CN107722140B - Hyaluronic acid cholesterol chloroformate polymer and preparation method and application thereof - Google Patents
Hyaluronic acid cholesterol chloroformate polymer and preparation method and application thereof Download PDFInfo
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- CN107722140B CN107722140B CN201710912122.1A CN201710912122A CN107722140B CN 107722140 B CN107722140 B CN 107722140B CN 201710912122 A CN201710912122 A CN 201710912122A CN 107722140 B CN107722140 B CN 107722140B
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- hyaluronic acid
- chloroformate
- polymer
- drug delivery
- cystamine
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 77
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 77
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 77
- QNEPTKZEXBPDLF-JDTILAPWSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] carbonochloridate Chemical compound C1C=C2C[C@@H](OC(Cl)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 QNEPTKZEXBPDLF-JDTILAPWSA-N 0.000 title claims abstract description 63
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- ZKSVYBRJSMBDMV-UHFFFAOYSA-N 1,3-diphenyl-2-benzofuran Chemical compound C1=CC=CC=C1C1=C2C=CC=CC2=C(C=2C=CC=CC=2)O1 ZKSVYBRJSMBDMV-UHFFFAOYSA-N 0.000 description 1
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- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
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- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
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- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/227—Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Materials Engineering (AREA)
- Acoustics & Sound (AREA)
- Dispersion Chemistry (AREA)
- Radiology & Medical Imaging (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a disulfide bond connected hyaluronic acid cholesterol chloroformate comb type polymer, a preparation method and application thereof. The polymer is obtained by reacting hyaluronic acid with cholesteryl chloroformate through cystamine dihydrochloride. The polymer has good biocompatibility, good biodegradability and low toxicity. Compared with normal cells, the surface of most of cancer cells can specifically express a receptor targeted by hyaluronic acid, so that the polymer serving as an anticancer drug carrier can well target the cancer cells, and the utilization rate of the drug and toxic and side effects on other organ tissues are reduced. Meanwhile, as the disulfide bond on the cystamine dihydrochloride can be specifically degraded by the glutathione with high expression in cancer cells, the polymer has the characteristics of intelligent response and release as an anticancer drug carrier, and has the characteristics of good stability, long in-vivo circulation time and the like.
Description
Technical Field
The invention belongs to the technical field of preparation of high molecular polymers, and particularly relates to a disulfide bond-linked hyaluronic acid cholesterol chloroformate polymer, and a preparation method and application thereof.
Background
Hyaluronic Acid (HA) is a high molecular compound with good biocompatibility, easy degradation in vivo and low toxicity, and its basic mechanism is a large polysaccharide composed of two disaccharide units, D-glucuronic acid and N-acetylglucosamine. The hyaluronic acid-chitosan/. Meanwhile, hyaluronic acid can also specifically target a CD44 receptor highly expressed by tumor cells, so that the hyaluronic acid HAs been widely used for treating cancers, and HA is designed as a carrier of a targeted drug.
Cholesterol chloroformate (cholesteryl chloroformate), also known as cholesteryl chloroformate, is a derivative of cholesterol, which is widely present in the human body, particularly in brain and nerve tissues, most abundantly present in kidney, liver, spleen, bile and skin, as a fat-soluble molecule. Cholesterol is an essential substance for animal tissue cells, and not only is a raw material for synthesizing bile acid, vitamin D and steroid hormone by organisms, but also is an important component for forming cell membranes, so that the nano-drug using cholesteryl chloroformate as a carrier has stronger penetrating capability when crossing cell membrane barriers, and is widely applied to the synthesis of nano-drug carriers.
Cystamine dihydrochloride is a small molecule which can be reduced by glutathione, and after the cystamine dihydrochloride is transported into cells as a part of a nano-drug carrier, because the disulfide bond is subjected to reduction reaction and is broken due to high concentration of glutathione in the cells, the nanostructure is disintegrated, and the small molecule drug coated in the carrier is released, the cystamine dihydrochloride is widely applied to the design and research and development of nano-drugs as a switch of the nanostructure.
IR-780 iodide, as a small molecule drug, can be used to study the drug release and accumulation behavior at the disease site due to its own fluorescence properties and photoacoustic imaging effects, and as an imaging diagnostic molecular probe, is widely studied, and at the same time, has been widely used in basic scientific research due to its photodynamic therapy and photothermal therapy effects. However, since IR-780 iodide is a hydrophobic molecule, it is difficult to directly apply it to the body. Therefore, IR-780 needs to be hydrophilically modified prior to application.
The amphiphilic polymer with hydrophilic and hydrophobic ends has strong self-assembly capacity of molecules in a specific solvent, can form stable micelles, and has the functions of medicine storage and controlled release through the interaction with small molecule medicines. Therefore, the research on the amphiphilic polymer which is connected by the disulfide bond and simultaneously has hydrophilic and hydrophobic ends has important application value.
Disclosure of Invention
The first purpose of the invention is to provide a disulfide-linked hyaluronic acid cholesterol chloroformate polymer which has high response sensitivity, targeted release, degradability and low toxicity and has amphipathy.
It is a second object of the present invention to provide a method for preparing a disulfide-linked hyaluronic acid cholesterol chloroformate polymer.
A third object of the present invention is to provide the use of a disulfide-linked hyaluronic acid cholesterol chloroformate polymer as a pharmaceutical carrier.
The fourth purpose of the invention is to provide a preparation method of the disulfide-linked hyaluronic acid cholesterol chloroformate polymer as a drug carrier for encapsulating IR780 to form nano-particles.
In order to achieve the purpose, the invention provides the following technical scheme:
a disulfide bond linked hyaluronic acid cholesterol chloroformate comb type polymer has a structure shown in formula I,
wherein x is an integer of 3-6, y is an integer of 12-24, and the ratio of x to y is 1: 2-8.
The dispersion index of the disulfide-linked hyaluronic acid cholesterol chloroformate comb polymer is 0.18-0.19, and the weight-average molecular weight is 7500-13700Da, preferably 11800-13000 Da.
The disulfide-linked hyaluronic acid cholesterol chloroformate comb-type polymer has good solubility and stability.
The invention also provides a preparation method of the disulfide-linked hyaluronic acid cholesterol chloroformate comb polymer, which comprises the following steps:
(a) reacting organic amine and cystamine dihydrochloride in a first organic solvent to obtain cystamine;
(b) reacting the cholesteryl chloroformate with cystamine in a second organic solvent to obtain cholesteryl chloroformate-cystamine;
(c) in a third organic solvent, reacting cholesteryl chloroformate-cystamine with hyaluronic acid under the action of an amidation activator to obtain the hyaluronic acid-cystamine-cholesteryl chloroformate comb polymer.
Wherein the reaction process of the step (a) is as follows:
in the step (a), the reaction is to stir at 0 ℃ for 2.5-3.5h and then return to room temperature to obtain cystamine.
Preferably, the organic amine is triethylamine or pyridine;
preferably, the first organic solvent consists of acetonitrile and dichloromethane in a volume ratio of 2: 1.
The reaction sequence of step (b) is as follows:
in step (b): firstly dissolving cholesteryl chloroformate in a second organic solvent, then dropwise adding the solution containing the cholesteryl chloroformate into the cystine solution, and stirring at room temperature; after the reaction is finished, washing with water, removing the organic solvent and drying;
wherein the second organic solvent is dichloromethane.
The molar ratio of the cholesteryl chloroformate to cystamine dihydrochloride is 1: 10.
The reaction time is 16-24 h.
The reaction sequence of step (c) is as follows:
in step (c): putting Hyaluronic Acid (HA) into a third organic solvent (volume ratio is 1:1), and performing ultrasonic treatment to completely dissolve the HA; adding the product cholesterol chloroformate-cystamine obtained in the step (b) into a solution containing hyaluronic acid, and performing ultrasonic treatment to completely dissolve the product cholesterol chloroformate-cystamine; adding an amide activating agent, and reacting at room temperature; after the reaction is finished, removing the organic solvent, dialyzing and freeze-drying to obtain the target product.
Wherein the molar ratio of the hyaluronic acid to the product obtained in the step (b) is 4/1-6/1, preferably 5/1, and the weight average molecular weight of the hyaluronic acid is 6600-12000Da, preferably 9000-11000 Da.
Preferably, the third organic solvent is a mixture of water and tetrahydrofuran in a volume ratio of 1/2-2/1, preferably 1: 1.
Preferably, the amide activator can be 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), or a mixture of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) in a mass ratio of 1:1, preferably HATU; the hyaluronic acid is mixed with the amide activator in a molar ratio of 1/2-1/1, preferably 1: 2.
Preferably, the reaction time is 16-24 h.
The disulfide-linked hyaluronic acid cholesterol chloroformate polymer simultaneously comprises a hydrophilic part and a hydrophobic part, wherein the hydrophilic part is hyaluronic acid, the hydrophobic part is cholesterol chloroformate, and the amphiphilic derivative can be self-assembled into a disulfide-linked hyaluronic acid cholesterol chloroformate polymer micelle in an aqueous solution.
The invention also provides application of the disulfide-linked hyaluronic acid cholesterol chloroformate polymer in preparing a stimulus-responsive drug delivery carrier.
The invention also provides a stimulus-responsive drug delivery vehicle containing the disulfide-bond hyaluronic acid cholesterol chloroformate polymer.
The stimulus responsive drug delivery vehicle further comprises an IR780 drug encapsulated by the disulfide bonded hyaluronic acid cholesterol chloroformate polymer. The stimulus-responsive drug delivery carrier is a nanoparticle which has a regular spherical structure, and the particle size is 150-250nm, preferably 200-210 nm; the dispersion coefficient is 0.220-0.318. The stimulus response type drug delivery carrier material has the advantages of good stability, long in-vivo circulation time, strong cell uptake, high response sensitivity, targeted release and the like.
The preparation method of the stimulus-responsive drug delivery carrier can adopt an emulsion solvent evaporation method, a self-assembly method and a double-emulsion method, and preferably adopts the emulsion solvent evaporation method; the emulsion solvent evaporation method is a traditional method for preparing the drug-loaded nanoparticles, and has the advantages of simple operation, traditional method and higher preparation efficiency. The method comprises the following specific steps:
(1) dissolving a disulfide-linked hyaluronic acid cholesterol chloroformate polymer in water, and keeping the polymer in a non-dissolved state;
(2) adding a trichloromethane solution containing IR780 into the mixture obtained in the step (1) and dissolving;
(3) and (3) carrying out ultrasonic treatment on the mixed solution obtained in the step (2), removing trichloromethane, centrifuging, and taking supernatant fluid to obtain the product.
Wherein, in the step (2), the concentration of the chloroform solution containing IR780 is 1mg/ml, and the mass ratio of the disulfide-linked hyaluronic acid cholesterol chloroformate polymer to the IR780 is 10/1-20/1.
Wherein, in the step (2), the volume ratio of the aqueous solution of the disulfide-linked hyaluronic acid cholesterol chloroformate polymer to the IR780 medicine solution is 10/1.
Wherein, in the step (3), the ultrasonic conditions are as follows: setting the power to be 95-105W, turning on the ultrasonic wave for 1-2s, turning off the ultrasonic wave for 2-3s, and setting the ultrasonic wave time to be 4-8 min; preferably, the power is 100W, ultrasound on for 2s, ultrasound off for 3s, cycling, total ultrasound for 5 min.
Drawings
FIG. 1 is an infrared spectrum of the cholesteryl chloroformate, cholesteryl cysteamine, hyaluronic acid, disulfide-linked hyaluronic acid cholesteryl chloroformate polymer of example 1.
FIG. 2 is a transmission electron micrograph of disulfide bonded hyaluronic acid cholesteryl chloroformate polymer encapsulating IR780 drug-forming nanoparticles of example 2;
FIG. 3 is a graph showing the distribution of the particle size of IR780 drug-loaded nanoparticles encapsulated by the disulfide-linked hyaluronic acid cholesterol chloroformate polymer in example 2 in a light scattering diagram;
FIG. 4 is a photo-acoustic image of nanoparticles formed by encapsulating IR780 drug with disulfide-linked hyaluronic acid cholesteryl chloroformate polymer in example 2;
FIG. 5 is a photothermal graph of the IR780 drug-loaded nanoparticle formed from the disulfide-linked hyaluronic acid cholesteryl chloroformate polymer of example 2;
FIG. 6 is a graph of the photodynamic force of the IR780 drug-loaded nanoparticles of the disulfide-linked hyaluronic acid cholesterol chloroformate polymer of example 2.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
The following examples of cholesteryl chloroformate, cholesteryl cysteamine, hyaluronic acid, disulfide-linked hyaluronic acid cholesteryl chloroformate polymer were subjected to infrared spectroscopic detection under the following conditions: the sample and KBr were mixed at a mass ratio of 1:50, ground into a transparent thin sheet, and detected by an infrared spectrometer (manufactured by Perkin-Elmer, USA, model number Spectrum one).
The nanoparticles formed by coating IR780 drug with the disulfide-linked chloroformate polymer of hyaluronic acid cholesterol obtained in the following examples were characterized by dynamic light scattering (Zetasizer NanoZS) and transmission electron microscopy (FEI, Tecnai G220S-TWIN, 200 kV).
Photoacoustic signal detection was performed on nanoparticles formed by coating IR780 drug with the disulfide-linked hyaluronic acid cholesterol chloroformate polymer obtained in the following examples. In the testing process, IR780 absorbs near-infrared laser in a super-resolution small animal photoacoustic imaging system (iThera, model number MOST invision 128), and photoacoustic signals of the material can be obtained by detecting the intensity of vibration waves. Self-assembly medicine-carrying nanoparticle aqueous solutions with different concentrations are prepared in an experiment, the nanoparticle solution is placed in a super-resolution small animal photoacoustic imaging system, photoacoustic signals are measured, and photoacoustic intensity graphs of the nanoparticle aqueous solutions with different concentrations are drawn.
The method comprises the steps of detecting the photothermal heating effect of nanoparticles formed by disulfide bond-linked hyaluronic acid cholesterol chloroformate polymer-entrapped IR780 drug, testing, wherein IR780 can generate photothermal effect under the irradiation of near-infrared laser, preparing 4 drug-loaded nanoparticle solutions with different concentrations, irradiating the nanoparticle solutions with different concentrations for 10min by using a near-infrared laser (Beijing L ashave optoelectro Technology co.ltd, model L wIR L808) and laser excited at power of 0.6W/cm2 and 808nm, respectively, controlling the starting temperature at room temperature, recording the solution temperature by using an infrared thermal imager every 10s, and drawing a heating curve.
The photodynamic effect detection is carried out on the nanoparticles formed by the IR780 medicament encapsulated by the disulfide bond-linked hyaluronic acid cholesterol chloroformate polymer obtained in the following examples. The testing process comprises the following steps: under the condition of near-infrared laser irradiation, a fluorescent probe 3-Diphenylisobenzofuran (DPBF) is adopted to detect Reactive Oxygen Species (ROS) in the drug-loaded nano solution. Using a near infrared laser (set power of 0.6W/cm)2) Irradiating the solution for 10min, measuring the absorption value of the solution at the wavelength of about 422nm by using an ultraviolet spectrophotometer (the model is TU-1810, the GmbH of Beijing general analytical instruments, Inc.) every 1min, and finally finishing and drawing a light power curve.
Cholesterol chloroformate was purchased from Alfaraasar and was analytically pure;
cystamine dihydrochloride was purchased from alfabraasar, and was analytically pure;
triethylamine was purchased from west longe chemical corporation and analyzed;
hyaluronic acid was purchased from melphalan bio, and was analytically pure;
2- (7-Benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) was purchased from AJohnson Matthey corporation and was analytically pure;
IR780 iodide was obtained from Alfaraasar.
EXAMPLE 1 preparation of disulfide-linked hyaluronic acid Cholesterol chloroformate polymers
Step (a): 1.35g of cystamine dihydrochloride and 37.8ml of triethylamine are dissolved in 140ml of a mixed solution of acetonitrile and dichloromethane, wherein the volume ratio of the acetonitrile to the dichloromethane is 2: 1. Stirring at 0 deg.C for 3 hr, and then returning to room temperature and continuing stirring to dissolve to obtain cystamine solution.
Step (b): 0.27g of cholesteryl chloroformate was dissolved in 10ml of methylene chloride, and after 20min, the cholesteryl chloroformate solution was added dropwise to the cystamine solution obtained in step (a), and stirred at room temperature for 16-24 h. And after the reaction is finished, washing the mixture for three times by using water, removing dichloromethane by rotary evaporation after the water washing is finished, and drying the mixture in a vacuum drying oven.
And (c) putting 264 mu mol of hyaluronic acid into 50ml of water and tetrahydrofuran (volume ratio of 1:1) solution, performing ultrasonic treatment for about 30min to completely dissolve the hyaluronic acid, adding 52.8 mu mol of the product obtained in the step (b) into the hyaluronic acid solution, performing ultrasonic treatment for about 30min to completely dissolve the hyaluronic acid, after the dissolution is completed, adding 264 mu mol of HATU into the solution, reacting at room temperature for 16-24h, removing THF through rotary evaporation, after the rotary evaporation is completed, dialyzing in water for three days by using a 3500 ηα molecular weight dialysis bag, and finally freeze-drying the product in the dialysis bag.
The infrared detection of the obtained product has the following results:
in FIG. 1, first, an infrared spectrum of cholesteryl chloroformate (Chol) was obtained at 2942cm-1The left and right peaks are-CH2-and-CH3Peak of stretching vibration of 1777cm-1The peak of stretching vibration of C ═ O is due to the electron-withdrawing induction effect of Cl atom, so that the polarity of C ═ O decreases, the double bond property of carbonyl group increases, the wave number of stretching vibration of carbonyl group increases, and the wave number increases from 1715cm-1Increased to 1777cm-1。
Secondly, the infrared spectrum of the intermediate product cholesterol cysteamine (Chol-Cys) is 2942cm-1The left and right peaks are-CH2-and-CH3Expansion peak of 1698cm-1The peak was found to be a stretching vibration peak of C ═ O, and the wave number of C ═ O was reduced by 3336cm since a urethane group was formed by the reaction-1Is the stretching vibration peak of NH.
Hyaluronic Acid (HA) Infrared Spectrum, 3000cm-1～3500cm-1Is the expansion of-OH in hyaluronic acidPeak vibration 2885cm-1The left and right peaks are-CH3and-CH2Peak of stretching vibration of-1609 cm-1The left and right peaks are C ═ O stretching vibration peaks in the amide group in hyaluronic acid.
Finally, the synthesized disulfide-linked hyaluronic acid cholesterol chloroformate polymer infrared spectrogram is 3357cm-1The left and right peaks are the superposition of NH stretching vibration peak of intermediate product Chol-Cys and OH stretching vibration peak of HA, 2942cm-1The nearby peak is-CH2-and-CH3Peak of stretching vibration of 1648cm-1The adjacent peak is an amide group stretching vibration peak of HA.
The four spectra are combined to determine the nature, the intermediate product is grafted on HA, and the obtained product is Chol-Cys-HA.
According to tests, x is an integer of 3-6, y is an integer of 12-24, the ratio of x to y is 1:2-8, the dispersion index is 0.18-0.19, and the weight-average molecular weight is 11800-13000.
Example 2 the polymer prepared in example 1 entrapped IR780 drug formed nanoparticles
A preparation method of nanoparticles comprises the following steps:
(1) dissolving 10mg of carrier material, namely hyaluronic acid cholesterol chloroformate polymer connected by disulfide bonds in 5m L water, and keeping the undissolved state;
(2) preparing an IR780 trichloromethane solution with the concentration of 1mg/m L, adding 0.5m L into the mixture obtained in the step (1), and shaking on a vortex oscillator to dissolve the material.
(3) The power was then set to 100W in the cell disruptor. And (4) turning on the ultrasound for 2s, turning off the ultrasound for 3s, circulating, and carrying out ultrasound on the solution for 5 min.
(4) The solution after sonication was transferred to a round bottom flask and chloroform was removed by rotary evaporation.
(5) And centrifuging the solution in a centrifuge to obtain supernatant to obtain the stimulus-responsive drug delivery carrier nanoparticles.
Through detection, the disulfide bond-linked hyaluronic acid cholesterol chloroformate polymer entraps the IR780 medicine to form nanoparticles with regular spherical structures; the particle size is 205.2 + -1.4 nm, and the dispersion index is 0.229 + -0.009.
Fig. 2 and 3 are a transmission electron micrograph and a light scattering schematic of nanoparticles formed by encapsulating IR780 drug with disulfide-linked hyaluronic acid cholesterol chloroformate polymer in example 2, respectively.
Fig. 4, 5 and 6 are a photoacoustic graph, a photothermal graph and a photodynamic graph, respectively, of nanoparticles formed by disulfide-linked hyaluronic acid cholesteryl chloroformate polymer encapsulating IR780 drug in example 2.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (11)
1. A stimulus response type drug delivery carrier is characterized in that the drug delivery carrier is a nanoparticle, has a regular spherical structure, has a particle size of 150-;
the stimulus responsive drug delivery vehicle comprises: disulfide-linked hyaluronic acid cholesterol chloroformate comb polymers and IR780 medicaments encapsulated by the same; wherein the mass ratio of the disulfide-linked hyaluronic acid cholesterol chloroformate comb polymer to the IR780 medicament is 10/1-20/1;
the structure of the hyaluronic acid cholesterol chloroformate comb-type polymer connected by disulfide bonds is shown as a formula I,
wherein x is an integer of 3-6, y is an integer of 12-24, and the ratio of x to y is 1: 2-8.
2. The stimulus responsive drug delivery vehicle of claim 1, wherein the particle size is 200-210 nm.
3. The stimulus responsive drug delivery vehicle of claim 1, wherein the weight average molecular weight of the disulfide linked hyaluronic acid cholesterol chloroformate comb polymer is 7500-13700 Da.
4. The stimulus responsive drug delivery vehicle of claim 3, wherein the weight average molecular weight of the disulfide linked hyaluronic acid cholesterol chloroformate comb polymer is 11800-13000 Da.
5. The stimulus responsive drug delivery vehicle of claim 1, wherein the disulfide linked hyaluronic acid cholesterol chloroformate comb polymer has a dispersion index in the range of 0.18 to 0.19.
6. The stimulus responsive drug delivery vehicle of claim 1, wherein the disulfide linked hyaluronic acid cholesterol chloroformate comb polymer is prepared by a method comprising the steps of:
(a) reacting organic amine and cystamine dihydrochloride in a first organic solvent to obtain cystamine;
(b) reacting the cholesteryl chloroformate with cystamine in a second organic solvent to obtain cholesteryl chloroformate-cystamine;
(c) in a third organic solvent, reacting cholesteryl chloroformate-cystamine with hyaluronic acid under the action of an amidation activator to obtain the hyaluronic acid-cystamine-cholesteryl chloroformate comb polymer.
7. The stimulus-responsive drug delivery vehicle according to claim 6, wherein in step (a), the reaction is performed by stirring at 0 ℃ for 2.5-3.5h and then returning to room temperature to obtain cystamine.
8. The stimulus responsive drug delivery vehicle of claim 6, wherein in step (b), the cholesteryl chloroformate is dissolved in the second organic solvent, and then the solution containing the cholesteryl chloroformate is added dropwise to the cystamine solution, and stirred at room temperature; and after the reaction is finished, washing with water, removing the organic solvent and drying.
9. The stimulus-responsive drug delivery vehicle of claim 8, wherein in step (c), hyaluronic acid is placed in a third organic solvent and sonicated to completely dissolve it; adding the product cholesterol chloroformate-cystamine obtained in the step (b) into a solution containing hyaluronic acid, and performing ultrasonic treatment to completely dissolve the product cholesterol chloroformate-cystamine; adding an amide activating agent, and reacting at room temperature; after the reaction is finished, removing the organic solvent, dialyzing and freeze-drying to obtain the target product.
10. The stimulus responsive drug delivery vehicle of claim 9, wherein the amide activator is 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate, or a 1:1 mixture of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide in a mass ratio of 1: 1.
11. A method of preparing a stimuli-responsive drug delivery vehicle according to any one of claims 1 to 10, comprising:
(1) dissolving a disulfide-linked hyaluronic acid cholesterol chloroformate comb-type polymer in water, and keeping a non-dissolved state;
(2) adding a trichloromethane solution containing IR780 into the mixture obtained in the step (1) and dissolving;
(3) carrying out ultrasonic treatment on the mixed solution obtained in the step (2), removing trichloromethane, centrifuging, and taking supernatant fluid to obtain the product;
wherein, in the step (2), the concentration of the chloroform solution containing IR780 is 1 mg/ml;
wherein, in the step (3), the ultrasonic conditions are as follows: the power is set to be 95-105W, the ultrasonic is turned on for 1-2s, the ultrasonic is turned off for 2-3s, and the total ultrasonic time is 4-8 min.
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