CN110075306B - Preparation method of near-infrared light-controlled visible drug carrier - Google Patents
Preparation method of near-infrared light-controlled visible drug carrier Download PDFInfo
- Publication number
- CN110075306B CN110075306B CN201910351885.2A CN201910351885A CN110075306B CN 110075306 B CN110075306 B CN 110075306B CN 201910351885 A CN201910351885 A CN 201910351885A CN 110075306 B CN110075306 B CN 110075306B
- Authority
- CN
- China
- Prior art keywords
- soluble
- ucnps
- water
- nanoparticles
- conversion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
Abstract
The invention discloses a near-infrared light-controlled drug carrier, namely a carrier with drug loading capacity formed by encapsulating water-soluble upconversion nano particles (Ligand-UCNPs) by an o-nitrobenzyl ester amphiphilic molecular vesicle, belonging to the field of surfactants, wherein the total number of alkyl carbon atoms of a fatty chain is 6-36. The preparation method of the carrier comprises three parts: synthetic oil-soluble up-conversion nanoparticles (OA-UCNPs); synthesizing water-soluble up-conversion nanoparticles (Ligand-UCNPs); the o-nitrobenzyl ester amphiphilic molecules encapsulate the upconversion nanoparticles. The o-nitrobenzyl ester amphiphilic molecule has ultraviolet light cleavability, introduces up-conversion nanoparticles (UCNPs) which have large penetration depth to tissues and can convert near infrared light with small harm to human bodies into ultraviolet light, can overcome the defects of small penetration depth of ultraviolet light and large harm to human bodies, achieves the aim of photolysis drug release, and is a potential near infrared light-controlled drug release carrier.
Description
Technical Field
The invention relates to a preparation method of a near-infrared light-controlled visible drug carrier, in particular to a carrier material with an o-nitrobenzyl ester ultraviolet light degradation group and water-soluble up-conversion nano particles (Ligand-UCNPs) which are excited by near-infrared light to release ultraviolet light for compounding, belonging to the field of surfactant compounding.
Background
The light is a clean energy source, has the characteristics of non-invasiveness, high space-time resolution and remote real-time regulation and control, and is favored by light-operated drug release. Due to the strong scattering properties of soft tissue to Ultraviolet (UV) and visible light, the tissue penetration depth is low. Therefore, the laser (700-1000nm) using the Near Infrared (NIR) light source can realize deeper tissue penetration, detect deeper and smaller targets and has less damage to normal cells and tissues of a human body compared with ultraviolet light and visible light. Therefore, the system for triggering drug delivery by near infrared light has better clinical application prospect.
The o-nitrobenzyl ester has a special ultraviolet-responsive structure, ester bonds can be broken under ultraviolet irradiation, the effect of controllable release of the medicine is achieved, and researches on the ultraviolet controllable release of the o-nitrobenzyl ester are concerned in recent years. Han et al synthesized a polymer with ortho-nitro-dibenzyl ester as a repeating unit, which rapidly cleaved the backbone under UV irradiation, thereby causing rapid release of the drug. Nadezda Fomina et al reported in JACS that a polymer with o-nitrobenzyl ester as a switch was synthesized, and under ultraviolet and near infrared light irradiation, the o-nitrobenzyl ester degradation initiated the sequential degradation of the side chain and the main chain, achieving the rapid release of the drug. Anilkumar et al synthesized an o-nitrobenzyl ester compound with polyethylene glycol as a hydrophilic end and a long carbon chain as a hydrophobic end, and proved that the compound formed micelles with drug-loading capacity in water and had certain anticancer performance after photodegradation. Kang et al synthesized polymers with o-nitrobenzyl esters as the junction to connect hydrophilic groups and hydrophilic oil groups, and destroyed the hydrophilic-lipophilic balance under the irradiation of ultraviolet light to achieve the rapid release of the drug.
In recent years, UCNPs have been favored to convert NIR into ultraviolet light or visible light, and have become one of the research hotspots in the biomedical field. Liu and the like design an azobenzene liposome nano structure (UCNP @ Azo-Lipo) of UCNP, which can convert absorbed near infrared light into ultraviolet light and visible light, so that the cis-trans configuration of the azobenzene derivative is reversibly changed, continuous rotation provides power for drug release, and controllable release of the drug is realized. Chien and the like synthesize a o-nitrobenzyl alcohol light cage protective targetingfolate-PEGylated UCNPs@SiO2The drug DOX is loaded, after the nanoparticles are gathered at the tumor position, ultraviolet light emitted by the NIR excited UCNPs cuts off an o-nitrobenzyl ester bond to expose a folic acid targeting group, and the drug is released and the tumor cells are killed after the folic acid targeting group is endocytosed by the tumor cells. Yan et al synthesized an o-nitrobenzyl ester polymer encapsulating UCNPs, released ultraviolet light under 980nm excitation to induce the o-nitrobenzyl ester bond to break, and gel sol to transform to release bioactive molecules.
According to the method, the characteristic that the o-nitrobenzyl ester structure is broken under ultraviolet and the characteristic that the up-conversion nanoparticles (UCNPs) are excited under near infrared light to release ultraviolet and visible light are compounded together, namely, vesicles formed by the o-nitrobenzyl ester amphiphilic molecules encapsulate water-soluble up-conversion nanoparticles (Ligand-UCNPs) modified by ligands, so that the vesicles can achieve near infrared light-controlled release of the medicine at a tumor position. Amphiphilic small molecules self-assemble to form vesicle-encapsulated Ligand modified water-soluble upconversion nanoparticles (Ligand-UCNPs) are not reported.
Disclosure of Invention
The invention aims to prepare a near-infrared light-controlled drug carrier by adopting vesicle-encapsulated water-soluble upconversion nanoparticles (Ligand-UCNPs) formed by o-nitrobenzyl ester amphiphilic molecules, and the vesicle formed by the o-nitrobenzyl ester amphiphilic molecules is ruptured under near-infrared light, so that the near-infrared light-controlled drug release capability is realized.
The invention provides two surfactants containing o-nitrobenzyl ester photosensitive groups, which have the following structural general formula:
general formula I
General formula II
The general formula I is named as m, n-P-DTPA, and the general formula II is named as m, n-ONB-DTPA.
In the formula, CnH2n+1,n＝6,8,10,12,14,16,18；CmH2m+1，m＝0,6,8,10,12,14,16,18。
The invention relates to a synthetic method of general formula I m, n-P-DTPA, which comprises the following steps:
(1) and (3) dehydration reaction: adding diethylenetriamine pentaacetic acid, anhydrous acetic anhydride and anhydrous pyridine into a single-neck flask, heating to reflux under the protection of nitrogen, reacting for 12-24 h, performing suction filtration, washing a filter cake to be colorless, and performing vacuum drying at 50-80 ℃ to obtain diethylenetriamine pentaacetic anhydride.
Synthesis of Diethylenetriamine bisanhydride (DTPAA) of formula 1
(2) Hydroxyl substitution reaction: dissolving 4-bromomethyl-3-nitrobenzoic acid and potassium carbonate in a mixed solution of acetone and water, carrying out reflux reaction for 5 hours, adjusting the reaction solution to be acidic, extracting with ethyl acetate for three times, combining an organic layer, drying with anhydrous sodium sulfate, and filtering rotary-dried tawny 4-hydroxymethyl-3-nitrobenzoic acid.
Synthesis of 24-hydroxymethyl-3-nitrobenzoic acid of formula
(3) Amidation reaction: dissolving 4-hydroxymethyl-3-nitrobenzoic acid and secondary amine in a polar solvent, sequentially adding BOP and DIPEA, stirring at normal temperature overnight, pouring the reaction solution into a large amount of water, extracting with ethyl acetate for three times, sequentially washing an organic layer with acid, water, sodium bicarbonate, saturated salt, anhydrous sodium sulfate, drying, filtering, rotary steaming, and separating by column chromatography to obtain the faint yellow 4-hydroxymethyl-3-nitrobenzamide.
Synthesis of 34-hydroxymethyl-3-nitrobenzamides of formula
(4) Esterification reaction: adding diethylenetriamine pentaacetic acid dianhydride into an anhydrous polar solvent, heating to 60-90 ℃ for dissolving, cooling to room temperature, dropwise adding 4-hydroxymethyl-3-nitrobenzamide dissolved in the anhydrous polar solvent, reacting at 10-50 ℃ for 24-36h under the protection of nitrogen, adding a proper amount of water into a reaction solution to generate a milky liquid, centrifuging to obtain a lower-layer yellow solid, and performing column chromatography separation to obtain (4-diethylenetriamine pentaacetic acid ester) -3-nitrobenzamide.
Synthesis of (4-diethylenetriamine pentaacetic acid ester) -3-nitrobenzamide of formula 4
In the above reaction, in step (2), the 4-bromomethyl-3-nitrobenzoic acid: the molar ratio of the potassium carbonate is 1: 1-1: 5, and the volume ratio of the acetone to the water is 1: 1-1: 4. In the step (3), the 4-hydroxymethyl-3-nitrobenzoic acid: secondary amine: BOP: the molar ratio of DIPEA is 1:0.5-3:1: 0.5-4. In the steps (3), (4) and (5), the polar solvent is one of chloroform, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol and water.
A method for synthesizing the general formula IIm, n-ONB-DTPA comprises the following steps:
(1) and (3) demethylation reaction: dissolving 6-nitro piperonal in an organic solvent, dropwise adding the solution into an organic solvent of aluminum chloride under ice bath, and reacting for 1-5h in ice bath. After the reaction is finished, pouring the reaction liquid into hydrobromic acid, and stirring at room temperature for 36-54 h. Diluting the reaction mixture with a large amount of water, extracting for 2-5 times with ethyl acetate, drying with anhydrous magnesium sulfate, suction-filtering to obtain filtrate, spin-drying, recrystallizing in solvent, and suction-filtering to obtain pure yellow 4, 5-dihydroxy-2-nitrobenzaldehyde.
Synthesis of formula 54, 5-dihydroxy-2-nitrobenzaldehyde
(2) And (3) etherification reaction: adding alkali solution and bromoalkane into organic solution of 4, 5-dihydroxy-2-nitrobenzaldehyde, and reacting at 60 ℃ for 10-24h under the protection of nitrogen. Diluting the reaction mixture with a large amount of water, extracting with diethyl ether for 2-5 times, drying with anhydrous magnesium sulfate, suction-filtering to obtain filtrate, spin-drying, recrystallizing in solvent, and suction-filtering to obtain yellow solid 4, 5-alkoxy-2-nitrobenzaldehyde.
Synthesis of 64, 5-alkoxy-2-nitrobenzaldehydes of formula
(3) Reduction reaction: adding sodium borohydride into a mixed solution of 4, 5-alkoxy-2-nitrobenzaldehyde and methanol and tetrahydrofuran, reacting at-7-0 ℃ for 10-60min, and reacting at room temperature for 1-6 h. And (3) after the reaction is finished, removing the solvent by rotary evaporation, washing the solid by hydrochloric acid, extracting the solid by chloroform for 2-5 times, drying by anhydrous magnesium sulfate, and carrying out suction filtration and rotary evaporation to obtain a light yellow solid 4, 5-alkoxy-2-nitrobenzyl alcohol.
Synthesis of 74, 5-alkoxy-2-nitrobenzols of formula
(4) Esterification reaction: adding an anhydrous solvent into diethylenetriamine pentaacetic acid dianhydride, heating to 60-90 ℃ for dissolving, cooling to room temperature, dropwise adding 4, 5-alkoxy-2-nitrobenzyl alcohol dissolved in the anhydrous solvent, reacting at 10-50 ℃ for 24-36h under the protection of nitrogen, adding a proper amount of water into a reaction liquid to generate a milky liquid, centrifuging to obtain a lower-layer yellow solid, and performing column chromatography separation to obtain the diethylenetriamine pentaacetic acid-4, 5-alkoxy-2-nitrobenzyl monoester.
Synthesis of 4, 5-alkoxy-2-nitrobenzyl monoester of diethylenetriaminepentaacetic acid of formula 8
In the reaction, the material charging amount of the first step is 6-nitro piperonal: the molar ratio of aluminum chloride is 1: 2-1: 6. The second step is to feed 4, 5-dihydroxy-2-nitrobenzaldehyde: alkali: the molar ratio of the bromoalkane is 1: 2-5: 2-6. In the third step, the material charging amount is 4, 5-alkoxy-2-nitrobenzaldehyde: the molar ratio of sodium borohydride is 1: 2-5. The material charge in the fourth step is 4, 5-alkoxy-2-nitrobenzol: the mol ratio of diethylenetriamine pentaacetic anhydride is 1: 1-5.
Further, in the above technical solution, in the steps (1), (2) and (4), the organic solvent is one of chloroform, dichloromethane, dichloroethane, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and tetrahydrofuran.
Further, in the above technical solution, in steps (1) and (2), the recrystallization solvent is one of diethyl ether, acetonitrile, methanol, and water.
Further, in the above technical solution, in the step (2), the alkali solution is one of sodium hydroxide, potassium carbonate, and sodium carbonate.
Further, in the above technical scheme, in the step (3), the ratio of the mixed solution of methanol and tetrahydrofuran is 1:1-5: 1.
The invention provides a near-infrared light-controlled visible drug carrier, which is water-soluble up-conversion nanoparticles encapsulated by a carrier material with an o-nitrobenzyl ester structure in a general formula I or a general formula II.
Further, in the above technical solution, the water-soluble upconversion nanoparticles (Ligand-UCNPs) are upconversion nanoparticles modified with biotin, 2-aminoethylphosphonic acid, or polyethylene glycol Ligand.
Further, in the above technical solution, the upconversion nanoparticles are selected from NaYF4,Yb0.2/Tm0.005。
The invention relates to a preparation method of a near-infrared light-controlled visible drug carrier, which is characterized by comprising the following steps: (1) synthesis of oil-soluble Up-converting nanoparticles (OA-UCNPs)
CF is prepared by3COONa,Y(CF3COO)3,Yb(CF3COO)3And Tm (CF)3COO)3Dissolving 10mL of oleic acid and 10mL of octadecene according to a molar ratio (2:0.759:0.2:0.005) and placing the mixture into a three-neck flask, heating the mixture in vacuum for 110-130 ℃ to remove water for 0.5-1h, and then quickly heating the mixture to 290-320 ℃ to react for 1-2 h. Naturally cooling to room temperature, adding methanol, washing and centrifuging to obtain a white solid.
(2) Synthesis of Water-soluble Up-converting nanoparticles (Ligand-UCNPs)
And adding 5mL of 0.1M hydrochloric acid solution into the obtained solid, performing ultrasonic treatment for 1-3h, extracting with diethyl ether to remove oleic acid, and centrifuging to obtain a white solid. Vigorously stirring the obtained white solid and a ligand solution (biotin, 2-aminoethyl phosphonic acid, polyethylene glycol and the like) for 1-4h, adding the obtained dispersion solution into 10mL monoethylene glycol, stirring at the temperature of 100 ℃ and 160 ℃ for 1-5h, removing water, transferring the obtained dispersion solution into a 50mL high-pressure reaction kettle, reacting at the temperature of 120 ℃ and 180 ℃ for 1-4h, and centrifuging to obtain a white solid which is dispersed in an aqueous solution.
(3) O-nitrobenzyl ester amphiphilic molecule encapsulated up-conversion nanoparticle
Dissolving a certain amount of o-nitrobenzyl ester amphiphilic molecules by using a small amount of chloroform and methanol, forming a uniform film by using a small flask through vacuum rotary evaporation, standing the film in a vacuum drying oven overnight, adding the up-conversion material dispersed in the water solution into the small flask, hydrating for 2-7h, and performing ultrasonic treatment for 5-60min to form a uniform and clear solution.
Advantageous effects of the invention
(1) The invention indirectly realizes the near-infrared light-controlled drug release by utilizing the characteristic that the structure of o-nitrobenzyl ester is broken under ultraviolet and the characteristic that upconversion nano particles (UCNPs) are excited under near-infrared light to release ultraviolet and visible light.
(2) Ultraviolet absorption of amphiphilic molecules with an o-nitrobenzyl ester structure can be well matched with an ultraviolet region of fluorescence emission of up-conversion nanoparticles (UCNPs).
(3) Amphiphilic molecules with an o-nitrobenzyl ester structure can well encapsulate water-soluble up-conversion nanoparticles (Biotin-UCNPs).
Drawings
FIG. 1 is the XRD diffractogram of the oil-soluble upconversion nanoparticles (OA-UCNPs) of example 1;
FIG. 2 is the oil-soluble upconversion nanoparticle NaYF of example 14,Yb0.2/Tm0.005(OA-UCNPs) and acid treated upconversion nanoparticles NaYF4,Yb0.2/Tm0.005And biotin-modified up-conversion nanoparticles NaYF4,Yb0.2/Tm0.005(Biotin-UCNPs) infrared spectra;
FIG. 3 is the acid treated upconversion nanoparticles NaYF of example 14,Yb0.2/Tm0.005And biotin-modified upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(Biotin-UCNPs) and thermogravimetric curves of Biotin;
FIG. 4 is the acid treated upconversion nanoparticles NaYF of example 1 under 980nm excitation4,Yb0.2/Tm0.005Up-conversion nano-particle NaYF modified by solution and biotin4,Yb0.2/Tm0.005Fluorescence emission spectra of (Biotin-UCNPs) solutions;
FIG. 5 shows the modified up-conversion nanoparticles NaYF of example 14,Yb0.2/Tm0.005(Biotin-UCNPs) transmission electron micrographs;
FIG. 6 shows the UV-VIS absorption spectrum of 14,14-P-DTPA in water and 980nm excitation of biotin-modified upconversion nanoparticles NaYF in example 14,Yb0.2/Tm0.005(Biotin-UCNPs) fluorescence emission curves;
FIG. 7 shows the modified upconversion nanoparticles NaYF of 14,14-P-DTPA encapsulated with biotin under excitation of 980nm in example 14,Yb0.2/Tm0.005(Biotin-UCNPs) and the fluorescence emission spectra of the solution before and after comparison;
FIG. 8 shows the modified upconversion nanoparticles NaYF of example 1 after the encapsulation of biotin by 14,14-P-DTPA4,Yb0.2/Tm0.005(Biotin-UCNPs) transmission electron microscopy images.
Detailed Description
The process of the present invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
The carriers in the examples were prepared by the following method:
the synthesis method of the general formula I m, n-P-DTPA comprises the following steps:
(1) and (3) dehydration reaction: adding diethylenetriamine pentaacetic acid, anhydrous acetic anhydride and anhydrous pyridine into a single-neck flask, heating to reflux under the protection of nitrogen, reacting for 12-24 h, performing suction filtration, washing a filter cake to be colorless, and performing vacuum drying at 50-80 ℃ to obtain diethylenetriamine pentaacetic anhydride.
Synthesis of Diethylenetriamine bisanhydride (DTPAA) of formula 1
(2) Hydroxyl substitution reaction: dissolving 4-bromomethyl-3-nitrobenzoic acid and potassium carbonate in a mixed solution of acetone and water, carrying out reflux reaction for 5 hours, adjusting the reaction solution to be acidic, extracting with ethyl acetate for three times, combining an organic layer, drying with anhydrous sodium sulfate, and filtering rotary-dried tawny 4-hydroxymethyl-3-nitrobenzoic acid.
Synthesis of 24-hydroxymethyl-3-nitrobenzoic acid of formula
(3) Amidation reaction: dissolving 4-hydroxymethyl-3-nitrobenzoic acid and secondary amine in a polar solvent, sequentially adding BOP and DIPEA, stirring at normal temperature overnight, pouring the reaction solution into a large amount of water, extracting with ethyl acetate for three times, sequentially washing an organic layer with acid, water, sodium bicarbonate, saturated salt, anhydrous sodium sulfate, drying, filtering, rotary steaming, and separating by column chromatography to obtain the faint yellow 4-hydroxymethyl-3-nitrobenzamide.
Synthesis of 34-hydroxymethyl-3-nitrobenzamides of formula
(4) Esterification reaction: adding diethylenetriamine pentaacetic acid dianhydride into an anhydrous polar solvent, heating to 60-90 ℃ for dissolving, cooling to room temperature, dropwise adding 4-hydroxymethyl-3-nitrobenzamide dissolved in the anhydrous polar solvent, reacting at 10-50 ℃ for 24-36h under the protection of nitrogen, adding a proper amount of water into a reaction solution to generate a milky liquid, centrifuging to obtain a lower-layer yellow solid, and performing column chromatography separation to obtain (4-diethylenetriamine pentaacetic acid ester) -3-nitrobenzamide.
Synthesis of (4-diethylenetriamine pentaacetic acid ester) -3-nitrobenzamide of formula 4
In the above reaction, in step (2), the 4-bromomethyl-3-nitrobenzoic acid: the molar ratio of the potassium carbonate is 1: 1-1: 5, and the volume ratio of the acetone to the water is 1: 1-1: 4. In the step (3), the 4-hydroxymethyl-3-nitrobenzoic acid: secondary amine: BOP: the molar ratio of DIPEA is 1:0.5-3:1: 0.5-4. In the steps (3), (4) and (5), the polar solvent is one of chloroform, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol and water.
A method for synthesizing the general formula IIm, n-ONB-DTPA comprises the following steps:
(1) and (3) demethylation reaction: dissolving 6-nitro piperonal in an organic solvent, dropwise adding the solution into an organic solvent of aluminum chloride under ice bath, and reacting for 1-5h in ice bath. After the reaction is finished, pouring the reaction liquid into hydrobromic acid, and stirring at room temperature for 36-54 h. Diluting the reaction mixture with a large amount of water, extracting for 2-5 times with ethyl acetate, drying with anhydrous magnesium sulfate, suction-filtering to obtain filtrate, spin-drying, recrystallizing in solvent, and suction-filtering to obtain pure yellow 4, 5-dihydroxy-2-nitrobenzaldehyde.
Synthesis of formula 54, 5-dihydroxy-2-nitrobenzaldehyde
(2) And (3) etherification reaction: adding alkali solution and bromoalkane into organic solution of 4, 5-dihydroxy-2-nitrobenzaldehyde, and reacting at 60 ℃ for 10-24h under the protection of nitrogen. Diluting the reaction mixture with a large amount of water, extracting with diethyl ether for 2-5 times, drying with anhydrous magnesium sulfate, suction-filtering to obtain filtrate, spin-drying, recrystallizing in solvent, and suction-filtering to obtain yellow solid 4, 5-alkoxy-2-nitrobenzaldehyde.
Synthesis of 64, 5-alkoxy-2-nitrobenzaldehydes of formula
(3) Reduction reaction: adding sodium borohydride into a mixed solution of 4, 5-alkoxy-2-nitrobenzaldehyde and methanol and tetrahydrofuran, reacting at-7-0 ℃ for 10-60min, and reacting at room temperature for 1-6 h. And (3) after the reaction is finished, removing the solvent by rotary evaporation, washing the solid by hydrochloric acid, extracting the solid by chloroform for 2-5 times, drying by anhydrous magnesium sulfate, and carrying out suction filtration and rotary evaporation to obtain a light yellow solid 4, 5-alkoxy-2-nitrobenzyl alcohol.
Synthesis of 74, 5-alkoxy-2-nitrobenzols of formula
(4) Esterification reaction: adding an anhydrous solvent into diethylenetriamine pentaacetic acid dianhydride, heating to 60-90 ℃ for dissolving, cooling to room temperature, dropwise adding 4, 5-alkoxy-2-nitrobenzyl alcohol dissolved in the anhydrous solvent, reacting at 10-50 ℃ for 24-36h under the protection of nitrogen, adding a proper amount of water into a reaction liquid to generate a milky liquid, centrifuging to obtain a lower-layer yellow solid, and performing column chromatography separation to obtain the diethylenetriamine pentaacetic acid-4, 5-alkoxy-2-nitrobenzyl monoester.
Synthesis of 4, 5-alkoxy-2-nitrobenzyl monoester of diethylenetriaminepentaacetic acid of formula 8
In the reaction, the material charging amount of the first step is 6-nitro piperonal: the molar ratio of aluminum chloride is 1: 2-1: 6. The second step is to feed 4, 5-dihydroxy-2-nitrobenzaldehyde: alkali: the molar ratio of the bromoalkane is 1: 2-5: 2-6. In the third step, the material charging amount is 4, 5-alkoxy-2-nitrobenzaldehyde: the molar ratio of sodium borohydride is 1: 2-5. The material charge in the fourth step is 4, 5-alkoxy-2-nitrobenzol: the mol ratio of diethylenetriamine pentaacetic anhydride is 1: 1-5.
In the steps (1), (2) and (4), the organic solvent is one of chloroform, dichloromethane, dichloroethane, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and tetrahydrofuran.
In the steps (1) and (2), the recrystallization solvent is one of diethyl ether, acetonitrile, methanol and water.
In the step (2), the alkali solution is one of sodium hydroxide, potassium carbonate and sodium carbonate.
In the step (3), the ratio of the mixed solution of the methanol and the tetrahydrofuran is 1:1-5: 1.
Example 114, 14-P-DTPA and Biotin modified upconversion nanoparticles NaYF4,Yb0.2/Tm0.005Compounding
(1) Synthesis of oil-soluble upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(OA-UCNPs)
272mg of CF3COONa(2mmol),394.3mg Y(CF3COO)3(0.795mmol),102.4mg Yb(CF3COO)3(0.2mmol) and 2.54mg Tm (CF)3COO)3(0.005mmol) is dissolved in 10mL of oleic acid and 10mL of octadecene and placed in a three-neck flask, vacuum heated at 120 ℃ for dewatering for 1h, and then rapidly heated to 320 ℃ for reaction for 1 h. Naturally cooling to room temperature, adding methanol, washing and centrifuging to obtain a white solid. The white solid was dried and its XRD diffractogram was measured by an X-ray diffractometer and compared to a standard card such as figure 1, indicating correct structure.
(2) Synthesis of biotin-modified upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(Biotin-UCNPs)
And adding 5mL of 0.1M hydrochloric acid solution into the obtained solid, performing ultrasonic treatment for 3 hours, extracting with diethyl ether to remove oleic acid, and centrifuging to obtain a white solid. Vigorously stirring the obtained white solid and 5mL of biotin solution for 3h, adding the obtained dispersion solution into 10mL of monoethylene glycol, stirring at 105 ℃ for 1h, removing water, transferring the obtained dispersion solution into a 20mL high-pressure reaction kettle, reacting at 160 ℃ for 3h, centrifuging to obtain a white solid, and dispersing the white solid in an aqueous solution.
Upconversion nanoparticles NaYF versus oil solubility4,Yb0.2/Tm0.005(OA-UCNPs) and acid treated upconversion nanoparticles NaYF4,Yb0.2/Tm0.005And biotin-modified up-conversion nanoparticles NaYF4,Yb0.2/Tm0.005(Biotin-UCNPs) Infrared SpectroscopyFIG. 4, acid treated upconversion nanoparticles NaYF4,Yb0.2/Tm0.005Infrared spectrum versus oil soluble upconversion nanoparticles NaYF4,Yb0.2/Tm0.005The infrared spectrogram is obviously changed, and the characteristic absorption peak of oleic acid basically disappears, which shows that the acid-treated upconversion nano particle NaYF4,Yb0.2/Tm0.005Oleic acid is hardly present on the surface; up-conversion nanoparticle NaYF modified by biotin4,Yb0.2/Tm0.005The infrared spectrum is 2925cm-1And 2957cm-1Is represented by CH2Peak of stretching vibration of 1563cm-1Is treated as a stretching vibration peak of CO, and verifies that biotin is successfully modified to up-convert nano-particle NaYF4,Yb0.2/Tm0.005。
Contrast acid treated upconversion nanoparticles NaYF4,Yb0.2/Tm0.005And biotin-modified upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(Biotin-UCNPs) and a thermogravimetric curve of Biotin, as shown in FIG. 3, the Biotin starts to obviously lose weight at about 300 ℃, and the up-conversion nano-particle NaYF modified by the Biotin4,Yb0.2/Tm0.005Also begins to obviously lose weight at about 300 ℃ and the weight loss rate reaches 9.9 percent compared with the acid-treated upconversion nano particle NaYF4,Yb0.2/Tm0.005No obvious weight loss is generated at about 300 ℃, and the side verifies that biotin is successfully modified to up-convert nano-particle NaYF4,Yb0.2/Tm0.005。
Comparing acid treated upconversion nanoparticles NaYF under excitation of 980nm4,Yb0.2/Tm0.005Up-conversion nano-particle NaYF modified by solution and biotin4,Yb0.2/Tm0.005Fluorescence emission spectrum of (Biotin-UCNPs) solution, as shown in FIG. 4, the up-conversion nanoparticle NaYF after Biotin modification4,Yb0.2/Tm0.005The fluorescence emission spectrogram has no obvious change, which shows that the modification of the up-conversion nano particles by the biotin has no obvious influence on the fluorescence emission.
Menses is biologicalUpconversion nanoparticles NaYF after element modification4,Yb0.2/Tm0.005(Biotin-UCNPs) transmission electron micrographs, as shown in FIG. 5, the particle size is around 25 nm.
(3)14,14-P-DTPA (modified biotin-encapsulated) modified upconversion nanoparticle NaYF (NaYF)4,Yb0.2/Tm0.005
Dissolving 5mg of 14,14-P-DTPA (5mmol) in a small amount of chloroform and methanol to form a uniform film, vacuum rotary evaporating the uniform film in a small flask, placing the uniform film in a vacuum drying oven overnight, and dispersing 5mL of biotin-modified upconversion nanoparticles NaYF dispersed in an aqueous solution4,Yb0.2/Tm0.005Adding into a small flask, hydrating for 5h, and performing ultrasonic treatment for 10min to obtain a uniform and clear solution.
Comparing the ultraviolet-visible absorption spectrum of 14,14-P-DTPA with the fluorescence emission curve of water-soluble up-conversion nanoparticles (Biotin-UCNPs) under 980nm excitation, as shown in FIG. 6, the up-conversion nanoparticles NaYF after Biotin modification under 980nm excitation4,Yb0.2/Tm0.005The fluorescence emission curve can be well covered by a 14,14-P-DTPA ultraviolet visible absorption spectrogram at 365nm, which shows that the up-conversion nano particle NaYF modified by biotin under excitation of 980nm4,Yb0.2/Tm0.005The emitted ultraviolet light is well absorbed by 14, 14-P-DTPA.
Comparing 14,14-P-DTPA encapsulated biotin modified up-conversion nanoparticles NaYF excited at 980nm4,Yb0.2/Tm0.005Fluorescence emission spectra of the solutions before and after (Biotin-UCNPs) as shown in FIG. 7, it is verified that 14,14-P-DTPA can absorb the up-conversion nanoparticle NaYF modified by Biotin under excitation of 980nm4,Yb0.2/Tm0.005The released ultraviolet light.
14,14-P-DTPA (modified biotin-encapsulated up-conversion nanoparticle) NaYF (NaYF)4,Yb0.2/Tm0.005As shown in FIG. 8, in a transmission electron micrograph, 14,14-P-DTPA can well encapsulate biotinPost-sexual upconversion nanoparticles NaYF4,Yb0.2/Tm0.005And the particle size is about 210 nm.
Example 210, 10-P-DTPA modified upconversion nanoparticles NaYF with 2-aminoethylphosphonic acid4,Yb0.2/Tm0.005Compounding
(1) Synthesis of oil-soluble upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(OA-UCNPs)
As in example 1(1)
(2) Synthesis of 2-aminoethylphosphonic acid modified upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(AEP-UCNPs)
The obtained solid is added with 5mL of 0.1M hydrochloric acid solution for ultrasonic treatment for 2h, the washed oleic acid is extracted by ether, and the white solid is obtained by centrifugation. Vigorously stirring the obtained white solid and 5mL of 2-aminoethyl phosphonic acid solution for 2h, adding the obtained dispersion solution into 10mL of monoethylene glycol, stirring at 140 ℃ for 1h, removing water, transferring the mixture into a 20mL high-pressure reaction kettle, reacting at 130 ℃ for 3h, centrifuging to obtain a white solid, and dispersing the white solid in an aqueous solution.
(3)10,10-P-DTPA encapsulated 2-aminoethylphosphonic acid modified up-conversion nanoparticle NaYF4,Yb0.2/Tm0.005
Dissolving 4.4mg of 10,10-P-DTPA (5mmol) in a small amount of chloroform and methanol to form a uniform film, vacuum rotary evaporating the uniform film in a small flask, placing the uniform film in a vacuum drying oven overnight, and dispersing 5mL of 2-aminoethyl phosphonic acid dispersed in an aqueous solution to modify the upconversion nanoparticles NaYF4,Yb0.2/Tm0.005Adding into a small flask, hydrating for 4h, and performing ultrasonic treatment for 20min to obtain a uniform and clear solution.
Example 310, 10-ONB-DTPA and Biotin modified upconversion nanoparticles NaYF4,Yb0.2/Tm0.005Compounding
(1) Synthesis of oil-soluble upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(OA-UCNPs)
As in example 1(1)
(2) Synthesis of biotin modified upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(Biotin-UCNPs)
As in example 1(2)
(3)10,10-ONB-DTPA (diethylene triamine pentaacetic acid) encapsulated biotin modified upconversion nano particle NaYF (NaYF)4,Yb0.2/Tm0.005
Dissolving 4.4mg of 10,10-ONB-DTPA (5mmol) in a small amount of chloroform and methanol to form a uniform film, placing the film in a vacuum drying oven overnight, and dispersing 5mL of biotin-modified upconversion nanoparticle NaYF dispersed in an aqueous solution4,Yb0.2/Tm0.005Adding into a small flask, hydrating for 5h, and performing ultrasonic treatment for 30min to obtain a uniform and clear solution.
Example 414, 14-ONB-DTPA modified Up-converting nanoparticles NaYF with 2-Aminoethylphosphonic acid4,Yb0.2/Tm0.005Compounding
(1) Synthesis of oil-soluble upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(OA-UCNPs)
As in example 1(1)
(2) Synthesis of 2-aminoethylphosphonic acid modified upconversion nanoparticles NaYF4,Yb0.2/Tm0.005(AEP-UCNPs)
As in example 2(2)
(3)14,14-ONB-DTPA encapsulated 2-aminoethylphosphonic acid modified up-conversion nanoparticle NaYF4,Yb0.2/Tm0.005
Dissolving 4.9mg of 14,14-ONB-DTPA (5mmol) in a small amount of chloroform and methanol as shown in the above formula, vacuum rotary evaporating in a small flask to form a uniform film, standing in a vacuum oven overnight, and dispersing 5mL of the solution in a solvent2-aminoethylphosphonic acid modified upconversion nanoparticles NaYF in aqueous solution4,Yb0.2/Tm0.005Adding into a small flask, hydrating for 6h, and performing ultrasonic treatment for 60min to obtain a uniform and clear solution.
Claims (5)
1. A near-infrared light-controlled visible drug carrier is characterized in that the near-infrared light-controlled visible drug carrier is water-soluble up-conversion nanoparticles encapsulated by a carrier material with an o-nitrobenzyl ester structure shown in a general formula I or a general formula II:
general formula I
General formula II
The general formula I is named as m, n-P-DTPA, the general formula II is named as m, n-ONB-DTPA
In the formula, CnH2n+1,n＝6,8,10,12,14,16,18；CmH2m+1,m＝0,6,8,10,12,14,16,18。
2. The near-infrared optically controlled visual drug carrier of claim 1, wherein: the water-soluble upconversion nanoparticles are upconversion nanoparticles modified with biotin, 2-aminoethylphosphonic acid, or a polyethylene glycol ligand.
3. The near-infrared optically controlled visual drug carrier of claim 2, wherein: the up-conversion nano particles are NaYF4,Yb0.2/Tm0.005。
4. The near-infrared optically controlled visible drug carrier of claim 3, wherein: the water-soluble up-conversion nano-particles are prepared by firstly preparing CF3COONa,Y(CF3COO)3,Yb(CF3COO)3And Tm (CF)3COO)3Dissolved in oleic acid andheating octaene to 280-320 ℃ to prepare oil-soluble up-conversion nanoparticles OA-UCNPs, and then carrying out ligand exchange on the obtained oil-soluble up-conversion nanoparticles OA-UCNPs to obtain water-soluble up-conversion nanoparticles; the ligand is selected from biotin, 2-aminoethyl phosphonic acid or polyethylene glycol.
5. The method for preparing a near-infrared optically controlled visible drug carrier according to claim 1, wherein: and compounding the carrier material with the water-soluble up-conversion nano particles by using a spinning ultrasonic hydration method, so that the carrier material encapsulates the water-soluble up-conversion nano particles.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910351885.2A CN110075306B (en) | 2019-04-28 | 2019-04-28 | Preparation method of near-infrared light-controlled visible drug carrier |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910351885.2A CN110075306B (en) | 2019-04-28 | 2019-04-28 | Preparation method of near-infrared light-controlled visible drug carrier |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110075306A CN110075306A (en) | 2019-08-02 |
| CN110075306B true CN110075306B (en) | 2020-11-06 |
Family
ID=67417462
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910351885.2A Expired - Fee Related CN110075306B (en) | 2019-04-28 | 2019-04-28 | Preparation method of near-infrared light-controlled visible drug carrier |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110075306B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112047974B (en) * | 2020-09-09 | 2021-10-15 | 山东大学 | Photodegradable bridged silane and preparation method thereof |
| CN115040687A (en) * | 2022-04-06 | 2022-09-13 | 四川大学 | Biological glue for internal wounds, preparation method and application thereof |
| CN114931583B (en) * | 2022-05-27 | 2023-09-22 | 四川大学 | Preparation method of core-shell near-infrared light-controlled sequential release hydrogel |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130115295A1 (en) * | 2009-11-22 | 2013-05-09 | Qiang Wang | Rare Earth-Doped Up-Conversion Nanoparticles for Therapeutic and Diagnostic Applications |
| CN101785862B (en) * | 2010-02-10 | 2012-05-30 | 吉林大学 | Infrared light triggering controllable drug carrier and preparation method thereof based on up-conversion material |
| WO2013181076A1 (en) * | 2012-05-30 | 2013-12-05 | University Of Massachusetts Medical School | Coated up-conversion nanoparticles |
| US20140147391A1 (en) * | 2012-11-28 | 2014-05-29 | The Hong Kong Polytechnic University | BIOPROBE BASED ON SINGLE-PHASE UPCONVERSION NANOPARTICLES (UCNPs) FOR MULTI-MODAL BIOIMAGING |
| CN103623437B (en) * | 2013-12-01 | 2015-08-19 | 中国科学院上海硅酸盐研究所 | A kind of imaging nano-probe material and its preparation method and application |
| CN103980434B (en) * | 2014-05-19 | 2016-08-24 | 苏州大学 | A kind of amphipathic nature polyalcohol, its preparation method, composite Nano pharmaceutical carrier and preparation method thereof |
| KR102042661B1 (en) * | 2015-08-06 | 2019-11-08 | 광주과학기술원 | Complex for detecting target material and method for detecting target material using the same |
| CN105833791B (en) * | 2016-03-30 | 2017-10-24 | 大连理工大学 | A kind of surfactant containing adjacent nitro benzyl ester light degradation group and preparation method thereof |
| CN106620700B (en) * | 2016-12-28 | 2020-07-24 | 中国科学院长春光学精密机械与物理研究所 | Compound and application thereof |
| CN108853497B (en) * | 2018-07-04 | 2021-04-06 | 青岛大学 | Construction of targeted photodynamic nanoprobe based on up-conversion nanoparticles and ultrathin silicon dioxide layer |
-
2019
- 2019-04-28 CN CN201910351885.2A patent/CN110075306B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| A Multifunctional Lipid Incorporating Active Targeting and Dual-Control Release Capabilities for Precision Drug Delivery;Chenyu Liu et al;《ACS Appl. Mater. Interfaces》;20191127(第12期);第70-85页 * |
| Fast coating of hydrophobic upconversion nanoparticles by NaIO4-induced polymerization of dopamine: Positively charged surfaces and in situdeposition of Au nanoparticles;Wei Zhang et al;《Applied Surface Science》;20200601(第527期);第1-8页 * |
| 基于上转换发光纳米探针的赭曲霉毒素A检测方法研究;戴邵亮;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20170215(第02期);第B024-384页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110075306A (en) | 2019-08-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110075306B (en) | Preparation method of near-infrared light-controlled visible drug carrier | |
| Zhang et al. | The fast-growing field of photo-driven theranostics based on aggregation-induced emission | |
| Dong et al. | Poly (ethylene glycol) conjugated nano-graphene oxide for photodynamic therapy | |
| Hou et al. | pH-Sensitive self-assembling nanoparticles for tumor near-infrared fluorescence imaging and chemo–photodynamic combination therapy | |
| Cui et al. | Amphiphilic chitosan modified upconversion nanoparticles for in vivo photodynamic therapy induced by near-infrared light | |
| Tang et al. | NIR light-responsive nanocarriers for controlled release | |
| JP5577329B2 (en) | pH-sensitive metal nanoparticles and method for producing the same | |
| Deng et al. | Multifunctional hollow CaF2: Yb3+/Er3+/Mn2+-poly (2-Aminoethyl methacrylate) microspheres for Pt (IV) pro-drug delivery and tri-modal imaging | |
| Chen et al. | Preparation and photodynamic therapy application of NaYF4: Yb, Tm–NaYF4: Yb, Er multifunctional upconverting nanoparticles | |
| CN108192590B (en) | Preparation method of polyazobenzene multifunctional nanoparticles based on rare earth up-conversion material | |
| Zhou et al. | Monomer zinc phthalocyanine/upconversion nanoparticle coated with hyaluronic acid crosslinked gel as NIR light-activated drug for in vitro photodynamic therapy | |
| JP6867084B2 (en) | New cationic polyphosphazene compounds, polyphosphazene-drug conjugate compounds and methods for producing them | |
| Pradeepkumar et al. | Natural solvent-assisted synthesis of amphiphilic co-polymeric nanomicelles for prolonged release of camptothecin delivery | |
| Wang et al. | One-step self-assembly of ZnPc/NaGdF 4: Yb, Er nanoclusters for simultaneous fluorescence imaging and photodynamic effects on cancer cells | |
| Yu et al. | A triple-stimulus responsive melanin-based nanoplatform with an aggregation-induced emission-active photosensitiser for imaging-guided targeted synergistic phototherapy/hypoxia-activated chemotherapy | |
| CA3226732A1 (en) | Micelle complex and drug carrier comprising same | |
| Liu et al. | Multilayered upconversion nanocomposites with dual photosensitizing functions for enhanced photodynamic therapy | |
| JP5624545B2 (en) | Metal porphyrin derivatives, nanoparticles containing them, and their use in photodynamic therapy | |
| CN113101365A (en) | Photodynamic nano platform with mitochondrion targeting characteristic and preparation method and application thereof | |
| CN112107542A (en) | Has tumor pH and H2O2Multifunctional polymer micelle with specific activated antitumor activity and preparation method thereof | |
| CN103755888B (en) | A kind of amphipathic nature polyalcohol and preparation, magnetic hollow nano-medicament carrier and its preparation method | |
| Hu et al. | A ros-sensitive diselenide-crosslinked polymeric nanogel for NIR controlled release | |
| CN112656950B (en) | Camptothecin-polycaprolactone coupled prodrug, preparation method and application thereof | |
| CN115040650A (en) | Preparation and application methods of quinoline cyanine photo-thermal nanoparticles with aggregation-enhanced photo-thermal characteristics | |
| CN111632152B (en) | PH-GSH double-responsiveness nano curcumin prodrug drug loading system |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20201106 Termination date: 20210428 |