CN111214460A - Folic acid-chitosan-nano-selenium tumor targeted drug delivery system and preparation method thereof - Google Patents
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Abstract
The invention discloses a folate-chitosan-nano-selenium tumor targeted drug-loading system and a preparation method thereof, the targeted drug-loading system consists of three components of folic acid, chitosan and nano-selenium, folic acid is activated, the folic acid is combined with the chitosan to be used as a stabilizer and a coating agent, and then the folic acid is combined with the nano-selenium to form the folate-chitosan-nano-selenium drug-loading system with the tumor targeting effect. The targeting drug-loaded system prepared by the invention has the advantages of small average particle size, uniform particle size distribution, stable property, easy realization of the method, simple operation and strong repeatability.
Description
Technical Field
The invention relates to the technical field of targeting nanometer, in particular to a folate-chitosan-nano-selenium tumor targeting drug loading system and a preparation method thereof.
Background
According to the statistics of the national cancer center, the number of new malignant tumor cases per year in China is more than 350 ten thousand, and the number of death cases is more than 200 ten thousand, wherein lung cancer, breast cancer, gastric cancer and the like are the most common malignant tumors. With the research on the molecular mechanism of tumor, tumor receptors attract extensive attention. The expression of the folate receptor is highly conserved in normal cells and highly expressed in most malignant tumor cells, and the targeted therapy of tumors by using the folate receptor is an effective means. Under physiological conditions, the solubility of the antitumor drug in aqueous solution is low, and after folic acid is directly coupled with drug molecules, the solubility of the drug in polar solution can be further reduced, so that the bioavailability of the drug is reduced. Therefore, finding a proper way for coupling folic acid and drugs to improve bioavailability has extremely important application value. Nanotechnology is an effective means for improving drug efficacy, but most of traditional Nanoparticles (NPs) are rapidly phagocytosed by a reticuloendothelial system after entering the body, so that the number of nanoparticles reaching tumor cells is reduced, and the drug efficacy is reduced, which greatly limits the research and application of nanoparticles in the field of medicine. The folic acid targeting molecule combined with nanotechnology can be used as an effective way to improve bioavailability.
In addition, selenium (Se) can improve the treatment effect of chemotherapeutic drugs and reduce the toxic and side effects of the chemotherapeutic drugs and the drug resistance of tumors. However, the existing data show that the inorganic selenium has obvious effect only at the eutrophication level and the high dosage, but the dosages are close to the toxicity level of the selenium, and the dosage is difficult to control when in use.
It is believed that only ionic selenium is biologically active and toxic, and that selenium in the zero valence state is inactive. Compared with common zero-valent selenium, the nano selenium has obviously changed physical and chemical properties, can be absorbed and utilized by human body, and can exert the specific functions of inorganic selenium and organic selenium. However, the nano selenium is unstable in property and is very easy to be converted into gray or black elemental selenium which is thermally stable but has activity passivation.
Chitosan (CS) as a natural polymer material can exert antitumor activity by activating the immune system, has good biodegradability and biocompatibility, and these unique properties make it a desirable nanoparticle carrier.
Disclosure of Invention
The invention aims to: the targeted drug-loaded system prepared by the method has the advantages of small average particle size, uniform particle size distribution, stable property, easy realization of the preparation method, simple operation and strong repeatability.
The technical solution of the invention is as follows: the folic acid-chitosan-nano selenium tumor targeted drug delivery system activates folic acid through N-hydroxysuccinimide and diimine hydrochloride; synthesizing folic acid-chitosan by acylation reaction, and purifying by dialysis; the nano-selenium is prepared by reducing sodium selenite through ascorbic acid, and is combined with folic acid-chitosan to finally form a nano-targeted drug-loading system.
The preparation method of the folic acid-chitosan-nano selenium tumor targeted drug delivery system comprises the following steps:
(a) activation of Folate (FA): accurately weighing 1.0 g-2.0 g of folic acid, dissolving in 60-120 mL of dimethyl sulfoxide, and stirring at room temperature to completely dissolve the folic acid; adding 0.2 g-0.4 g N-hydroxysuccinimide (NHS) and 0.2 g-1.2 g carbodiimide hydrochloride (EDC & HCl) and uniformly mixing; adding 2-10 mL of triethylamine; placing the mixture in a room temperature environment, and reacting for 24-48 h in a dark place to obtain activated folic acid;
(b) construction of folate-chitosan (FA-CS) System: weighing chitosan, dissolving the chitosan in an acetic acid solution with the mass concentration of 1% to obtain a chitosan stock solution with the mass concentration of 5% -15%; slowly dripping the prepared chitosan stock solution into the activated folic acid prepared in the step (a), placing the activated folic acid in a water bath kettle at the temperature of 40-70 ℃ for reaction for 12-48 h, and adjusting the pH of the system to 9.0 to terminate the reaction; wherein the mass ratio of the activated folic acid to the chitosan is 1: 1-2: 1, and the processes are carried out in a dark place;
(c) purification of folate-chitosan (FA-CS) system: preparing 0.01-0.05 mol/L Phosphate Buffer Solution (PBS), and boiling the dialysis bag with distilled water for 15 minutes; putting the folic acid-chitosan prepared in the step (b) into a dialysis bag, and putting the dialysis bag into PBS buffer solution to remove unreacted folic acid; then transferring the mixture into deionized water for continuous dialysis to remove various inorganic salts; the dialysis process is carried out for 3 days, and the dialysis medium is replaced for 2 times every day; placing the dialyzed folic acid-chitosan in a centrifuge tube, centrifuging for 30min at 4000r/min, discarding the supernatant, adding deionized water, shaking, discarding the supernatant, and repeating the steps for 3 times to remove the residual dimethyl sulfoxide; washing with acetone for 3 times to remove unreacted raw materials; transferring the purified folic acid-chitosan into a watch glass, putting the watch glass into a vacuum drying oven, and carrying out vacuum drying at room temperature to obtain folic acid-chitosan;
(d) preparation and purification of folic acid-chitosan-nano selenium (FA-CS-SeNPs): dissolving the folic acid-chitosan prepared in the step (c) in an acetic acid solution with the mass concentration of 1-5%, and performing ultrasonic dissolution to prepare a folic acid-chitosan solution with the concentration of 1-5 mg/mL; putting 2 mL-6 mL of folic acid-chitosan solution into a beaker, adding 200 muL-600 muL of 0.10mol/L sodium selenite solution, magnetically stirring at room temperature for 6h, transferring the solution into an EP tube, adding 0.10mol/L excess ascorbic acid solution, supplementing 1% acetic acid solution to 10mL, fully mixing, standing at room temperature for 24 h; and (3) putting the crude FA-CS-SeNPs into a dialysis bag, performing dialysis treatment for 24 hours by using deionized water, and changing water for 2 times during the dialysis treatment to obtain the purified folic acid-chitosan-nano selenium (FA-CS-SeNPs).
The invention has the advantages that: the method takes chitosan as a drug carrier and folic acid as a tumor targeting ligand to construct a folic acid-chitosan nano selenium (FA-CS-SeNPs) drug-carrying system with targeting property, reasonably utilizes chitosan resources, deeply develops nano selenium, and has important guiding significance for researching sustained-release preparations taking folic acid receptors as targets.
Drawings
FIG. 1 is the 1-day folate-chitosan-nanoselenium particle size distribution of example 1;
FIG. 2 is the 7-day folate-chitosan-nanoselenium particle size distribution of example 1;
FIG. 3 is the 15-day folate-chitosan-nanoselenium particle size distribution of example 1;
FIG. 4 is a transmission electron micrograph of folate-chitosan-nano-selenium of example 2;
FIG. 5 is the folic acid-chitosan complex of example 3 after vacuum drying.
Detailed Description
The technical solution of the present invention will be further described with reference to the following examples. The following description is only exemplary of the present invention and is not intended to limit the present invention in any way. The description herein is intended to be illustrative of the invention and is not intended to be limiting.
Example 1: the folic acid-chitosan-nano selenium is prepared by the following steps
(a) Activation of Folate (FA): accurately weighing 1.0g of folic acid, dissolving in 60mL of dimethyl sulfoxide, stirring at room temperature to completely dissolve folic acid, adding 0.28g N-hydroxysuccinimide (NHS) and 0.8g of carbodiimide hydrochloride (EDC. HCl), uniformly mixing, adding 6.0mL of triethylamine, placing the mixture in a room-temperature environment, and reacting for 24 hours in a dark place to obtain activated folic acid;
(b) construction of folate-chitosan (FA-CS) System: weighing chitosan, dissolving the chitosan in an acetic acid solution with the mass concentration of 1%, and preparing a chitosan stock solution with the mass concentration of 10%; slowly dripping the prepared chitosan stock solution into the activated folic acid prepared in the step (a), placing the activated folic acid in a water bath kettle at 50 ℃ for reaction for 24 hours, and adjusting the pH of the system to 9.0 to terminate the reaction; wherein the mass ratio of the activated folic acid to the chitosan is 1.5:1, and the processes are carried out in a dark place;
(c) purification of folate-chitosan (FA-CS) system: preparing 0.01mol/L Phosphate Buffer Solution (PBS), and boiling the dialysis bag with distilled water for 15 minutes; putting the folic acid-chitosan prepared in the step (b) into a dialysis bag, and putting the dialysis bag into PBS buffer solution to remove unreacted folic acid; then transferring the mixture into deionized water for continuous dialysis to remove various inorganic salts; the dialysis process is carried out for 3 days, and the dialysis medium is replaced for 2 times every day; placing the dialyzed folic acid-chitosan in a centrifuge tube, centrifuging for 30min at 4000r/min, discarding the supernatant, adding deionized water, shaking, discarding the supernatant, and repeating the steps for 3 times to remove the residual dimethyl sulfoxide; washing with acetone for 3 times to remove unreacted raw materials; transferring the purified folic acid-chitosan into a watch glass, putting the watch glass into a vacuum drying oven, and carrying out vacuum drying at room temperature to obtain folic acid-chitosan;
(d) preparation and purification of folic acid-chitosan-nano selenium (FA-CS-SeNPs): dissolving the folic acid-chitosan prepared in the step (c) in an acetic acid solution with the mass concentration of 1%, and performing ultrasonic dissolution to prepare a folic acid-chitosan solution with the concentration of 1 mg/mL; putting 2 mL-6 mL of folic acid-chitosan solution into a beaker, adding 400 mu L of 0.10mol/L sodium selenite solution, magnetically stirring for 6 hours at room temperature, then transferring the solution into an EP tube, adding 0.10mol/L excess ascorbic acid solution, supplementing 1% acetic acid solution to 10mL, fully mixing uniformly, standing for 24 hours at room temperature; and (3) filling the prepared FA-CS-SeNPs crude product into a dialysis bag, performing dialysis treatment for 24 hours by using deionized water, and changing water for 2 times during the dialysis treatment to obtain the purified folic acid-chitosan-nano selenium (FA-CS-SeNPs).
FIG. 1 is the 1-day folate-chitosan-nanoselenium particle size distribution of example 1; FIG. 2 is the 7-day folate-chitosan-nanoselenium particle size distribution of example 1; FIG. 3 is the 15-day folate-chitosan-nanoselenium particle size distribution of example 1; the particle size of folate-chitosan-nano-selenium on different days is shown in table 1.
TABLE 1 particle size of folate-chitosan-nanoselenium on different days
Example 2: the folic acid-chitosan-nano selenium is prepared by the following steps
(a) Activation of Folate (FA): accurately weighing 1.5g of folic acid, dissolving in 100mL of dimethyl sulfoxide, stirring at room temperature to completely dissolve folic acid, adding 0.3g N-hydroxysuccinimide (NHS) and 0.8g of carbodiimide hydrochloride (EDC. HCl), uniformly mixing, adding 8mL of triethylamine, placing the mixture in a room-temperature environment, and reacting for 48 hours in a dark place to obtain activated folic acid;
(b) construction of folate-chitosan (FA-CS) System: weighing chitosan, dissolving the chitosan in an acetic acid solution with the mass concentration of 1%, and preparing a chitosan stock solution with the mass concentration of 5%; slowly dripping the prepared chitosan stock solution into the activated folic acid prepared in the step (a), placing the activated folic acid in a water bath kettle at 40 ℃ for reaction for 12 hours, and adjusting the pH of the system to 9.0 to stop the reaction; wherein the mass ratio of the activated folic acid to the chitosan is 1:1, and the processes are carried out in a dark place;
(c) purification of folate-chitosan (FA-CS) system: preparing 0.05mol/L Phosphate Buffer Solution (PBS), and boiling the dialysis bag with distilled water for 15 minutes; putting the folic acid-chitosan prepared in the step (b) into a dialysis bag, and putting the dialysis bag into PBS buffer solution to remove unreacted folic acid; then transferring the mixture into deionized water for continuous dialysis to remove various inorganic salts; the dialysis process is carried out for 3 days, and the dialysis medium is replaced for 2 times every day; placing the dialyzed folic acid-chitosan in a centrifuge tube, centrifuging for 30min at 4000r/min, discarding the supernatant, adding deionized water, shaking, discarding the supernatant, and repeating the steps for 3 times to remove the residual dimethyl sulfoxide; washing with acetone for 3 times to remove unreacted raw materials; transferring the purified folic acid-chitosan into a watch glass, putting the watch glass into a vacuum drying oven, and carrying out vacuum drying at room temperature to obtain folic acid-chitosan;
(d) preparation and purification of folic acid-chitosan-nano selenium (FA-CS-SeNPs): dissolving the folic acid-chitosan prepared in the step (c) in an acetic acid solution with the mass concentration of 2%, and performing ultrasonic dissolution to prepare a folic acid-chitosan solution with the concentration of 2 mg/mL; putting 3mL of folic acid-chitosan solution into a beaker, adding 200 mu L of 0.10mol/L sodium selenite solution, magnetically stirring for 6h at room temperature, transferring the solution into an EP tube, adding 0.10mol/L excess ascorbic acid solution, supplementing 1% acetic acid solution to 10mL, fully mixing, standing at room temperature for 24 h; and (3) filling the prepared FA-CS-SeNPs crude product into a dialysis bag, performing dialysis treatment for 24 hours by using deionized water, and changing water for 2 times during the dialysis treatment to obtain the purified folic acid-chitosan-nano selenium (FA-CS-SeNPs).
FIG. 4 is a transmission electron micrograph of folate-chitosan-nano-selenium obtained in example 2.
Example 3: the folic acid-chitosan-nano selenium is prepared by the following steps
(a) Activation of Folate (FA): accurately weighing 2.0g of folic acid, dissolving in 120mL of dimethyl sulfoxide, stirring at room temperature to completely dissolve folic acid, adding 0.4g N-hydroxysuccinimide (NHS) and 1.2g of carbodiimide hydrochloride (EDC. HCl), uniformly mixing, adding 10mL of triethylamine, placing the mixture in a room-temperature environment, and reacting for 48 hours in a dark place to obtain activated folic acid;
(b) construction of folate-chitosan (FA-CS) System: weighing chitosan, dissolving the chitosan in an acetic acid solution with the mass concentration of 1%, and preparing a chitosan stock solution with the mass concentration of 15%; slowly dripping the prepared chitosan stock solution into the activated folic acid prepared in the step (a), placing the activated folic acid in a water bath kettle at 70 ℃ for reaction for 48 hours, and adjusting the pH of the system to 9.0 to terminate the reaction; wherein the mass ratio of the activated folic acid to the chitosan is 2:1, and the processes are carried out in a dark place;
(c) purification of folate-chitosan (FA-CS) system: preparing 0.01mol/L Phosphate Buffer Solution (PBS), and boiling the dialysis bag with distilled water for 15 minutes; putting the folic acid-chitosan prepared in the step (b) into a dialysis bag, and putting the dialysis bag into PBS buffer solution to remove unreacted folic acid; then transferring the mixture into deionized water for continuous dialysis to remove various inorganic salts; the dialysis process is carried out for 3 days, and the dialysis medium is replaced for 2 times every day; placing the dialyzed folic acid-chitosan in a centrifuge tube, centrifuging for 30min at 4000r/min, discarding the supernatant, adding deionized water, shaking, discarding the supernatant, and repeating the steps for 3 times to remove the residual dimethyl sulfoxide; washing with acetone for 3 times to remove unreacted raw materials; transferring the purified folic acid-chitosan into a watch glass, putting the watch glass into a vacuum drying oven, and carrying out vacuum drying at room temperature to obtain folic acid-chitosan;
(d) preparation and purification of folic acid-chitosan-nano selenium (FA-CS-SeNPs): dissolving the folic acid-chitosan prepared in the step (c) in an acetic acid solution with the mass concentration of 5%, and performing ultrasonic dissolution to prepare a folic acid-chitosan solution with the concentration of 5 mg/mL; putting 6mL of folic acid-chitosan solution into a beaker, adding 500 mu L of 0.10mol/L sodium selenite solution, magnetically stirring for 6h at room temperature, transferring the solution into an EP tube, adding 0.10mol/L excess ascorbic acid solution, supplementing 1% acetic acid solution to 10mL, fully mixing, standing for 24h at room temperature; and (3) filling the prepared FA-CS-SeNPs crude product into a dialysis bag, performing dialysis treatment for 24 hours by using deionized water, and changing water for 2 times during the dialysis treatment to obtain the purified folic acid-chitosan-nano selenium (FA-CS-SeNPs).
As shown in FIG. 5, the Zeta potentials of folic acid-chitosan-nano-selenium for different days of the vacuum-dried folic acid-chitosan complex of example 3 are shown in Table 2.
TABLE 2 Folic acid-Chitosan-Nano-selenium Zeta potential on different days
Claims (2)
1. The folic acid-chitosan-nano-selenium tumor targeted drug delivery system is characterized in that: activating folic acid by N-hydroxysuccinimide and diimine hydrochloride; synthesizing folic acid-chitosan by acylation reaction, and purifying by dialysis; the nano-selenium is prepared by reducing sodium selenite through ascorbic acid, and is combined with folic acid-chitosan to finally form a nano-targeted drug-loading system.
2. The preparation method of the folate-chitosan-nano-selenium tumor targeted drug delivery system according to claim 1, which comprises the following steps:
(a) activation of Folate (FA): accurately weighing 1.0 g-2.0 g of folic acid, dissolving in 60-120 mL of dimethyl sulfoxide, and stirring at room temperature to completely dissolve the folic acid; adding 0.2 g-0.4 g N-hydroxysuccinimide (NHS) and 0.2 g-1.2 g carbodiimide hydrochloride (EDC & HCl) and uniformly mixing; adding 2-10 mL of triethylamine; placing the mixture in a room temperature environment, and reacting for 24-48 h in a dark place to obtain activated folic acid;
(b) construction of folate-chitosan (FA-CS) System: weighing chitosan, dissolving the chitosan in an acetic acid solution with the mass concentration of 1% to obtain a chitosan stock solution with the mass concentration of 5% -15%; slowly dripping the prepared chitosan stock solution into the activated folic acid prepared in the step (a), placing the activated folic acid in a water bath kettle at the temperature of 40-70 ℃ for reaction for 12-48 h, and adjusting the pH of the system to 9.0 to terminate the reaction; wherein the mass ratio of the activated folic acid to the chitosan is 1: 1-2: 1, and the processes are carried out in a dark place;
(c) purification of folate-chitosan (FA-CS) system: preparing 0.01-0.05 mol/L Phosphate Buffer Solution (PBS), and boiling the dialysis bag with distilled water for 15 minutes; putting the folic acid-chitosan prepared in the step (b) into a dialysis bag, and putting the dialysis bag into PBS buffer solution to remove unreacted folic acid; then transferring the mixture into deionized water for continuous dialysis to remove various inorganic salts; the dialysis process is carried out for 3 days, and the dialysis medium is replaced for 2 times every day; placing the dialyzed folic acid-chitosan in a centrifuge tube, centrifuging for 30min at 4000r/min, discarding the supernatant, adding deionized water, shaking, discarding the supernatant, and repeating the steps for 3 times to remove the residual dimethyl sulfoxide; washing with acetone for 3 times to remove unreacted raw materials; transferring the purified folic acid-chitosan into a watch glass, putting the watch glass into a vacuum drying oven, and carrying out vacuum drying at room temperature to obtain folic acid-chitosan;
(d) preparation and purification of folic acid-chitosan-nano selenium (FA-CS-SeNPs): dissolving the folic acid-chitosan prepared in the step (c) in an acetic acid solution with the mass concentration of 1-5%, and performing ultrasonic dissolution to prepare a folic acid-chitosan solution with the concentration of 1-5 mg/mL; putting 2 mL-6 mL of folic acid-chitosan solution into a beaker, adding 200 muL-600 muL of 0.10mol/L sodium selenite solution, magnetically stirring at room temperature for 6h, transferring the solution into an EP tube, adding 0.10mol/L excess ascorbic acid solution, supplementing 1% acetic acid solution to 10mL, fully mixing, standing at room temperature for 24 h; and (3) putting the crude FA-CS-SeNPs into a dialysis bag, performing dialysis treatment for 24 hours by using deionized water, and changing water for 2 times during the dialysis treatment to obtain the purified folic acid-chitosan-nano selenium (FA-CS-SeNPs).
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CN114569554A (en) * | 2022-03-01 | 2022-06-03 | 福建省医学科学研究院 | Tumor-targeting triptolide emulsion and preparation method thereof |
CN115176869A (en) * | 2022-08-02 | 2022-10-14 | 安徽创冠富硒生物科技有限公司 | Preparation process of selenium-rich biological feed |
CN115708807A (en) * | 2022-11-08 | 2023-02-24 | 武汉轻工大学 | Preparation method of nano-selenium-loaded starch nano-micelle material and pharmaceutical preparation |
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CN112957483A (en) * | 2021-02-24 | 2021-06-15 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of intestinal targeted photoacoustic imaging contrast agent and product thereof |
CN114392245A (en) * | 2022-01-10 | 2022-04-26 | 自然资源部第三海洋研究所 | Dopamine-embedded nano-selenium assembly compound and preparation method thereof |
CN114392245B (en) * | 2022-01-10 | 2023-10-10 | 自然资源部第三海洋研究所 | Dopamine-embedded nano-selenium assembled compound and preparation method thereof |
CN114569554A (en) * | 2022-03-01 | 2022-06-03 | 福建省医学科学研究院 | Tumor-targeting triptolide emulsion and preparation method thereof |
CN115176869A (en) * | 2022-08-02 | 2022-10-14 | 安徽创冠富硒生物科技有限公司 | Preparation process of selenium-rich biological feed |
CN115708807A (en) * | 2022-11-08 | 2023-02-24 | 武汉轻工大学 | Preparation method of nano-selenium-loaded starch nano-micelle material and pharmaceutical preparation |
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