CN107837233B - Temperature-sensitive nano-targeting folic acid copolymer micelle for tumors - Google Patents
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Abstract
The invention discloses a temperature-sensitive nano-targeting folic acid copolymer micelle for tumors. The PEG-COthe-PNIPAAm-FA is prepared from folic acid-N-bromosuccinimide (FA-NBS) and polyethylene glycol-poly-N-isopropyl acrylamide gel (PEG-CO-PNIPAAm) material is formed into a folic acid mediated targeting polymer with temperature-sensitive characteristic according to the mass ratio of 1:0.5-1:10, a polyethylene glycol (PEG) hydrophilic section of the material can form a film-like structure to wrap poly N-isopropyl acrylamide (PNIPAAm) to form a hydrophobic inner core, and the hydrophobic inner core wraps an anticancer drug; the drug carrier encapsulates the insoluble antitumor drug, quickly reaches the tumor part under the folic acid targeting, so that the drug carrier effectively avoids macrophages, quickly releases the drug at the temperature higher than the low critical solution temperature, and constructs a folic acid receptor temperature-sensitive targeted nano drug-loaded micelle drug delivery system.
Description
Technical Field
The invention relates to the field of novel drug carriers, in particular to a temperature-sensitive nano-targeting folic acid copolymer micelle for tumors.
Background
Diseases such as tumor, rheumatoid arthritis and the like endanger the health and life of human bodies, and how to improve the therapeutic index is the responsibility of medical researchers, so that the method also has important practical significance. In recent years, nanotechnology has been widely applied to numerous fields of biomedicine, and drug-loaded nanoparticles prepared by means of nanotechnology are widely concerned and deeply studied. The amphiphilic macromolecular block copolymer can spontaneously form a self-assembly structure in water: nanoparticles with a typical core-shell structure, with the hydrophobic end facing inwards and the hydrophilic end facing outwards. Hydrophobic drugs enter the hydrophobic core of the nanoparticle by virtue of interaction between the hydrophobic drug and the hydrophobic core in the nanoparticle to form the embedded hydrophobic drug-loaded nanoparticle, so that the poly-N-isopropyl acrylamide (PNIPAAm) hydrophilic gel serving as a novel drug release system has unique reversible temperature-sensitive characteristic and shows a Low Critical Solution Temperature (LCST). Pure PNIPAAm is in an expanded state when the external temperature is below the LCST and shrinks above this temperature.
Folic Acid (FA) is a small molecule vitamin with a pterin ring in its molecular structure. Compared with proteins such as monoclonal antibodies, small molecular polypeptides and the like, folic acid has the characteristics of stable structure, low price, no immunity and the like. The folic acid and the Folate Receptor (FR) have strong binding force, can be efficiently mediated to carry out endocytosis to enter tumor cells, and is a target substance with high application value. Folate receptors are widely distributed in normal and tumor tissues, while the FR on the surface of tumor cells is much higher in number and activity than normal cells. FR is expressed less in most neonatal normal tissues, limited to the apical membrane of epithelial cells that are difficult to access in the blood circulation, and highly expressed on the surface of a variety of malignant cells, including ovarian, colorectal, breast, liver, lung, and renal cell carcinomas, among others. If FA is connected on the surface modification of the nanoparticle, the targeting recognition and targeting combination of the nanoparticle to tumor cells can be effectively realized by utilizing the specific combination between FA ligand and FR receptor. Thereby avoiding the cytotoxic effect of the nanoparticle-embedded chemotherapeutic drug on normal tissues, improving the treatment effect on tumors and increasing the chemotherapy tolerance of cancer patients.
The ideal anticancer drug or drug carrier system can reach the tumor part in a targeting way and take effect quickly, and has no adverse reaction to normal tissues. In recent years, the self-assembly two-block polymer carrier folic acid-polyethylene glycol-polyglutamic acid (folate-PEG-PNIPAAM) has attracted much attention. The PNIPAAM can be self-assembled to form a hydrophobic core, the hydrophobic core can be wrapped with anticancer drug adriamycin (DOX), the PEG hydrophilic section can form a membrane-like structure to be wrapped on the surface of the hydrophobic core, and the drug carrier can quickly reach a tumor part under the folate targeting.
Disclosure of Invention
The invention aims to solve the technical problem of providing a temperature-sensitive nano-targeting folic acid copolymer micelle for tumor, aiming at synthesizing PEG-CO-PNIPAAm-FA; the temperature-sensitive material can spontaneously form amphiphilic temperature-sensitive nanoparticles with PNIPAAm as an inner core and PEG/PNIPAAm/PNHMAAm as a hydrophilic coronary shell in water. The drug-loaded temperature-sensitive nanoparticles do not release drug when the external temperature is lower than LCST, and release drug rapidly when the external temperature is higher than LCST; the hydrophobic inner core is a drug storage, the outer core is hydrophilic, and after intravenous injection, local ON-OFF (ON-OFF) intelligent drug release control can be realized due to local high temperature and osmotic retention (EPR) of a tumor part or assisted by local heating of a solid tumor part; the hydrophilic shell of the carrier also has long circulation, can avoid the uptake of reticuloendothelial system (RES) to improve the therapeutic index of solid tumors, and realizes the targeted drug release at tumor parts and the targeted removal of tumor cells.
The technical scheme adopted by the invention comprises the following steps:
(1) preparation of PEO-co-PNIPAAm: putting PEG, PNIPAAm, AIBN and anhydrous DMF at a certain ratio into a polymerization tube filled with magnetons, mixing uniformly, freezing, vacuumizing, thawing in a high-purity nitrogen environment, circulating for three times, and vacuum sealing. Reacting for 4 hours to obtain a white solid product;
(2) preparation of FA-NBS activated lipid: dissolving FA in anhydrous DMF, adding NBS and DCC according to a certain ratio of FA, NBS and DCC, mixing uniformly, and reacting for 14 hours at room temperature in a dark place; filtering DCC by-products to remove, precipitating the filtrate in a mixed solution of acetone and ether with the volume ratio of 3:7, filtering to obtain yellow solid, washing the yellow solid with acetone and ether for three times, and drying the yellow solid in a vacuum drying oven to obtain yellow solid;
(3) preparation of PEO-co-PNIPAAm-FA: dissolving FA-NBS in anhydrous pyridine, slowly adding PEO-co-PNIPAAm according to the mass ratio of FA-NBS to PEO-co-PNIPAAm of 1:1-1:5, reacting for 15h at 20 ℃, obtaining powder, and drying in a vacuum drying oven to obtain a product;
(4) preparing adriamycin (DOX) drug-loaded micelle, dissolving the PEO-co-PNIPAAm-FA prepared in the step (3) in anhydrous chloroform in inert gas, adding an acetonitrile solution of DOX, shaking uniformly, carrying out rotary evaporation to form a film, then putting the film into a vacuum drying oven to volatilize the organic solution completely, hydrating the organic solution with a certain amount of 10mM HBS with pH7.4, oscillating the solution in water bath at 35 ℃ for 30min, and filtering the solution with a 240nm film to remove the drug which is not loaded to obtain the drug-loaded micelle solution.
The PEG-COThe number average molecular weight of-PNIPAAm-FA was 24000 and PDI (Polymer Dispersion index) was 3.1.
Preferably, the FA-NBS and PEG-COThe mass ratio of the-PNIPAAm material is 1:1, and the ester group of the FA-NBS and the PEG-CO-PNIPAAm hydroxyl group are polymerized into the temperature-sensitive PEG-CO-PNIPAAm-FA。
Preferably, the mass ratio of the polyethylene glycol acrylate to the PNIPAAm in the step (1) is as follows: 1:20-1:10.
Preferably, the mass ratio of FA, NBS and DCC in step (2) is: 2:0.5:0.6.
Preferably, the hydrophobic anticancer drug in the drug-loaded micelle of step (4) is Doxorubicin (DOX).
By adding PEG-COAnalysis of nuclear magnetic characterization of PNIPAAm-FA can obtain hydrogen of methylene, amide and benzene ring grafted on folic acid molecules, and magnetic data shows that PEG-PNIPAAm-FA is successfully prepared; by PEG-COFT-IR characterization of-PNIPAAm-FA can obtain strong absorption of 3300cm-1 and absorption of 1700cm-1 belonging to amino and carbonyl on folic acid molecule, respectively, and absorption peaks of 1640cm-1, 1520cm-1 and 1430cm-1 prove benzene ring on folic acid, so that infrared structure also proves that folic acid molecule is successfully modified on PEG-PNIPAAm.
The temperature-sensitive nano-targeting folic acid copolymer micelle for the tumor has the following beneficial effects: the drug-loaded temperature-sensitive nanoparticles do not release drug when the external temperature is lower than LCST, and release drug rapidly when the external temperature is higher than LCST; the PNIPAAM can be self-assembled to form a hydrophobic core, an anticancer drug Doxorubicin (DOX) can be wrapped in the hydrophobic core, the PEG hydrophilic section can form a membrane-like structure to be wrapped on the surface of the hydrophobic core, the drug carrier can quickly reach a tumor part under the folic acid targeting, so that the drug-loaded micelle has the characteristic of effectively avoiding macrophages, entraps an insoluble antitumor drug, quickly releases the drug when the external temperature is 5 ℃ higher than LCST, and constructs a folic acid receptor temperature-sensitive targeted nano drug-loaded micelle drug delivery system.
Drawings
FIG. 1 is a scheme showing the synthesis of Folate-PEG-PNIPAAM.
FIG. 2 is a schematic diagram of a nanoparticle with a core-shell structure constructed by self-assembly of Folate-PEG-PNIPAAM.
FIG. 3 shows the molecular weight characterization of PEG-co-PNIPAAm-FA,
the copolymer PEG-co-PNIPAAm-FA can be obtained by GPC, and the Mn is 24000 and the PDI is 3.1.
FIG. 4 shows nuclear magnetic analysis of PEG-co-PNIPAAm-FA,
nuclear magnetic result analysis: the PEG content was calculated to be 8% by integration of the hydrogen signals for PEG at 3.58 and PNIPAAm at 3.94. 2.70,2.82,2.89,5.28,6.93,7.45,7.95 correspond to the methylene, amide and benzene ring hydrogens of the folate molecule; nuclear magnetic data shows that PEG-PNIPAAm-FA is successfully prepared.
FIG. 5 is a FT-IR characterization of PEG-co-PNIPAAm-FA,
and (3) infrared result analysis: the strong absorption of 3300cm-1 and the absorption of 1700cm-1 belong to amino and carbonyl on folic acid molecules respectively, and the absorption peaks of 1640cm-1, 1520cm-1 and 1430cm-1 prove benzene rings on folic acid. Therefore, the infrared structure also proves that folic acid molecules are successfully modified on the PEG-PNIPAAm.
Fig. 6 is a schematic diagram of active targeting and intracellular drug release of nanoparticles to tumor cells.
FIG. 7 shows the surface topography of PEG-co-PNIPAAm-FA and sample control by using secondary electron image of sample, with Folate-PEG-PNIPAAm in dark color and PEG-PNIPAAm in light color.
FIG. 8 is the in vitro release curve of the adriamycin/follate-PEG-PNIPAAM nano-particle with drug loading rate of 5.6%,
the adriamycin drug-loaded nano-particle is in a sustained release state at 37 ℃ and in a burst release state at 43 ℃, and about 90 percent of adriamycin is finally released from the nano-particle at 43 ℃, which is much higher than the release ratio of adriamycin at 37 ℃.
FIG. 9 shows a scratch contrast test of a hepatoma cell line,
the first, second and third figures show that the adriamycin/Folate-PEG-PNIPAAM nanoparticles release more adriamycin to the liver cancer cell line after being placed in the environment of 40 ℃ for 5 minutes.
FIG. 10 is a comparison graph of the transwell assay of a hepatoma cell line,
the graph IV, the graph V and the graph VI are respectively a liver cancer cell line without drug administration, a liver cancer cell line with adriamycin/Folate-PEG-PNIPAAM nano-particles and a liver cancer cell line with adriamycin/Folate-PEG-PNIPAAM nano-particles which are placed in the environment of 40 ℃ for 5 minutes, and the comparison of the graph IV, the graph V and the graph VI shows that the liver cancer cell line with adriamycin/Folate-PEG-PNIPAAM nano-particles which are placed in the environment of 40 ℃ for 5 minutes has obviously reduced invasion capacity.
Figure 11 shows the staining of rabbit liver VX2 pathological section and apoptosis after RF ablation,
the left arrow shows the area of coagulation necrosis with disappearance of cellular and tissue structures, and the right arrow shows apoptotic cells that are apoptotic.
Detailed Description
The technical solutions in the embodiments of the present invention are described in detail below, and it is obvious that the embodiments are only a part of the embodiments of the present invention, and not all embodiments; all other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.
Example 1
Preparation of PEO-co-PNIPAAm:
(1) weighing 8g of monomer N-isopropyl acrylamide, adding the monomer N-isopropyl acrylamide into a polymerization tube with magnetons, weighing 10g of organic solvent N, N-dimethylformyl, slowly adding the organic solvent N, N-dimethylformyl into the polymerization tube, and uniformly stirring and mixing;
(2) weighing 0.4g of stabilizer polyethylene glycol acrylate and 0.04g of initiator azobisisobutyronitrile, uniformly mixing, adding into the polymerization tube filled with the solution in the step (1), and uniformly stirring and mixing;
(3) freezing a polymerization tube filled with a mixed solution consisting of monomer N-isopropylacrylamide, polyethylene glycol acrylate, an initiator and an organic solvent for 3 hours to obtain a solid, vacuumizing the polymerization tube, and unfreezing the polymerization tube in a high-purity nitrogen environment; freezing, vacuumizing, unfreezing and repeatedly circulating for three times;
(4) freezing, vacuumizing and unfreezing the polymerization tube, circulating for three times, sealing in vacuum, and reacting for 4 hours at the temperature of 20 ℃ to obtain 6.1g of white solid.
Preparation of FA-NBS activated lipid:
(1) weighing 2g of FA, dissolving in anhydrous DMF, adding 0.5g of NBSY, and shaking up; then 0.6g of DCC is added and shaken up;
(2) reacting for 14 hours at room temperature in a dark condition; filtering DCC by-product after reaction;
(3) and (3) putting the filtrate into a mixed solution of acetone and ether with the volume ratio of 3:7 for precipitation, filtering to obtain a yellow solid, repeating the precipitation for 3 times, putting the yellow solid into a vacuum drying oven, and drying at 70 ℃ to obtain a yellow solid product.
Preparation of PEO-co-PNIPAAm-FA:
(1) dissolving 3g of FA-NBS in anhydrous pyridine, weighing 5g of PEO-co-PNIPAAm, slowly adding the PEO-co-PNIPAAm into the pyridine solution, and shaking up;
(2) reacting for 15h at 20 ℃, putting the obtained powder in a vacuum drying oven, drying at 70 ℃, and drying to obtain 2.5g of a product.
4. Preparation of adriamycin (DOX) drug-loaded micelle,
(1) dissolving the PEO-co-PNIPAAm-FA prepared in the step (3) in anhydrous chloroform in inert gas, adding an acetonitrile solution of DOX, shaking up, carrying out rotary evaporation to form a film, and then putting the film into a vacuum drying oven to volatilize the organic solution completely;
(2) hydrating with a certain amount of HBS with pH of 10mM 7.4, oscillating in 35 deg.C water bath for 30min, and filtering with 240nm membrane to remove the drug not entrapped, to obtain drug-loaded micelle solution.
Example 2
Preparation of PEO-co-PNIPAAm:
(1) weighing 8g of monomer N-isopropyl acrylamide, adding the monomer N-isopropyl acrylamide into a polymerization tube with magnetons, weighing 10g of organic solvent N, N-dimethylformyl, slowly adding the organic solvent N, N-dimethylformyl into the polymerization tube, and uniformly stirring and mixing;
(2) weighing 0.35g of stabilizer polyethylene glycol acrylate and 0.04g of initiator azobisisobutyronitrile, uniformly mixing, adding into the polymerization tube filled with the solution in the step (1), and uniformly stirring and mixing;
(3) freezing a polymerization tube filled with a mixed solution consisting of monomer N-isopropylacrylamide, polyethylene glycol acrylate, an initiator and an organic solvent for 2 hours to obtain a solid, vacuumizing the polymerization tube, and unfreezing the polymerization tube in a high-purity nitrogen environment; freezing, vacuumizing, unfreezing and repeatedly circulating for three times;
(4) freezing, vacuumizing and unfreezing the polymerization tube, circulating for three times, sealing in vacuum, and reacting for 3 hours at 25 ℃ to obtain 5.9g of white solid.
Preparation of FA-NBS activated lipid:
(1) weighing 10g of FA, dissolving in anhydrous DMF, adding 2.5g of NBSY, and shaking up; then 3.5g of DCC is added and shaken up;
(2) reacting for 16 hours at room temperature in a dark condition; filtering DCC by-product after reaction;
(3) and (3) putting the filtrate into a mixed solution of acetone and ether with the volume ratio of 3:7 for precipitation, filtering to obtain a yellow solid, repeating the precipitation for 3 times, putting the yellow solid into a vacuum drying oven, and drying at 75 ℃ to obtain a yellow solid product.
Preparation of PEO-co-PNIPAAm-FA:
(1) dissolving 5g of FA-NBS in anhydrous pyridine, weighing 5g of PEO-co-PNIPAAm, slowly adding the PEO-co-PNIPAAm into the pyridine solution, and shaking up;
(2) reacting for 15h at 20 ℃, putting the obtained powder in a vacuum drying oven, drying at 75 ℃, and drying to obtain the product.
4. Preparation of adriamycin (DOX) drug-loaded micelle,
(1) dissolving the PEO-co-PNIPAAm-FA prepared in the step (3) in anhydrous chloroform in inert gas, adding an acetonitrile solution of DOX, shaking up, carrying out rotary evaporation to form a film, and then putting the film into a vacuum drying oven to volatilize the organic solution completely;
(2) hydrating with a certain amount of HBS with pH of 10mM 7.5, oscillating in water bath at 40 deg.C for 20min, and filtering with 230nm membrane to remove the drug not entrapped, to obtain drug-loaded micelle solution.
The above disclosure is only for a few specific embodiments of the present invention, but the present invention is not limited thereto, and any variations and modifications that can be made by those skilled in the art are intended to fall within the scope of the present invention.
Claims (6)
1. A temperature-sensitive nano-targeting folic acid copolymer micelle for tumors is characterized in that PEG-COthe-PNIPAAm-FA is prepared from folic acid-N-bromosuccinimide (FA-NBS) and polyethylene glycol-poly-N-isopropyl acrylamide gel (PEG-COPNIPAAm) to form a folic acid mediated targeting polymer with temperature-sensitive characteristic, wherein a polyethylene glycol (PEG) hydrophilic section of the polymer can form a membrane-like structure to wrap poly N-isopropyl acrylamide (PNIPAAm) to form a hydrophobic core, and the hydrophobic core wraps an anticancer drug.
2. A temperature-sensitive nano-targeting folic acid copolymer micelle for tumors is characterized in that the preparation of the temperature-sensitive nano-targeting folic acid copolymer micelle comprises the following steps:
(1) preparation of PEG-co-PNIPAAm: putting polyethylene glycol acrylate, PNIPAAm, Azobisisobutyronitrile (AIBN) and anhydrous Dimethylformamide (DMF) into a polymerization tube filled with magnetons according to a certain ratio, uniformly mixing, freezing, vacuumizing, thawing in a high-purity nitrogen environment, circulating for three times, and vacuum sealing. Reacting for 4 hours to obtain a white solid product;
(2) preparation of FA-NBS activated lipid: dissolving Folic Acid (FA) in anhydrous DMF, adding NBS and DCC according to a certain ratio of FA, N-bromosuccinimide (NBS) and N, N' -Dicyclohexylcarbodiimide (DCC), mixing uniformly, and reacting for 14 hours at room temperature in a dark place; filtering DCC by-products to remove, precipitating the filtrate in a mixed solution of acetone and ether with the volume ratio of 3:7, filtering to obtain yellow solid, washing the yellow solid with acetone and ether for three times, and drying the yellow solid in a vacuum drying oven to obtain yellow solid;
(3) preparation of PEO-co-PNIPAAm-FA: dissolving FA-NBS in anhydrous pyridine, slowly adding PEO-co-PNIPAAm according to a certain ratio of FA-NBS to PEO-co-PNIPAAm, reacting for 15h at 20 ℃ to obtain powder, and drying in a vacuum drying oven to obtain a product;
(4) preparing adriamycin (DOX) drug-loaded micelle, dissolving the PEO-co-PNIPAAm-FA prepared in the step (3) in anhydrous chloroform in inert gas, adding an acetonitrile solution of DOX, shaking uniformly, carrying out rotary evaporation to form a film, then putting the film into a vacuum drying oven to volatilize the organic solution completely, hydrating the organic solution with a certain amount of 10mM HBS with pH7.4, oscillating the solution in water bath at 35 ℃ for 30min, and filtering the solution with a 240nm film to remove the drug which is not loaded to obtain the drug-loaded micelle solution.
3. The temperature-sensitive nano-targeting folic acid copolymer micelle for tumor according to claim 1, characterized in that the PEG-COThe number average molecular weight of PNIPAAm-FA was 24000 and the Polymer Dispersibility Index (PDI) was 3.1.
4. The temperature-sensitive nano-targeting folic acid copolymer micelle for tumor according to claim 1, wherein the FA-NBS and PEG-CO-PNIPAAm in a mass ratio of: 1:5-1:1.
5. The temperature-sensitive nano-targeting folic acid copolymer micelle for tumors according to claim 2, wherein the mass ratio of the polyethylene glycol acrylate to PNIPAAm in the step (1) is as follows: 1:20-1:10.
6. The temperature-sensitive nano-targeted folate copolymer micelle for tumor use according to claim 2, wherein the mass ratio of FA, NBS and DCC in step (2) is as follows: 2:0.5:0.6.
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