluble column [5] arene as a main molecule;
2) carrying out host-guest complexation on a guest molecule disulfide bond and a pyridine salt modified phenylboronic acid derivative and a host molecule water-soluble column [5] arene to prepare a compound with a pH-GSH dual response;
3) connecting a pH-GSH double-response compound with curcumin in an aqueous solution through a boron ester bond to form an amphiphilic curcumin prodrug molecule and construct a nano curcumin prodrug system;
4) the amphiphilic curcumin prodrug molecule forms nano particles by utilizing the hydrophilic and hydrophobic effects to form a pH-GSH dual-responsiveness nano curcumin prodrug drug-carrying system.
4. The use of the pH-GSH dual-responsive nanocurchin prodrug drug delivery system of claim 1 or 2 for anticancer drug delivery.
5. The use of claim 4, wherein the release of curcumin is promoted by the use of a lower pH environment of lysosomes, inclusion bodies and the like in cancer cells to promote the break of the boroester bond in the system and the increase of the hydrophobicity of the water-soluble carboxylate; and meanwhile, the GSH with higher concentration in the cancer cells promotes the disulfide bonds in the system to be rapidly broken, and the breaking of the nano particles is accelerated, so that the loaded anti-cancer drugs are rapidly released in the cancer cells, the purpose of drug combination is achieved, and the killing power to the cancer cells is improved.
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