CN108210932B - Preparation method of charge-driven self-assembled chitosan-based drug-loaded nanoparticles - Google Patents
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Abstract
The invention discloses a preparation method of charge-driven self-assembled chitosan-based drug-loaded nanoparticles, which comprises the following steps: (1) forming a block copolymer of PEG and poly benzyl glutamate by amino PEG-induced benzyl glutamate-N-carbonyl cyclic internal anhydride, hydrolyzing the block copolymer under an alkaline condition, and removing a benzyl group at the end of the poly benzyl glutamate to form a PEG-PGA block copolymer; (2) preparing a chitosan-based adriamycin prodrug; (4) and preparing the charge-driven self-assembly nano particles. The materials selected by the strategy for preparing the doxorubicin-loaded chitosan-based nanoparticles are PEG and PGA materials which have been generally proved to have good biocompatibility, and the strategy for forming the chitosan nanoparticles has good biocompatibility and biomedical prospect.
Description
Technical Field
The invention belongs to the field of functional material preparation, and particularly relates to a preparation method of charge-driven self-assembled chitosan-based drug-loaded nanoparticles.
Background
Chitosan (CS) is a natural polymer polysaccharide with punctuation, has the characteristics of no toxicity, degradability, good biocompatibility, low immunogenicity and the like, and can be used as a biomedical material. Due to its positive nature, it can be used as a negatively charged DNA, RNA, and other biomacromolecule delivery material. It has also been shown that chitosan has a similar function as hyaluronic acid targeting CD44 (highly expressed factor in tumor tissue). In addition, unlike many nanoparticles, chitosan-modified nanoparticles are predominantly distributed to the nucleus after endocytosis, which is more advantageous for the delivery of anti-tumor drugs. Because most of the antitumor drugs (such as adriamycin, paclitaxel, etc.) influence the division of tumor cells by influencing the replication of DNA, thereby inhibiting the growth of tumor cells. Therefore, the chitosan-based nanoparticles have important application prospects in the targeted delivery of anti-tumor drugs.
Although chitosan has better properties in the delivery of antitumor drugs, most chitosan nanoparticles are prepared by a cross-linking strategy with genipin or glutaraldehyde in an emulsifying or micro-emulsifying environment. This strategy carries the risk of organic solvents and cross-linking agents (glutaraldehyde or genipin) remaining in the nanoparticles. Glutaraldehyde has high biological toxicity, is easy to bring health risks, and is not suitable for being applied to biological materials in large quantities. Although genipin is considered a relatively safe crosslink, it remains in large quantities and is also prone to health risks.
Disclosure of Invention
The invention aims to provide a preparation method of charge-driven self-assembly chitosan-based drug-loaded nanoparticles, which utilizes charge interaction to form nanoparticles in a water-based solvent system through self-assembly, is not suitable for a cross-linking agent and reduces the risk of solvent residue.
In order to realize the first purpose of the invention, the technical scheme comprises the following steps:
(1) forming a block copolymer of PEG and poly benzyl glutamate by amino PEG-induced benzyl glutamate-N-carbonyl cyclic internal anhydride, hydrolyzing the block copolymer under an alkaline condition, and removing a benzyl group at the end of the poly benzyl glutamate to form a PEG-PGA block copolymer;
(2) weighing adriamycin hydrochloride solution and polypeptide, dissolving 1mmol of each adriamycin hydrochloride solution and polypeptide in 50ml of nitrogen-nitrogen dimethyl formamide, adding 2mmol of N, N-diisopropylethylamine, magnetically stirring, adding HATU solution, stirring at room temperature in a dark place, then stopping the reaction at-20 ℃, dialyzing in a dialysis bag, and freeze-drying the product to obtain an adriamycin polypeptide derivative (DOX-PEP-NH-Fmoc);
(3) adding 20% piperidine into the product synthesized in the step 2, stirring at room temperature for 5min, quickly placing the product in cooling liquid, adding succinic anhydride, placing the product in room temperature for reaction for 10min after the color is changed, precipitating with diethyl ether, centrifuging for 10min for 1, removing the Fmoc protective group of the DOX-PEP-NH-Fmoc product, adjusting the pH value to 6.95, dialyzing in a dialysis bag to remove small molecular byproducts, and freeze-drying to prepare the DOX-PEP-CONH-CH2-CH2-COOH; weighing DOX-PEP-CONH-CH2-CH2dissolving-COOH in DMF, performing ultrasonic treatment for 5min, adding 1-ethyl-3, 3-dimethyl-aminopropyl carbodiimide (EDC) and 4-Dimethylaminopyridine (DMAP), shaking, uniformly mixing, performing ultrasonic treatment for 10min, gradually dropwise adding the mixed solution into 2- (N-morpholine) ethanesulfonic acid solution containing chitosan under magnetic stirring, reacting overnight at normal temperature, dialyzing with a dialysis bag, and drying to obtain chitosan-polypeptide-adriamycin derivative (DOX-PEP-CS);
(4) preparing charge-driven self-assembled chitosan-based drug-loaded nanoparticles:
and (3) dissolving the DOX-PEP-CS prepared in the step (3) in a 2- (N-morpholine) ethanesulfonic acid buffer solution, wherein the pH value of the 2- (N-morpholine) ethanesulfonic acid buffer solution is 5.0, and adding the PEG-PGA block copolymer obtained in the step (1) under vigorous stirring to obtain the doxorubicin-loaded chitosan-based nanoparticles.
Further setting that the step (1) is as follows: dissolving 1.2 g of glutamic acid benzyl ester-N-carbonyl cyclic internal anhydride in 20 mL of anhydrous nitrogen-dimethyl formamide, mixing with amino PEG, reacting at 38 ℃ for 48 hours under the protection of nitrogen, dialyzing to obtain a block copolymer of PEG and poly benzyl glutamate, and removing benzyl under the action of NaOH to form the PEG-PGA block copolymer.
Further setting the mass ratio of the added amount of the PEG-PGA block copolymer of the step (4) to the DOX-PEP-CS to be (0.25:1-1.5: 1).
The innovative mechanism of the invention is as follows:
i have synthesized a block copolymer comprising polyethylene glycol and polyglutamic acid (PEG-PGA). Due to its nature of amphoteric dissociation, polypeptides undergo charge transfer in solution environments at pH above or below their isoelectric point. When the pH value of the solution is less than the isoelectric point of the solution, the solution is positive, and when the pH value of the solution is greater than the isoelectric point, the solution is negative. The isoelectric point of the polyglutamic acid segment is less than 3, so that it has a negative point at a pH greater than 5. Based on this, the present inventors utilized charge interaction to allow chitosan and PEG-PGA to self-assemble in a buffer to form nanoparticles. The size and the potential of the nanoparticles can be conveniently adjusted by regulating the content of the block copolymer, and the controllable self-assembly of the chitosan-based nanoparticles is realized. This strategy self-assembles to form nanoparticles in an aqueous environment without the use of cross-linking agents and microemulsified solvent systems, reducing the risk of organic agent use and cross-linking agent residue. This system is different from the reported strategy of using PEG and polyacrylamide methyl propane sulfonate anions (PAMPs), and this polyanion system has poor biocompatibility and may have a large health risk. The materials selected by the strategy for preparing the chitosan nanoparticles are PEG and PGA materials which are generally proved to have good biocompatibility, and the strategy for forming the chitosan nanoparticles has good biocompatibility and biomedical prospect.
The invention has the advantages that:
(1) chitosan is a chain polysaccharide, and the preparation of chitosan nanoparticles requires the formation of nanoparticles in a microemulsified solvent system, which is easy to cause the risk of organic solvent and cross-linking agent residue. The invention utilizes charge interaction, forms nano particles by self-assembly in a water-based solvent system, does not use a cross-linking agent, and reduces the risk of solvent residue.
(2) The size and the potential of the prepared adriamycin-loaded chitosan-based nano particle are controllable.
(3) The materials selected by the strategy for preparing the doxorubicin-loaded chitosan-based nanoparticles are PEG and PGA materials which have been generally proved to have good biocompatibility, and the strategy for forming the chitosan nanoparticles has good biocompatibility and biomedical prospect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is within the scope of the present invention for those skilled in the art to obtain other drawings based on the drawings without inventive exercise.
FIG. 1 is a schematic of the preparation process of the present invention;
FIG. 2 is a diagram showing the molecular structure of a block copolymer of PEG-PGA prepared according to the present invention;
FIG. 3 is a graph showing the relationship between the particle size and potential of nanoparticles prepared according to the present invention and the concentration of PEG-PGA block copolymer;
FIG. 4 is a graph representing particle size and potential measurements of PEG-PGA block copolymers at different concentrations;
FIG. 5 is a graphical representation of the morphology of nanoparticles prepared in accordance with the present invention;
FIG. 6 test graph of drug-loaded Doxorubicin (DOX) nanoparticles for inhibiting tumor cell activity.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
The English abbreviation's Chinese description of the materials involved in the embodiments of the present invention:
MES represents 2- (N-morpholine) ethanesulfonic acid;
HATU is a pharmaceutical intermediate and a commonly used polypeptide condensation reagent, and is applied to the reaction of synthesizing peptide bond by carboxyl and amino. The system is named as 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate;
PEG represents polyethylene glycol;
PGA represents polyglutamic acid;
PEG-PGA represents a block copolymer of polyethylene glycol and polyglutamic acid;
hcl for doxorubicin hcl;
PEP represents a polypeptide;
DMF means nitrogen dimethylformamide;
DIPEA represents N, N-diisopropylethylamine;
DOX-PEP-NH-Fmoc represents a polypeptide derivative of doxorubicin;
DOX-PEP-CONH-CH2-CH2-COOH represents a carboxy-terminal doxorubicin polypeptide derivative;
CS represents chitosan;
EDC represents 1-ethyl-3, 3-dimethyl-aminopropylcarbodiimide;
DMAP represents 4-dimethylaminopyridine;
example 1
The embodiment of the invention comprises the following steps:
(1) preparation of PEG-PGA amphoteric dissociation copolymer:
the PEG-PGA block copolymer is formed by amino PEG-induced benzyl glutamate-N-carbonyl cyclic internal anhydride, the copolymer is hydrolyzed under alkaline condition, and benzyl at the end of the benzyl polyglutamate is removed. An example of the synthesis is as follows: 1.2 g of glutamic acid benzyl ester-N-carbonyl cyclic anhydride is dissolved in 20 mL of dry nitrogen dimethyl formamide and mixed with amino PEG to react for 48 hours at 38 ℃ under the protection of nitrogen. Dialyzing to obtain a block copolymer of PEG and poly benzyl glutamate, and removing benzyl under the action of NaOH to form PEG-PGA block copolymer. Referring to fig. 2, it can be confirmed that the PEG-PGA block copolymer has been successfully synthesized, and its molecular structural formula is:
(2) preparation of chitosan-based doxorubicin prodrug
Weighing adriamycin hydrochloride solution (A)Dox.HCl) and polypeptide (PEP) 1mmol are dissolved in 50ml of DMF, 2mmol of N, N-Diisopropylethylamine (DIPEA) is added, magnetic stirring is carried out, HATU solution is added, stirring is carried out at room temperature in a dark place, then the reaction is stopped at the temperature of-20 ℃, dialysis is carried out in a dialysis bag, and the product is freeze-dried to obtain DOX-PEP-NH-Fmoc product; adding 20% piperidine, stirring at room temperature for 5min, rapidly placing in coolant, adding succinic anhydride, reacting at room temperature for 10min after color change, precipitating with diethyl ether, centrifuging for 10min for 1, removing Fmoc protecting group of DOX-PEP-NH-Fmoc product, adjusting pH to 6.95, dialyzing in dialysis bag to remove small molecule byproduct, freeze drying, and making into DOX-PEP-CONH-CH2-CH2-COOH; weighing DOX-PEP-CONH-CH2-CH2dissolving-COOH in DMF, performing ultrasonic treatment for 5min, adding EDC and DMAP, shaking and uniformly mixing, performing ultrasonic treatment for 10min, gradually dropwise adding the mixed solution into a MES solution containing CS under magnetic stirring, reacting overnight at normal temperature, dialyzing by using a dialysis bag, drying and weighing to obtain DOX-PEP-CS.
(3) Preparing charge-driven self-assembled chitosan-based drug-loaded nanoparticles:
dissolving the chitosan-based prodrug in MES buffer solution (pH 5.0), adding different amounts (0.25:1-1.5:1) of PEG-PGA block copolymer under vigorous stirring to form composite nanoparticles, and measuring particle size, potential, morphology and thermodynamic properties.
From FIGS. 3 and 4, it is known that the particle size can be changed from 920 nm to 371 nm and the zeta potential can be changed from 52.7 mV to 41.5 mV by adjusting the concentration of the copolymer (0.25-1.5 mg/mL).
As shown in fig. 6, after DOX loading, the nanoparticles can increase the toxicity of the drug to tumor cells and decrease the toxicity to normal cells.
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (1)
1. A preparation method of charge-driven self-assembled chitosan-based drug-loaded nanoparticles is characterized by comprising the following steps:
(1) forming a block copolymer of PEG and poly benzyl glutamate by amino PEG-induced benzyl glutamate-N-carbonyl cyclic internal anhydride, hydrolyzing the block copolymer under an alkaline condition, and removing a benzyl group at the end of the poly benzyl glutamate to form a PEG-PGA block copolymer;
(2) weighing adriamycin hydrochloride solution and polypeptide, dissolving 1mmol of each in 50ml of nitrogen-nitrogen dimethyl formamide, adding 2mmol of N, N-diisopropylethylamine, magnetically stirring, adding HATU solution, stirring at room temperature in a dark place, then placing the reaction at-20 ℃ to stop the reaction, dialyzing in a dialysis bag, and freeze-drying the product to obtain the adriamycin polypeptide derivative;
(3) adding 20% piperidine into the product synthesized in the step 2, stirring at room temperature for 5min, quickly placing the product in cooling liquid, adding succinic anhydride, placing the product in room temperature for reaction for 10min after the color is changed, precipitating with diethyl ether, centrifuging for 10min, adjusting the pH value to 6.95, dialyzing in a dialysis bag to remove small molecular byproducts, and freeze-drying to obtain DOX-PEP-CONH-CH2-CH2-COOH; weighing DOX-PEP-CONH-CH2-CH2dissolving-COOH in nitrogen-nitrogen dimethylformamide, performing ultrasonic treatment for 5min, adding 1-ethyl-3, 3-dimethyl-aminopropyl carbodiimide and 4-dimethylaminopyridine, uniformly mixing by shaking, performing ultrasonic treatment for 10min, gradually dropwise adding the mixed solution into a 2- (N-morpholine) ethanesulfonic acid solution containing chitosan under magnetic stirring, reacting overnight at normal temperature, dialyzing by using a dialysis bag, and drying to obtain a chitosan-polypeptide-adriamycin derivative (DOX-PEP-CS);
(4) preparing charge-driven self-assembled chitosan-based drug-loaded nanoparticles:
dissolving DOX-PEP-CS prepared in the step (3) in 2- (N-morpholine) ethanesulfonic acid buffer solution, wherein the pH value of the 2- (N-morpholine) ethanesulfonic acid buffer solution is 5.0, and adding the PEG-PGA block copolymer in the step (1) under vigorous stirring to obtain the doxorubicin-loaded chitosan-based nanoparticles;
the step (1) is as follows: dissolving 1.2 g of glutamic acid benzyl ester-N-carbonyl cyclic internal anhydride in 20 mL of anhydrous nitrogen-dimethyl formamide, mixing with amino PEG, reacting at 38 ℃ for 48 hours under the protection of nitrogen, dialyzing to obtain a block copolymer of PEG and poly benzyl glutamate, and removing benzyl under the action of NaOH to form a PEG-PGA block copolymer;
the mass ratio of the added amount of the PEG-PGA block copolymer in the step (4) to the DOX-PEP-CS is 0.25:1-1.5: 1.
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| CN110105562B (en) * | 2019-04-23 | 2021-10-12 | 华东师范大学 | Two-block polymer containing dopamine ligand and synthetic method and application thereof |
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| CN113456825B (en) * | 2021-06-17 | 2023-07-11 | 温州医科大学 | Mitochondria-targeted glutathione derivative nano preparation and application thereof |
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| "Layer-by-Layer Assembled Multilayer Films of Methoxypoly(ethylene glycol)-block-poly-(a,L-glutamic acid) and Chitosan with Reduced Cell Adhesion";Bin Cao et al.;《Macromolecular Bioscience》;20110909;第11卷(第9期);第1211-1217页 * |
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