CN115708891A - Developing drug-loaded microsphere based on microfluidic technology and preparation method and application thereof - Google Patents
Developing drug-loaded microsphere based on microfluidic technology and preparation method and application thereof Download PDFInfo
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- CN115708891A CN115708891A CN202211412903.1A CN202211412903A CN115708891A CN 115708891 A CN115708891 A CN 115708891A CN 202211412903 A CN202211412903 A CN 202211412903A CN 115708891 A CN115708891 A CN 115708891A
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- drug
- loaded
- iodine
- molecular polymer
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a developing drug-loaded microsphere based on a microfluidic technology, a preparation method and application thereof, and relates to the technical field of biomedical material preparation. The microsphere prepared by the invention has good developing property, can facilitate observation in operation and improve embolization effect, and meanwhile, drug-loaded nanoparticles wrapped in the microsphere can slowly and continuously release drugs to avoid burst release, and the size of the microsphere is uniform and controllable. The invention solves the problems that the microspheres can not be accurately positioned and the drug release can not be controlled in the prior art.
Description
Technical Field
The invention relates to the technical field of biomedical material preparation, in particular to a developing drug-loaded microsphere based on a microfluidic technology, and a preparation method and application thereof.
Background
Liver cancer is one of the most common malignant tumors, with the increasing aging problem of the population, the number of liver cancer patients is rapidly increasing globally, heavy economic burden is brought to medical systems and patients, once liver cancer is discovered, about 80% of patients can only select minimally invasive interventional therapy, and clinically, the treatment for liver cancer still does not make substantial breakthrough. In recent years, the drug-loaded microspheres have obtained good liver cancer treatment effects through loading anti-tumor drugs and embolizing tumor blood vessels, and are widely concerned, however, the currently used microspheres can be quickly separated from a contrast agent in a human body, the microspheres have no developability, and in clinical operation, the position of the microspheres in the body and the evaluation of embolization effects are difficult, so that the development of embolization microspheres with both developability, drug loading and uniform and controllable size has important significance for liver cancer treatment.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide developing drug-loaded microspheres based on a microfluidic technology, and a preparation method and application thereof, so as to solve the problems that the microspheres cannot be accurately positioned, the drug release is uncontrollable and the sizes of the microspheres are not uniform in the prior art.
The technical scheme for solving the technical problems is as follows: providing a developing drug-loaded microsphere based on a microfluidic technology, wherein the developing drug-loaded microsphere is a high molecular polymer disubstituted by a photo-crosslinking group and iodine, drug-loaded nanoparticles and a photoinitiator, and the drug-loaded nanoparticles are wrapped in the microsphere prepared by microfluidic polymerization; wherein, the diameter of the microsphere is 420-470 μm, and the diameter of the drug-loaded nano particle is 80-100nm.
The beneficial effects of the invention are as follows: the microsphere prepared by the invention has good developing property, can be conveniently observed in operation and improve the embolization effect, and meanwhile, the drug-loaded nanoparticles wrapped in the microsphere can slowly and continuously release the drug to avoid burst release, and the size of the microsphere is uniform and controllable.
On the basis of the technical scheme, the invention can be further improved as follows:
furthermore, the drug in the drug-loaded nano-particles is methotrexate, adriamycin, gemcitabine, docetaxel or 5-fluorouracil.
Furthermore, the carrier in the drug-loaded nanoparticle is PLGA, PLGA-PEG, DSPE-PEG or PF127.
Further, the drug-loaded nanoparticles are prepared by the following method: dissolving a carrier and a drug in an organic solvent, dropwise adding the solution into water under the stirring condition, and then dialyzing for 1.5-2.5d to prepare the drug-loaded nanoparticles.
Further, dialysis was performed for 2d.
Further, the mass ratio of the carrier to the medicament is 4-6:1.
further, the mass ratio of the carrier to the drug is 5:1.
further, the mass volume ratio of the carrier, the organic solvent and the water is 38-42mg:3-5mL:14-16mL.
Further, the mass-volume ratio of the carrier, the organic solvent and the water is 40mg:4mL of: 15mL.
Further, the organic solvent is acetone or dimethyl sulfoxide.
The beneficial effect of adopting the further technical scheme is as follows: the drug-loaded nanoparticles are adopted for carrying drugs and then encapsulated into the microspheres, and the drug-loaded nanoparticles are released from the microspheres and can permeate into thinner capillary vessels, so that the release time of the drugs can be prolonged, and a better treatment effect can be achieved.
Further, the photo-crosslinking group and iodine disubstituted high molecular polymer is prepared by the following method: grafting iodine-containing compound and compound containing double bond functional group on the high molecular polymer to obtain the high molecular polymer with double substitution of photo-crosslinking group and iodine.
Further, when the high molecular polymer is a high molecular polymer containing carboxyl and polyhydroxy, the iodine-containing compound and the compound containing double bond functional group both contain amino, hydroxyl, carboxyl, acid anhydride group, epoxy group or acyl chloride group.
Further, when the high molecular polymer is sodium alginate, hyaluronic acid or carboxymethyl cellulose, the iodine-containing compound is 3-iodoaniline, 4-iodoaniline, 2, 4-diiodoaniline, 4-iodophenyl hydrazine, 4-iodobenzylamine, 3-iodopropanol, 2-iodoethanol, 4-iodobenzyl alcohol, 3-iodopropionic acid, 2-iodoacetic acid, 4-iodobutyric acid, triiodoacetic acid, diiodoacetic acid, iodoacetic anhydride, epoxyiodopropane, 2-iodobenzoyl chloride, 3-iodobenzoyl chloride, 4-iodobenzoyl chloride or 5-amino-2, 4, 6-triiodo-1, 3-phthaloyl chloride; the double bond-containing functional compound is 10-undecenol, 1-pent-3-ol, 1, 6-hept-4-ol, 1, 4-pentadien-3-ol, 1, 5-hexadienol, 2- (allylamino) ethane-1-ol, 4-allylformylaminophenylboronic acid, 11-but-3-enoic acid, 4-pentenoic acid, hept-6-enoic acid, undecenoic acid, 2-aminopent-4-enoic acid, 2-acetamidonon-8-enoic acid, 4- (allylamino) benzoic acid, 4- (prop-2-enamino) benzoic acid, 2- (prop-2-enamino) acetic acid, 2- (N-methylprop-2-enamino) acetic acid, ethyl-2-aminohex-5-enyl bridge ester, methyl 2-amino-4-methylpent-4-enoic acid, glycidyl methacrylate, methacrylic anhydride, 1, 2-epoxy-5-hexene or diallylcarbamoyl chloride.
Further, when the high molecular polymer is a high molecular polymer containing amino and polyhydroxy, the iodine-containing compound and the compound containing double bond functional groups both contain aldehyde groups, carboxyl groups, acid anhydride groups, epoxy groups or acyl chloride groups.
Further, when the high molecular polymer is chitosan, the iodine-containing compound is 4-iodobenzaldehyde, 3-iodopropionic acid, 2-iodoacetic acid, 4-iodobutyric acid, triiodoacetic acid, diiodoacetic acid, iodoacetic anhydride, epoxyiodopropane, 2-iodobenzoyl chloride, 3-iodobenzoyl chloride, 4-iodobenzoyl chloride or 5-amino-2, 4, 6-triiodo-1, 3-benzenedicarboxyl chloride; the compound containing double bond functional group is 4-allyl formyl aminophenylboronic acid, 11-butyl-3-olefine acid, 4-pentenoic acid, hept-6-olefine acid, undecylenic acid, 2-aminopent-4-olefine acid, 2-acetamido-non-8-olefine acid, 4- (allylamino) benzoic acid, 4- (prop-2-enamido) benzoic acid, 2- (prop-2-enamido) acetic acid, 2- (N-methylprop-2-enamido) acetic acid, ethyl-2-aminocyclohex-5-enebridge ester, 2-amino-4-methylpent-4-olefine acid methyl ester, glycidyl methacrylate, methacrylic anhydride, 1, 2-epoxy-5-hexene or diallyl carbamoyl chloride.
Further, when the high molecular polymer is a high molecular polymer containing carboxyl, amino and hydroxyl, the iodine-containing compound and the compound containing double bond functional groups both contain amino, hydroxyl, aldehyde group, carboxyl, acid anhydride group, epoxy group or acyl chloride group.
Further, when the high molecular polymer is gelatin, the iodine-containing compound is 3-iodoaniline, 4-iodoaniline, 2, 4-diiodoaniline, 4-iodophenylhydrazine, 4-iodobenzylamine, 3-iodopropanol, 2-iodoethanol, 4-iodobenzyl alcohol, 4-iodobenzaldehyde, 3-iodopropionic acid, 2-iodoacetic acid, 4-iodobutyric acid, triiodoacetic acid, diiodoacetic acid, iodoacetic anhydride, epiiodopropane, 2-iodobenzoyl chloride, 3-iodobenzoyl chloride, 4-iodobenzoyl chloride or 5-amino-2, 4, 6-triiodo-1, 3-benzenedicarboxyl chloride; the double bond-containing functional compound is 10-undecenol, 1-pent-3-ol, 1, 6-hept-4-ol, 1, 4-pentadien-3-ol, 1, 5-hexadienol, 2- (allylamino) ethane-1-ol, 4-allylformylaminophenylboronic acid, 11-but-3-enoic acid, 4-pentenoic acid, hept-6-enoic acid, undecenoic acid, 2-aminopent-4-enoic acid, 2-acetamidonon-8-enoic acid, 4- (allylamino) benzoic acid, 4- (prop-2-enamino) benzoic acid, 2- (prop-2-enamino) acetic acid, 2- (N-methylprop-2-enamino) acetic acid, ethyl-2-aminohex-5-enyl bridge ester, methyl 2-amino-4-methylpent-4-enoic acid, glycidyl methacrylate, methacrylic anhydride, 1, 2-epoxy-5-hexene or diallylcarbamoyl chloride.
Further, when the high molecular polymer is a high molecular polymer containing only polyhydroxy, the iodine-containing compound and the compound containing double bond functional group both contain carboxyl, acid anhydride group, epoxy group or acyl chloride group.
Further, when the high molecular polymer is polyvinyl alcohol, starch, cellulose, gellan gum, konjac glucomannan, gum arabic, lignin, dextran or bletilla polysaccharide, the iodine-containing compound is 3-iodopropionic acid, 2-iodoacetic acid, 4-iodobutyric acid, triiodoacetic acid, diiodoacetic acid, iodoacetic anhydride, epoxyiodopropane, 2-iodobenzoyl chloride, 3-iodobenzoyl chloride, 4-iodobenzoyl chloride or 5-amino-2, 4, 6-triiodo-1, 3-benzenedicarboxylic acid dichloride; the compound containing double bond functional group is 4-allyl formyl aminophenylboronic acid, 11-butyl-3-olefine acid, 4-pentenoic acid, hept-6-olefine acid, undecylenic acid, 2-aminopent-4-olefine acid, 2-acetamido-non-8-olefine acid, 4- (allylamino) benzoic acid, 4- (prop-2-enamido) benzoic acid, 2- (prop-2-enamido) acetic acid, 2- (N-methylprop-2-enamido) acetic acid, ethyl-2-amino hex-5-ene bridge ester, 2-amino-4 methyl pent-4-olefine acid methyl ester, glycidyl methacrylate, methacrylic anhydride, 1, 2-epoxy-5-hexene or diallyl carbamoyl chloride.
Further, the grafting method comprises the following specific steps:
(1.1) dissolving a compound containing double bonds and a high molecular polymer in a solvent, reacting for 24-48h, and then dialyzing and carrying out vacuum freeze drying to obtain a reactant I;
and (1.2) dissolving the reactant I prepared in the step (1.1) and an iodine-containing compound in a solvent, reacting for 24-48h, dialyzing, and carrying out vacuum freeze drying to prepare the high molecular polymer disubstituted by the photo-crosslinking group and the iodine.
Further, when the double bond functional group-containing compound in step (1.1) and the iodine-containing compound in step (1.2) both have an amino group, a hydroxyl group, an aldehyde group, a carboxyl group, an acid anhydride group, an epoxy group or an acid chloride group, step (1.1) and step (1.2) are combined into a further reaction.
Further, when the functional groups of the compound containing double bond functional group in the step (1.1) and the iodine-containing compound in the step (1.2) are amino, acid chloride, epoxy or aldehyde groups, the step (1.1) and the step (1.2) are combined into one-step reaction.
Further, when the high molecular polymer in the step (1.1) contains hydroxyl groups and the functional groups of the compound containing both iodine and double bond functional groups are acid anhydride groups or epoxy groups, the pH value is adjusted to 8 to 10 during the reaction.
Further, the solvent is water.
Further, when the polymer in step (1.1) contains hydroxyl group, and when the functional group of the iodine-containing compound and the double bond functional group-containing compound is amino group or carboxyl group, a condensing agent and a catalyst are added during the reaction.
Further, the mass ratio of the high molecular polymer, the condensing agent and the catalyst is 10:4-5:1-2.
Further, the mass ratio of the high molecular polymer, the condensing agent and the catalyst is 10:4.5:1.8.
further, the solvent was MES buffer.
Further, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the catalyst is N-hydroxysuccinimide.
Further, in the step (1.1), the mass-to-volume ratio of the high molecular polymer, the double bond-containing compound and the solvent is 10g:30-40mL:180-220mL.
Further, in the step (1.1), the mass-to-volume ratio of the high molecular polymer, the double bond-containing compound and the solvent is 10g:35mL of: 200mL.
Further, in the step (1.2), the mass ratio of the reactant I to the iodine-containing compound is 10:6-7.
Further, in the step (1.2), the mass ratio of the first reactant to the iodine-containing compound is 10:6.5.
further, in the further reaction, the mass-to-volume ratio of the high molecular polymer, the iodine-containing compound and the double bond-containing compound is 10g:4-6g:18-22mL.
Further, in the further reaction, the mass-to-volume ratio of the high molecular polymer, the iodine-containing compound and the double bond-containing compound is 10g:5g:20mL.
Further, in the further reaction, the mass-to-volume ratio of the high molecular polymer to the solvent is 10g:180-220mL.
Further, in the further reaction, the mass-to-volume ratio of the high molecular polymer to the solvent is 10g:200mL.
The invention also provides a preparation method of the developing drug-loaded microsphere based on the microfluidic technology, which comprises the following steps:
(1) Dissolving a photo-crosslinking group and iodine disubstituted high molecular polymer, drug-loaded nanoparticles and a photoinitiator in water to prepare a precursor solution;
(2) Taking the precursor solution prepared in the step (1) as a dispersion phase, obtaining microspheres by adopting a microfluidic technology, then irradiating for 10-30min by ultraviolet light, and centrifuging to prepare the developing drug-loaded microspheres based on the microfluidic technology.
Further, in the step (1), the concentrations of the photocrosslinking group and the iodine disubstituted high molecular polymer, the drug-loaded nano particles and the photoinitiator in the precursor solution are 1-8g/100mL, 0.1-1g/100mL and 0.1-0.5g/100mL respectively.
Further, in the step (1), the concentrations of the photocrosslinking group and the iodine disubstituted high molecular polymer, the drug-loaded nanoparticles and the photoinitiator in the precursor solution are 5g/100mL, 0.5g/100mL and 0.2g/100mL respectively.
Further, in the step (1), the photoinitiator is at least one of benzoin, benzoin bis-methyl ether, benzoin ethyl ether, benzoin isopropyl ether, benzoin butyl ether, diphenylethanone, α -dimethoxy- α -phenylacetophenone, α -diethoxyacetophenone, α -hydroxyalkylphenone, α -aminoalkylphenone, 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone, aroylphosphine oxide, bis-benzoylphenylphosphine oxide, benzophenone, 2, 4-dihydroxybenzophenone, michler's ketone, thiopropoxythrosanthrone and isopropyl thioxanthone.
Further, in the step (2), the continuous phase of the microfluidic technology is paraffin oil.
Further, the flow rate of the continuous phase was 20 to 80. Mu.L/min.
Further, in the step (2), the flow rate of the dispersed phase is 2-8 muL/min.
Further, in the step (2), the wavelength of the ultraviolet light is 365nm or 405nm, and the power is 2-20mw/cm 2 。
The invention has the following beneficial effects:
1. the invention mainly synthesizes a photo-crosslinking group and iodine disubstituted high molecular polymer, then the polymer, the drug-loaded nano particles and the photoinitiator are crosslinked to generate the microsphere with the developing and drug-loaded functions under the irradiation of ultraviolet light by the microfluidic device, the whole preparation process is simple, the selected raw materials are easy to obtain, the production cost is simplified, and the invention has huge application prospect in the field of interventional operation.
2. According to the invention, the micro-fluidic device is used for preparing the microspheres with uniform and controllable particle size and both developing function and drug-loading function under the ultraviolet light crosslinking condition, a series of microspheres with particle size ranges can be obtained by screening and preparing through controlling the micro-fluidic condition in the preparation process, meanwhile, drug-loading nano particles of different drugs can be wrapped, and the preparation scheme is flexible.
Drawings
FIG. 1 is a NMR chart of a high molecular weight polymer obtained in example 1;
FIG. 2 is a transmission electron micrograph of drug-loaded nanoparticles prepared in example 1;
FIG. 3 is a scanning electron microscope image of a blank drug-loaded microsphere prepared in comparative example 1;
FIG. 4 is a scanning electron micrograph of the developed drug-loaded microspheres prepared in example 1;
FIG. 5 is a graph showing the development effect of blank drug-loaded microspheres prepared in comparative example 1;
fig. 6 is a graph showing the development effect of the developed drug-loaded microspheres obtained in example 1.
Detailed Description
The principles and features of this invention are described below in conjunction with the following drawings, which are set forth by way of illustration only and are not intended to limit the scope of the invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1:
a developing drug-loaded microsphere based on a microfluidic technology and a preparation method thereof comprise the following steps:
(1) Preparation of methacrylic anhydrified hyaluronic acid:
weighing 35mL of Methacrylic Anhydride (MA) and 10g of hyaluronic acid, completely dissolving the Methacrylic Anhydride (MA) and the hyaluronic acid in deionized water, reacting at 4 ℃, adding a proper volume of sodium hydroxide solution (1 mol/L) at intervals in the reaction process, adjusting the pH of the reaction solution to 9, reacting for 48 hours, dialyzing the reaction solution by using deionized water to remove impurities, and performing vacuum freeze drying to obtain methacrylic anhydride-functionalized hyaluronic acid (HAMA); the reaction equation is as follows:
(2) Preparation of iodine-grafted methacrylic anhydrified hyaluronic acid:
precisely weighing 10g of methacrylic anhydrified hyaluronic acid and 6.5g of 2, 4-diiodoaniline, dissolving in 200mL of MES buffer (0.1mol, pH 5.0), adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,4.50 g) and N-hydroxysuccinimide (NHS, 1.8 g), stirring at 37 ℃ for 48 hours, finally dialyzing in deionized water (pH 7.4) for 3 days, and freeze-drying with a freeze dryer to obtain purified iodine-grafted methacrylic anhydrified hyaluronic acid; the reaction equation is as follows:
(3) Preparing medicine-carrying nano particles:
PLGA (40.0 mg) and gemcitabine (8.00 mg) were dissolved in acetone (4 mL), then added dropwise to 15mL water with slow stirring, and finally dialyzed in water for 2 days to prepare drug-loaded nanoparticles;
(4) Preparing microspheres:
in the dispersed phase water solution, the concentration of the iodine grafted methacrylic anhydrified hyaluronic acid is 5g/100mL, the concentration of the drug-loaded nano particles is 0.5g/100mL, the concentration of the photoinitiator is 0.2g/100mL, the continuous phase solution is paraffin oil (2% span80,0.6% tween), the microspheres are prepared by utilizing a microfluidic platform, the flow rates of the dispersed phase solution and the continuous phase solution are respectively 4 mu L/min and 40 mu L/min, the collected microsphere liquid drops are irradiated for 30min under an ultraviolet lamp, the wavelength of the ultraviolet lamp is 405nm, and the power is 10mw/cm 2 After illumination, the microspheres are collected centrifugally to prepare the developing drug-loaded microspheres based on the microfluidic technology.
Example 2:
a developing drug-loaded microsphere based on a microfluidic technology is prepared by the following steps:
(1) Preparation of methacrylic anhydrized sodium alginate:
weighing 35mL of Methacrylic Anhydride (MA) and 10g of sodium alginate, completely dissolving the Methacrylic Anhydride (MA) and the sodium alginate in deionized water, reacting at 4 ℃, adding a proper volume of sodium hydroxide solution (1 mol/L) at intervals in the reaction process to adjust the pH of the reaction solution to about 8, reacting for 48 hours, and dialyzing and removing impurities by using the deionized water and carrying out vacuum freeze drying to prepare the methacrylic anhydride sodium alginate;
(2) Preparation of iodine grafted methacrylic anhydridized sodium alginate:
10g of methacrylic anhydrified sodium alginate and 6.5g of 3-iodoaniline were precisely weighed and dissolved in 200mL of MES buffer (0.1 mol, pH 5.0), and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,4.50 g) and N-hydroxysuccinimide (NHS, 1.8 g) were added thereto. Then stirring for 48h at 37 ℃, finally dialyzing in deionized water (pH 7.4) for 3 days, and freeze-drying the solution by using a freeze dryer to prepare purified iodine grafted methacrylic anhydridized sodium alginate;
(3) Preparing medicine-carrying nano particles:
dissolving PLGA-PEG (40.0 mg) and adriamycin (8.00 mg) in dimethyl sulfoxide (4 mL), dropwise adding the solution into 15mL of water under the condition of slow stirring, and finally dialyzing the solution in the water for 2 days to prepare drug-loaded nanoparticles;
(4) Preparation of developing microspheres:
in the dispersed phase water solution, the concentration of iodine grafted methacrylic anhydridized sodium alginate is 5g/100mL, the concentration of drug-loaded nano particles is 0.5g/100mL, the concentration of photoinitiator is 0.2g/100mL, the continuous phase solution is paraffin oil (2% span80,0.6% tween), the microspheres are prepared by utilizing a microfluidic platform, the flow rates of the dispersed phase solution and the continuous phase solution are respectively 4 mu L/min and 40 mu L/min, the collected microsphere liquid drops are illuminated under an ultraviolet lamp for 30min, the wavelength of the ultraviolet lamp is 405nm, and the power is 10mw/cm 2 After illumination, the microspheres are collected centrifugally to prepare the developing drug-loaded microspheres based on the microfluidic technology.
Example 3:
a developing drug-loaded microsphere based on a microfluidic technology is prepared by the following steps:
(1) Preparation of methacrylic anhydrified gelatin:
weighing 35mL of Methacrylic Anhydride (MA) and 10g of gelatin, completely dissolving the Methacrylic Anhydride (MA) and the gelatin in deionized water, reacting at 60 ℃, adding a proper volume of sodium hydroxide solution (1 mol/L) at intervals in the reaction process to adjust the pH of the reaction solution to about 10, reacting for 48 hours, dialyzing with deionized water to remove impurities, and carrying out vacuum freeze drying to obtain methacrylic anhydrized gelatin;
(2) Preparation of iodine grafted methacrylic anhydrized gelatin:
precisely weighing 10g of methacrylic anhydride-functionalized gelatin and 6.5g of 4-iodoaniline, dissolving the mixture in 200mL of MES buffer (0.1mol, pH 5.0), adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,4.50 g) and N-hydroxysuccinimide (NHS, 1.8 g) thereto, stirring at 60 ℃ for 48 hours, finally dialyzing the mixture in deionized water (pH 7.4) for 3 days, and freeze-drying the mixture by using a freeze dryer to obtain purified iodine-grafted methacrylic anhydride-functionalized gelatin;
(3) Preparing medicine-carrying nano particles:
dissolving DSPE-PEG (40.0 mg) and paclitaxel (8.00 mg) in dimethyl sulfoxide (4 mL), adding dropwise into 15mL of water under slow stirring, and dialyzing in water for 2 days to obtain drug-loaded nanoparticles;
(4) Preparing the developing microspheres:
in the dispersed phase water solution, the concentration of the iodine grafted methacrylic anhydridized gelatin is 5g/100mL, the concentration of the drug-loaded nano particles is 0.5g/100mL, and the concentration of the photoinitiator is 0.2g/100mL. The continuous phase solution was paraffin oil (2% 2 And after illumination, centrifugally collecting the microspheres to prepare the developing drug-loaded microspheres based on the microfluidic technology.
Example 4:
a developing drug-loaded microsphere based on a microfluidic technology is prepared by the following steps:
(1) Preparation of double bond and iodine disubstituted chitosan:
weighing 20mL of 4-pentenoic acid, 5g of 3-iodopropionic acid and 10g of chitosan, completely dissolving in 200mL of MES buffer (0.1mol, pH 5.0), adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,4.50 g) and N-hydroxysuccinimide (NHS, 1.8 g), reacting for 48h, dialyzing with deionized water to remove impurities, and performing vacuum freeze drying to obtain double-bond and iodine disubstituted chitosan;
(2) Preparing medicine-carrying nano particles:
DSPE-PEG (40.0 mg) and 5-fluorouracil (8.00 mg) are dissolved in dimethyl sulfoxide (4 mL), then dropwise added into 15mL of water under the condition of slow stirring, and finally dialyzed in the water for 2 days to prepare drug-loaded nanoparticles;
(3) Preparation of developing microspheres:
in the dispersed phase water solution, the concentration of the double bond and iodine disubstituted chitosan is 5g/100mL, the concentration of the drug-loaded nano particles is 0.5g/100mL, the concentration of the photoinitiator is 0.2g/100mL, the continuous phase solution is paraffin oil (2%/span 80, 0.6%/tween), the microspheres are prepared by utilizing a microfluidic platform, the flow rates of the dispersed phase solution and the continuous phase solution are respectively 4 mu L/min and 40 mu L/min, the collected microsphere liquid drops are irradiated for 30min under an ultraviolet lamp, the wavelength of the ultraviolet lamp is 405nm, and the power is 10mw/cm 2 And after illumination, centrifugally collecting the microspheres to prepare the developing drug-loaded microspheres based on the microfluidic technology.
Example 5:
a developing drug-loaded microsphere based on a microfluidic technology is prepared by the following steps:
(1) Preparation of double bond and iodine disubstituted hyaluronic acid:
weighing 20mL of 1, 2-epoxy-5-hexene, 5g of iodoacetic anhydride and 10g of hyaluronic acid, completely dissolving in 200mL of water, adding a proper volume of sodium hydroxide solution (1 mol/L) at intervals in the reaction process to adjust the pH of the reaction solution to about 8, reacting for 48 hours, and dialyzing and removing impurities by using deionized water and performing a vacuum freeze-drying method to obtain double-bond and iodine disubstituted hyaluronic acid;
(2) Preparing medicine-carrying nano particles:
PLGA-PEG (40.0 mg) and methotrexate (8.00 mg) were dissolved in dimethyl sulfoxide (4 mL), added dropwise to 15mL of water with slow stirring, and finally dialyzed in water for 2 days to obtain drug-loaded nanoparticles;
(3) Preparing the developing microspheres:
in the dispersed phase aqueous solution, the concentration of the double bond and iodine disubstituted hyaluronic acid was 5g/100mL, the concentration of the drug-loaded nanoparticles was 0.5g/100mL, the concentration of the photoinitiator was 0.2g/100mL, the continuous phase solution was paraffin oil (2% 2 And after illumination, centrifugally collecting the microspheres to prepare the developing drug-loaded microspheres based on the microfluidic technology.
Example 6:
a developing drug-loaded microsphere based on a microfluidic technology and a preparation method thereof comprise the following steps:
(1) Preparation of double bond and iodine disubstituted sodium alginate:
weighing 20mL of 2-amino-4-methylpent-4-enoic acid methyl ester, 5g of 3-iodobenzylamine and 10g of hyaluronic acid, completely dissolving the materials in 200mL of MES buffer (0.1mol, pH 5.0), adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,4.50 g) and N-hydroxysuccinimide (NHS, 1.8 g), reacting for 48h, dialyzing with deionized water to remove impurities, and performing vacuum freeze drying to prepare the double-bond and iodine disubstituted sodium alginate;
(2) Preparing medicine-carrying nano particles:
PLGA-PEG (40.0 mg) and 5-fluorouracil (8.00 mg) are dissolved in dimethyl sulfoxide (4 mL), then dropwise added into 15mL of water under the condition of slow stirring, and finally dialyzed in the water for 2 days to prepare drug-loaded nanoparticles;
(3) Preparation of developing microspheres:
in the dispersed phase aqueous solution, the concentration of double bond and iodine disubstituted sodium alginate was 5g/100mL, the concentration of drug-loaded nanoparticles was 0.5g/100mL, the concentration of photoinitiator was 0.2g/100mL, the continuous phase solution was paraffin oil (2% span80,0.6% tween), the microspheres were prepared using a microfluidic platform, the flow rates of the dispersed phase and continuous phase solutions were 4. Mu.L/min and 40. Mu.L/min, respectively, for the collected solutionsIrradiating the microsphere liquid drop under an ultraviolet lamp for 30min, wherein the wavelength of the ultraviolet lamp is 405nm, and the power is 10mw/cm 2 And after illumination, centrifugally collecting the microspheres to prepare the developing drug-loaded microspheres based on the microfluidic technology.
Example 7:
a developing drug-loaded microsphere based on a microfluidic technology and a preparation method thereof comprise the following steps:
(1) Preparation of double bond and iodine disubstituted chitosan:
weighing 20mL of glycidyl methacrylate, 5g of iodoacetic anhydride and 10g of chitosan, completely dissolving the glycidyl methacrylate, the iodoacetic anhydride and the chitosan in 200mL of water, adding a proper volume of sodium hydroxide solution (1 mol/L) at intervals in the reaction process to adjust the pH of the reaction solution to about 8, reacting for 48 hours, and dialyzing with deionized water to remove impurities and carrying out vacuum freeze drying to obtain the double-bond and iodine disubstituted chitosan;
(2) Preparing medicine-carrying nano particles:
PLGA (40.0 mg) and doxorubicin (8.00 mg) were dissolved in acetone (4 mL), added dropwise to 15mL of water with slow stirring, and finally dialyzed in water for 2 days to obtain drug-loaded nanoparticles.
(3) Preparation of developing microspheres:
in the dispersed phase aqueous solution, the concentration of the double bond and iodine disubstituted chitosan was 5g/100mL, the concentration of the drug-loaded nanoparticles was 0.5g/100mL, the concentration of the photoinitiator was 0.2g/100mL, the continuous phase solution was paraffin oil (2% 2 And after illumination, centrifugally collecting the microspheres to prepare the developing drug-loaded microspheres based on the microfluidic technology.
Example 8:
a developing drug-loaded microsphere based on a microfluidic technology and a preparation method thereof comprise the following steps:
(1) Preparation of iodine-grafted methacrylic anhydrified hyaluronic acid:
weighing 35mL of methacrylic anhydride, 5g of iodo-acetic anhydride and 10g of hyaluronic acid, completely dissolving the methacrylic anhydride, the iodo-acetic anhydride and the hyaluronic acid in deionized water, reacting at 4 ℃, adding a proper volume of sodium hydroxide solution (1 mol/L) at intervals in the reaction process to adjust the pH of the reaction solution to about 10, reacting for 48 hours, dialyzing and removing impurities by using deionized water, and carrying out vacuum freeze drying to prepare the iodo-grafted methacrylic anhydridized hyaluronic acid;
(2) Preparing medicine-carrying nano particles:
PLGA-PEG (40.0 mg) and methotrexate (8.00 mg) were dissolved in dimethyl sulfoxide (4 mL), added dropwise to 15mL of water with slow stirring, and finally dialyzed in water for 2 days to obtain drug-loaded nanoparticles;
(3) Preparation of developing microspheres:
in the aqueous solution of the dispersed phase, the concentration of the iodine-grafted methacrylic anhydrified hyaluronic acid was 5g/100mL, the concentration of the drug-loaded nanoparticles was 0.5g/100mL, the concentration of the photoinitiator was 0.2g/100mL, the solution of the continuous phase was paraffin oil (2% span80,0.6% tween), the microspheres were prepared using a microfluidic platform, the flow rates of the dispersed phase and the continuous phase solutions were 4. Mu.L/min and 40. Mu.L/min, respectively, the collected microsphere liquid droplets were irradiated under an ultraviolet lamp for 30min, the wavelength of the ultraviolet lamp was 405nm, and the power was 10mw/cm 2 After illumination, the microspheres are collected centrifugally to prepare the developing drug-loaded microspheres based on the microfluidic technology.
Example 9:
a developing drug-loaded microsphere based on a microfluidic technology and a preparation method thereof comprise the following steps:
(1) Preparation of double bond and iodine disubstituted chitosan:
weighing 20mL of diallyl carbamoyl chloride, 5g of 3-iodobenzoyl chloride and 10g of chitosan, completely dissolving in 200mL of water, reacting for 48h, dialyzing with deionized water to remove impurities, and performing vacuum freeze drying to obtain double-bond and iodine disubstituted chitosan;
(2) Preparing medicine-carrying nano particles:
PLGA-PEG (40.0 mg) and 5-fluorouracil (8.00 mg) are dissolved in dimethyl sulfoxide (4 mL), then dropwise added into 15mL of water under the condition of slow stirring, and finally dialyzed in the water for 2 days to prepare drug-loaded nanoparticles;
(3) Preparation of developing microspheres:
in the dispersed phase water solution, the concentration of the double bond and iodine disubstituted chitosan is 5g/100mL, the concentration of the drug-loaded nano particles is 0.5g/100mL, the concentration of the photoinitiator is 0.2g/100mL, the continuous phase solution is paraffin oil (2 percent of span80,0.6 percent of tween), the microspheres are prepared by utilizing a microfluidic platform, the flow rates of the dispersed phase solution and the continuous phase solution are respectively 4 mu L/min and 40 mu L/min, the collected microsphere liquid drop is irradiated under an ultraviolet lamp for 30min, the wavelength of the ultraviolet lamp is 405nm, the power is 10mw/cm < 2 >, after the irradiation, the microspheres are collected by centrifugation, and the development drug-loaded microspheres based on the microfluidic technology are prepared.
Example 10:
a developing drug-loaded microsphere based on a microfluidic technology is prepared by the following steps:
in the step (3), in the dispersed phase aqueous solution, the concentration of the iodine grafted methacrylic anhydrized hyaluronic acid is 1g/100mL, the concentration of the drug-loaded nanoparticles is 0.1g/100mL, the concentration of the photoinitiator is 0.1g/100mL, the flow rates of the dispersed phase solution and the continuous phase solution are respectively 2 muL/min and 20 muL/min, the collected microsphere liquid drops are irradiated under an ultraviolet lamp for 10min, and the wavelength of the ultraviolet lamp is 365nm, which is the same as that in the example 8.
Example 11:
a developing drug-loaded microsphere based on a microfluidic technology is prepared by the following steps:
in the step (3), in the dispersed phase aqueous solution, the concentration of the iodine grafted methacrylic anhydrized hyaluronic acid is 8g/100mL, the concentration of the drug-loaded nanoparticles is 1g/100mL, the concentration of the photoinitiator is 0.5g/100mL, the flow rates of the dispersed phase solution and the continuous phase solution are respectively 8 muL/min and 80 muL/min, the collected microsphere liquid drops are irradiated under an ultraviolet lamp for 30min, the wavelength of the ultraviolet lamp is 405nm, and the rest is the same as that of the example 8.
Comparative example 1:
a blank drug-loaded microsphere based on a microfluidic technology is prepared by the following steps:
step (2) is not included, and the rest is the same as example 1.
Test examples
1. The polymer obtained in example 1 was subjected to hydrogen nuclear magnetic resonance spectroscopy, and the results are shown in FIG. 1 (HAMA-I, HAMA and HA, from the top). As can be seen from FIG. 1, the iodine grafted methacrylic anhydrified hyaluronic acid was successfully prepared.
2. The drug-loaded nanoparticles prepared in example 1 were examined by transmission electron microscopy, and the results are shown in fig. 2. As can be seen from FIG. 2, the drug-loaded nanoparticles were successfully prepared, and were spherical in structure, with a particle size of about 80-100nm.
3. The microspheres prepared in example 1 and comparative example 1 were examined by scanning electron microscopy, and the results are shown in FIGS. 3-4. As can be seen from FIGS. 3-4, the results show that the microspheres are successfully prepared, have spherical structures and sizes of about 400-500 μm.
4. The microspheres obtained in example 1 and comparative example 1 were subjected to development under an X-ray apparatus, and the results are shown in FIGS. 5 to 6.
As can be seen from fig. 5, the blank drug-loaded microspheres prepared in comparative example 1 did not have developing properties after X-ray irradiation;
as can be seen from FIG. 6, the black shade in the test tube is the hyaluronic acid developing microsphere, which proves that the developing drug-carrying microsphere prepared by the invention shows good developing property after being irradiated by X-ray.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The developing drug-loaded microsphere based on the microfluidic technology is characterized in that the developing drug-loaded microsphere is a high-molecular polymer disubstituted by a photocrosslinking group and iodine, drug-loaded nanoparticles and a photoinitiator, and the drug-loaded nanoparticles are wrapped in the microsphere prepared by microfluidic polymerization; wherein, the diameter of the microsphere is 420-470 μm, and the diameter of the drug-loaded nano particle is 80-100nm.
2. The developing drug-loaded microsphere based on the microfluidic technology as claimed in claim 1, wherein the drug in the drug-loaded nanoparticle is methotrexate, adriamycin, gemcitabine, docetaxel or 5-fluorouracil.
3. The developing drug-carrying microsphere based on the microfluidic technology of claim 1 or 2, wherein the carrier in the drug-carrying nanoparticle is PLGA, PLGA-PEG, DSPE-PEG or PF127.
4. The developing drug-loaded microsphere based on the microfluidic technology as claimed in claim 1, wherein the photo-crosslinking group and iodine disubstituted high molecular polymer is prepared by the following method: grafting iodine-containing compound and compound containing double bond functional group on the high molecular polymer to obtain the high molecular polymer with double substitution of photo-crosslinking group and iodine.
5. The developing drug-loaded microsphere based on the microfluidic technology as claimed in claim 4, wherein when the high molecular polymer is a high molecular polymer containing carboxyl and polyhydroxy, the iodine-containing compound and the compound containing double bond functional group both contain amino, hydroxyl, carboxyl, acid anhydride, epoxy or acyl chloride.
6. The developing drug-loaded microsphere based on the microfluidic technology as claimed in claim 4, wherein when the high molecular polymer is a high molecular polymer containing amino and polyhydroxy groups, the iodine-containing compound and the compound containing double bond functional groups both contain aldehyde groups, carboxyl groups, acid anhydride groups, epoxy groups or acyl chloride groups.
7. The developing drug-loaded microsphere based on the microfluidic technology as claimed in claim 4, wherein when the high molecular polymer is a high molecular polymer containing carboxyl, amino and hydroxyl, the iodine-containing compound and the compound containing double bond functional group both contain amino, hydroxyl, aldehyde, carboxyl, acid anhydride, epoxy or acyl chloride.
8. The developing drug-loaded microsphere based on the microfluidic technology as claimed in claim 4, wherein when the high molecular polymer is a high molecular polymer containing only polyhydroxy groups, the iodine-containing compound and the compound containing double bond functional groups both contain carboxyl groups, acid anhydride groups, epoxy groups or acid chloride groups.
9. The preparation method of the developing drug-loaded microsphere based on the microfluidic technology according to any one of claims 1 to 8, comprising the following steps:
(1) Dissolving a photo-crosslinking group and iodine disubstituted high molecular polymer, drug-loaded nanoparticles and a photoinitiator in water to prepare a precursor solution;
(2) And (2) taking the precursor solution prepared in the step (1) as a disperse phase, obtaining microspheres by adopting a micro-fluidic technology, irradiating for 10-30min by using ultraviolet light, and centrifuging to prepare the developing drug-loaded microspheres based on the micro-fluidic technology.
10. The method for preparing developing drug-loaded microspheres based on microfluidic technology of claim 9, wherein in step (1), the concentrations of the photo-crosslinking group and iodine disubstituted high molecular polymer, the drug-loaded nanoparticles and the photoinitiator in the precursor solution are 1-8g/100mL, 0.1-1g/100mL and 0.1-0.5g/100mL, respectively.
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