CN101361976A - Hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules and preparation method and use thereof - Google Patents
Hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules and preparation method and use thereof Download PDFInfo
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Abstract
The invention pertains to the technical field of nano materials and particularly relates to a polyalkylcyanoacrylate nano particle modified by hyaluronic acid, a preparation method and an application thereof. The polyalkylcyanoacrylate nano particle modified by hyaluronic acid contains at least one polyalkylcyanoacrylate as a hydrophobic kernel and hyaluronic acid as a hydrophilic coat. The nano particle is prepared by the following steps: the hyaluronic acid is dissolved in an acid solution and an ammonium ceric nitrate solution is added in a dropwise manner, stirred, the polyalkylcyanoacrylate which is uniformly mixed with the acid solution in advance is added in a dropwise manner, stirred for reaction and purified to obtain the nano particle with the particle size of 250nm to 850nm. Compared with the prior art, the size of the particle obtained is controlled within a nano range, with excellent dispersity. The preparation technological process is simple and can be controlled, without the use of organic reagents.
Description
Technical field
The invention belongs to technical field of nano material, be specifically related to a kind of hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules and its production and application.
Background technology
Alkyl cyanoacrylate (alkylcyanoacrylate, ACA) be the synthetic class adhesive of nineteen fifty-five U.S. Eastman company, nineteen fifty-nine is ratified as medical glue through FDA, Couvreur in 1979 etc. are used to prepare medicine carrying nanoparticle (Couvreur P first, et al., J.Pharm.Sci.1979,68,1521～1524).Existing a large amount of research reports utilize the Biodegradable material Polyalkylcyanoacrylanano to prepare the carrier of nanoparticle as small-molecule drug, protein and peptide and nucleic acid drug.These carriers have many advantages aspect medicament protection, the transhipment.But this class nanoparticle is easy to be taken as foreign body and removes from blood rapidly after the intravenous injection, thereby needs its surface is modified.
In recent years, hydrophilic polyose modification nanoparticle becomes a big research focus.Polysaccharide mostly is biological endogenous property material, and general avirulence is biodegradable, good biocompatibility.Have the specific polysaccharide receptor in the cell or tissue, make the polyose modification nanoparticle may have initiatively targeting.Hyaluronic acid be by β-D-N-acetylglucosamine and β-D-glucuronic acid be construction unit with β-1,3 and β-1, the linear anion mucopolysaccharide of a kind of straight chain that 4 glycosidic bonds alternately are formed by connecting extensively is present in organism soft connective tissue extracellular matrix (ECM), organism synovial fluid and the umbilical cord.Hyaluronic acid is separated from bovine vitreous body by U.S. Meyer etc. the earliest, and it repeats disaccharide unit at all species with all be consistent in organizing, and has reduced immunogenicity, can not cause the immunological rejection of hyaluronan molecule self.As polyanion electrolyte, it has a large amount of negative charges, negative ion concentrations around the scalable, the activity of inhibition plurality of enzymes.Bibliographical information such as epithelial cancer, ovarian cancer, colon cancer, gastric cancer and acute leukemia cells surface overexpression hyaluronic acid receptor CD44 and RHAMM (Jaracz S, et al., Bioorg.﹠amp are arranged; Med.Chem.2005,13,5043～5054).Utilize hyaluronic acid decorated nanoparticle to be expected to reach the active targeting in the purpose of tumor cell.
Traditional method for preparing the polyalkylcyanoacrylanano nano grain comprises emulsion polymerization and interfacial polymerization.The former is distributed to monomer in the acidic aqueous solution that contains surfactant or stabilizing agent, continues to stir 3～4h, obtains the nanoparticle of homogeneous framing structure.The latter is dissolved in oil phase, monomer, medicine in the organic solvent, stirs slowly to add to the aqueous phase that contains surfactant down, steams after reaction finishes and removes organic solvent, obtain nanocapsule (Wohlgemuth M, et al., the J Microencapsul of oil-containing nuclear, 2000,17 (4), 437～448).Chauvierre etc. adopt a kind of new ACA emulsion polymerization promptly in the presence of polysaccharide, by the redox system initiation ACA polymerization that cerium ion and polysaccharide are formed, synthetic polyose modification PACA nanoparticle (Chauvierre C, et al., Pharm.Res.2003,20,1786～1793).Employed polysaccharide has dextran, sulphuric acid dextran, heparin, hyaluronic acid, chitosan and pectin.Wherein dextran, sulphuric acid dextran, heparin modified nanoparticle particle diameter are 93～800nm; It is bigger that hyaluronic acid, chitosan, pectin are modified diameter of particle, is micron order, and concrete particle diameter is 30～59 μ m.
Summary of the invention
The purpose of this invention is to provide a kind of hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules.
Another object of the present invention provides the preparation method of above-mentioned hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules.
A further object of the invention provides the application of above-mentioned hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules, to overcome the deficiencies in the prior art and defective.
Design of the present invention is as follows:
Utilize the strong oxidizing property of ammonium ceric nitrate to make the fracture of hyaluronic acid sugar chain, produce free radical endways and cause alkyl cyanoacrylate polymerization formation hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules.Particle diameter can be controlled at nanometer range by control hyaluronan molecule amount, hyaluronic acid and alkyl cyanoacrylate rate of charge, ammonium ceric nitrate concentration.The alkyl cyanoacrylate reactivity is higher, and the nucleophile of trace is (as OH in the water under the room temperature
-) just can cause its polymerization.Reaction medium needs to be lower than 1 acid solution with pH and suppresses OH in the water
-Anionic initiation.Simultaneously, acid solution is easier makes the fracture of hyaluronic acid sugar chain produce free radical.
Acid condition (pH＜1) ammonium ceric nitrate down makes hyaluronic acid sugar chain oxidation scission, the terminal free radical that produces; Free radical causes the ACA polymerization; Polyreaction prolongs generation linear block copolymers hyaluronic acid Polyalkylcyanoacrylanano.Polymerization process is as follows:
Technical scheme of the present invention is as follows:
Hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules of the present invention is a hydrophobic inner core with at least a Polyalkylcyanoacrylanano, and hyaluronic acid is a hydrophilic outer shell.
Described hyaluronan molecule amount is 18,000～500,000Da.
Described alkyl cyanoacrylate is one or more in cyanacrylate, alpha-cyanoacrylate propyl ester, the positive butyl ester of alpha-cyanoacrylate, isobutylcyanoacrylate or the own ester of alpha-cyanoacrylate.
Described hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules, its particle diameter are 250～850nm.
Hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules of the present invention, its preparation method is as follows:
(1) hyaluronic acid is dissolved in pH0～1 acid solution, gets solution A;
(2) 30～60 ℃, drip final concentration and be 0.4～4.5mmol/L ammonium ceric nitrate acid solution (pH0～1) to solution A, stir, solution B;
(3) drip in advance alkyl cyanoacrylate with acid solution (pH0～1) mixing to solution B, feed intake by hyaluronic acid and alkyl cyanoacrylate mass ratio 1:1～1:10, stirring reaction 2～12h gets the hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules suspension;
(4) with above-mentioned suspension purification, promptly get hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules.
Used hyaluronan molecule amount is 18,000～500,000Da, and the excessive then particle diameter of molecular weight is bigger.
Described acid solution is a kind of in hydrochloric acid solution, phosphoric acid solution, citric acid solution, sulfuric acid solution or the salpeter solution.
Described alkyl cyanoacrylate is one or more in cyanacrylate, alpha-cyanoacrylate propyl ester, the positive butyl ester of alpha-cyanoacrylate, isobutylcyanoacrylate or the own ester of alpha-cyanoacrylate.
Reaction temperature is 30～60 ℃ in the step (2), and the too high then starting polymerization of temperature is too fast, is prone to precipitation.Preferred 40 ℃.
The ammonium ceric nitrate final concentration is 0.4～4.5mmol/L in the step (2), and concentration is lower than 0.4mmol/L, and starting polymerization speed is slow and formation nanoparticle quantity is few; Concentration is higher than 4.5mmol/L, the starting polymerization excessive velocities, and particle diameter increases and easily forms precipitation.
Hyaluronic acid and alkyl cyanoacrylate mass ratio are 1:1～1:10 in the step (3), and mass ratio is lower than 1:1, and the hydrophilic segment ratio is too high, and formation nanoparticle quantity is few and particle diameter is bigger than normal.The acid of preferably clear matter and alkyl cyanoacrylate mass ratio 1:2～1:6.
The response time is 2～12h in the step (3), and too short then reaction of time not exclusively.Preferred 3h.
The application of nanoparticle of the present invention in drug-supplying system comprises:
(1) protein and peptide class medicine;
(2) micromolecular water insoluble drug;
(3) cancer therapy drug;
(4) nucleic acid drug.
The invention has the advantages that:
(1) nanoparticle of the present invention, particle diameter is less, and its surface carries out hydrophilic and modify and can reduce reticuloendothelial cell and cytophagous engulfing, and realizes long circulation in the body;
(2) hyaluronic acid of nanoparticle finishing of the present invention is biological endogenous material, avirulence, biodegradable, it repeats disaccharide unit at all species with all be consistent in organizing, and has reduced immunogenicity, the immunological rejection that can not cause hyaluronan molecule self, as polyanion electrolyte, it has a large amount of negative charges, negative ion concentrations around the scalable, suppress the activity of plurality of enzymes, intravenous injection is difficult for causing haemolysis;
(3) utilize the characteristic of most tumors cell overexpression hyaluronic acid receptor CD44 and RHAMM, make nanoparticle of the present invention have initiatively targeting;
(4) nanoparticle of the present invention, the finishing hyaluronic acid has carboxyl, its can with the ligands specific combination, improve initiatively targeting.
(5) preparation process of the present invention simply, easily control, need not to use organic reagent.
Description of drawings
Fig. 1 is the transmission electron microscope picture (amplification is 50,000 times) of the nanoparticle among the embodiment 1;
The specific embodiment
Can further understand the present invention by the following specific embodiments.But they are not limitation of the invention.
Embodiment 1
Molecular weight 18, the hyaluronic acid of 000Da is dissolved in the 0.2M salpeter solution.40 ℃; nitrogen atmosphere drips the 0.2M salpeter solution that final concentration is the 0.8mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:2, stirring reaction 2h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 2
Molecular weight 18, the hyaluronic acid of 000Da is dissolved in the 0.2M salpeter solution.40 ℃; nitrogen atmosphere drips the 0.2M salpeter solution that final concentration is the 2.4mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:1, stirring reaction 12h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 3
Molecular weight 18, the hyaluronic acid of 000Da is dissolved in the 0.3M salpeter solution.30 ℃; nitrogen atmosphere drips the 0.3M salpeter solution that final concentration is the 1.2mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.3M salpeter solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:3, stirring reaction 2h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 4
Molecular weight 18, the hyaluronic acid of 000Da is dissolved in the 0.2M sulfuric acid solution.40 ℃; nitrogen atmosphere drips the 0.2M sulfuric acid solution that final concentration is the 0.4mmol/L ammonium ceric nitrate down and stirs; drip in advance cyanacrylate with 0.2M sulfuric acid solution mixing; feed intake by hyaluronic acid and cyanacrylate mass ratio 1:6, stirring reaction 12h gets hyaluronic acid decorated paracyanogen base ethyl acrylate nanoparticle suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated paracyanogen base ethyl acrylate nanoparticle.
Embodiment 5
Molecular weight 18, the hyaluronic acid of 000Da is dissolved in the 1M salpeter solution.40 ℃; nitrogen atmosphere drips the 1M salpeter solution that final concentration is the 0.4mmol/L ammonium ceric nitrate down and stirs; drip in advance alpha-cyanoacrylate propyl ester with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and alpha-cyanoacrylate propyl ester mass ratio 1:6, stirring reaction 3h gets hyaluronic acid decorated paracyanogen base propyl acrylate nanoparticle suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated paracyanogen base propyl acrylate nanoparticle.
Embodiment 6
Molecular weight 18, the hyaluronic acid of 000Da is dissolved in the 0.4M salpeter solution.40 ℃; nitrogen atmosphere drips the 0.4M salpeter solution that final concentration is the 3.2mmol/L ammonium ceric nitrate down and stirs; drip in advance alpha-cyanoacrylate propyl ester with 0.4M salpeter solution mixing; feed intake by hyaluronic acid and alpha-cyanoacrylate propyl ester mass ratio 1:3, stirring reaction 4h gets hyaluronic acid decorated paracyanogen base propyl acrylate nanoparticle suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated paracyanogen base propyl acrylate nanoparticle.
Embodiment 7
Molecular weight 18, the hyaluronic acid of 000Da is dissolved in the 0.2M salpeter solution.50 ℃; nitrogen atmosphere drips the 0.2M salpeter solution that final concentration is the 1.6mmol/L ammonium ceric nitrate down and stirs; drip in advance isobutylcyanoacrylate with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and isobutylcyanoacrylate mass ratio 1:10, stirring reaction 2h gets hyaluronic acid decorated Polyisobutyl cyanoacrylate nanoparticle suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated Polyisobutyl cyanoacrylate nanoparticle.
Embodiment 8
Molecular weight 100, the hyaluronic acid of 000Da is dissolved in the 0.2M hydrochloric acid solution.30 ℃; nitrogen atmosphere drips the 0.2M hydrochloric acid solution that final concentration is the 0.4mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.2M hydrochloric acid solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:1, stirring reaction 4h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 9
Molecular weight 100, the hyaluronic acid of 000Da is dissolved in the 0.5M salpeter solution.60 ℃; nitrogen atmosphere drips the 0.5M salpeter solution that final concentration is the 0.4mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:10, stirring reaction 12h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 10
Molecular weight 100, the hyaluronic acid of 000Da is dissolved in the 0.2M phosphoric acid solution.60 ℃; nitrogen atmosphere drips the 0.2M phosphoric acid solution that final concentration is the 0.4mmol/L ammonium ceric nitrate down and stirs; drip in advance cyanacrylate with 0.2M phosphoric acid solution mixing; feed intake by hyaluronic acid and cyanacrylate mass ratio 1:3, stirring reaction 8h gets hyaluronic acid decorated paracyanogen base ethyl acrylate nanoparticle suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated paracyanogen base ethyl acrylate nanoparticle.
Embodiment 11
Molecular weight 100, the hyaluronic acid of 000Da is dissolved in the 0.1M salpeter solution.40 ℃; nitrogen atmosphere drips the 0.1M salpeter solution that final concentration is the 4.5mmol/L ammonium ceric nitrate down and stirs; drip in advance cyanacrylate with 0.1M salpeter solution mixing; feed intake by hyaluronic acid and cyanacrylate mass ratio 1:2, stirring reaction 2h gets hyaluronic acid decorated paracyanogen base ethyl acrylate nanoparticle suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated paracyanogen base ethyl acrylate nanoparticle.
Embodiment 12
Molecular weight 100, the hyaluronic acid of 000Da is dissolved in the 0.1M salpeter solution.50 ℃; nitrogen atmosphere drips the 0.1M salpeter solution that final concentration is the 4.5mmol/L ammonium ceric nitrate down and stirs; drip in advance cyanacrylate with 0.1M salpeter solution mixing; feed intake by hyaluronic acid and cyanacrylate mass ratio 1:6, stirring reaction 4h gets hyaluronic acid decorated paracyanogen base ethyl acrylate nanoparticle suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated paracyanogen base ethyl acrylate nanoparticle.
Embodiment 13
Molecular weight 100, the hyaluronic acid of 000Da is dissolved in the 0.2M salpeter solution.30 ℃; nitrogen atmosphere drips the 0.2M salpeter solution that final concentration is the 3.0mmol/L ammonium ceric nitrate down and stirs; drip in advance alpha-cyanoacrylate propyl ester with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and alpha-cyanoacrylate propyl ester mass ratio 1:10, stirring reaction 2h gets hyaluronic acid decorated paracyanogen base propyl acrylate nanoparticle suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated paracyanogen base propyl acrylate nanoparticle.
Embodiment 14
Molecular weight 100, the hyaluronic acid of 000Da is dissolved in the 0.2M salpeter solution.60 ℃; nitrogen atmosphere drips the 0.2M salpeter solution that final concentration is the 1.6mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:6, stirring reaction 10h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 15
Molecular weight 100, the hyaluronic acid of 000Da is dissolved in the 1M salpeter solution.50 ℃; it is the 1M salpeter solution and the vigorous stirring of 1.2mmol/L ammonium ceric nitrate that nitrogen atmosphere drips final concentration down; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.3M salpeter solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:4, stirring reaction 6h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 16
Molecular weight 500, the hyaluronic acid of 000Da is dissolved in the 0.2M salpeter solution.40 ℃; nitrogen atmosphere drips the 0.2M salpeter solution that final concentration is the 1.6mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:4, stirring reaction 2h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 17
Molecular weight 500, the hyaluronic acid of 000Da is dissolved in the 1M hydrochloric acid solution.40 ℃; nitrogen atmosphere drips the 1M hydrochloric acid solution that final concentration is the 1.6mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.2M hydrochloric acid solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:2, stirring reaction 4h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 18
Molecular weight 500, the hyaluronic acid of 000Da is dissolved in the 0.2M citric acid solution.40 ℃; nitrogen atmosphere drips the 0.2M citric acid solution that final concentration is the 0.8mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.2M citric acid solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:1, stirring reaction 8h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 19
Molecular weight 500, the hyaluronic acid of 000Da is dissolved in the 0.1M salpeter solution.60 ℃; nitrogen atmosphere drips the 0.1M salpeter solution that final concentration is the 2.4mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.1M salpeter solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:2, stirring reaction 4h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 20
Molecular weight 500, the hyaluronic acid of 000Da is dissolved in the 0.2M salpeter solution.40 ℃; nitrogen atmosphere drips the 0.2M salpeter solution that final concentration is the 0.4mmol/L ammonium ceric nitrate down and stirs; drip in advance the positive butyl ester of alpha-cyanoacrylate with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and the positive butyl ester mass ratio of alpha-cyanoacrylate 1:4, stirring reaction 12h gets hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated poly-alkyl-alfa-cyanoacrylate nanoparticles.
Embodiment 21
Molecular weight 500, the hyaluronic acid of 000Da is dissolved in the 0.2M salpeter solution.60 ℃; nitrogen atmosphere drips the 0.2M salpeter solution that final concentration is the 0.4mmol/L ammonium ceric nitrate down and stirs; drip in advance isobutylcyanoacrylate with 0.2M salpeter solution mixing; feed intake by hyaluronic acid and isobutylcyanoacrylate mass ratio 1:6, stirring reaction 6h gets hyaluronic acid decorated Polyisobutyl cyanoacrylate nanoparticle suspension.With above-mentioned suspension dialysis purification, promptly get hyaluronic acid decorated Polyisobutyl cyanoacrylate nanoparticle.
Claims (12)
1, a kind of hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules is characterized in that with the Polyalkylcyanoacrylanano being hydrophobic inner core, and hyaluronic acid is a hydrophilic outer shell; Wherein alkyl cyanoacrylate is one or more in cyanacrylate, alpha-cyanoacrylate propyl ester, Tisuacryl, isobutylcyanoacrylate or the own ester of alpha-cyanoacrylate.
2, nanoparticle according to claim 1 is characterized in that the hyaluronan molecule amount is 18,000～500,000Da.
3,, it is characterized in that particle diameter is 250～850nm according to the described nanoparticle of claim 1～2.
4, a kind of preparation method of hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules as claimed in claim 1 is characterized in that preparation process is as follows:
(1) hyaluronic acid is dissolved in pH 0～1 acid solution, gets solution A;
(2) at 30～60 ℃, drip final concentration and be 0.4～4.5mmol/L ammonium ceric nitrate acid solution to solution A, stir, solution B; Ammonium ceric nitrate acid solution pH 0～1 wherein;
(3) drip in advance alkyl cyanoacrylate with the acid solution mixing of pH 0～1 to solution B, feed intake by hyaluronic acid and alkyl cyanoacrylate mass ratio 1:1～1:10, stirring reaction 2～12h gets olefin(e) acid Arrcostab nanoparticle suspension in the hyaluronic acid decorated paracyanogen base;
(4) with above-mentioned suspension purification, promptly get hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules.
5, nanoparticle preparation method according to claim 4 is characterized in that described acid solution is a kind of in hydrochloric acid solution, phosphoric acid solution, citric acid solution, sulfuric acid solution or the salpeter solution.
6, nanoparticle preparation method according to claim 4 is characterized in that described hyaluronan molecule amount is 18,000～500,000Da.
7, nanoparticle preparation method according to claim 4 is characterized in that described alkyl cyanoacrylate is one or more in cyanacrylate, alpha-cyanoacrylate propyl ester, Tisuacryl, isobutylcyanoacrylate or the own ester of alpha-cyanoacrylate.
8, nanoparticle preparation method according to claim 4 is characterized in that reaction temperature is 40 ℃ in the step (2).
9, nanoparticle preparation method according to claim 4 is characterized in that ammonium ceric nitrate concentration is 0.8～3mmol/L in the step (2).
10, nanoparticle preparation method according to claim 4 is characterized in that hyaluronic acid and alkyl cyanoacrylate mass ratio 1:1～1:6 in the step (3).
11, nanoparticle preparation method according to claim 4 is characterized in that the response time is 3h in the step (3).
12, a kind of hyaluronic acid modified polu-cyano acrylic acid alkyl ester nano granules as claimed in claim 1 is as the application of carrier for active principle, it is characterized in that active component is a protein and peptide class medicine, micromolecular water insoluble drug, cancer therapy drug or nucleic acid drug.
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| CN100374477C (en) * | 2005-07-07 | 2008-03-12 | 复旦大学 | Nano granules adhesive to mucous membrane, preparation method and application |
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| CN106619569A (en) * | 2016-12-09 | 2017-05-10 | 天津市肿瘤医院 | Tumor-targeting nanoparticles co-loading chemotherapy drug and nucleic acid and preparation method thereof |
| CN106619569B (en) * | 2016-12-09 | 2019-07-26 | 天津市肿瘤医院 | The cancer target nanoparticle and preparation method of chemotherapeutics and nucleic acid are carried altogether |
| CN106729735A (en) * | 2017-03-09 | 2017-05-31 | 国家纳米科学中心 | PH sensitive a kind of polypeptide polymer and its preparation method and application |
| CN106729735B (en) * | 2017-03-09 | 2020-05-12 | 国家纳米科学中心 | pH-sensitive polypeptide polymer and preparation method and application thereof |
| CN107596381A (en) * | 2017-09-21 | 2018-01-19 | 重庆市人民医院 | A kind of method of hyaluronic acid mediated synthetic modification cerium nano-quantum point and products thereof and application |
| CN107596381B (en) * | 2017-09-21 | 2019-03-26 | 重庆市人民医院 | A kind of method of hyaluronic acid mediated synthetic modification cerium nano-quantum point and products thereof and application |
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