CN109453378B - Light-operated nanoparticle assembly and preparation method and application thereof - Google Patents

Light-operated nanoparticle assembly and preparation method and application thereof Download PDF

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CN109453378B
CN109453378B CN201811391802.4A CN201811391802A CN109453378B CN 109453378 B CN109453378 B CN 109453378B CN 201811391802 A CN201811391802 A CN 201811391802A CN 109453378 B CN109453378 B CN 109453378B
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CN109453378A (en
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朱锦涛
刘园园
谭海英
张连斌
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Huazhong University of Science and Technology
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Abstract

The invention discloses a light-operated nanoparticle assembly and a preparation method and application thereof, belonging to the field of controlled release of drugs. The light-control nanoparticle assembly contains nanoparticles and a light-responsive polymer; the photoresponsive polymer is grafted to the surface of the nano particle through coordination, host-guest interaction or covalent bond; the photoresponsive group is attached to the polymer main chain or side chain. The light-controlled nanoparticle and the drug molecule are self-assembled to form a light-controlled nanoparticle assembly body coating the drug molecule, under the illumination condition, the photoresponse molecule on the polymer chain is changed, so that the structure of the polymer chain is changed, and the nanoparticle assembly body is disassembled, so that the coated drug molecule is released, and the light-controlled drug release is realized.

Description

Light-operated nanoparticle assembly and preparation method and application thereof
Technical Field
The invention belongs to the field of controlled release of medicines, and particularly relates to a light-operated nanoparticle assembly and a preparation method and application thereof.
Background
Cancer (i.e., malignant tumor) is one of the major diseases that endanger human health and life. Chemotherapy, which is one of the cancer treatment methods, has a great limitation in the effect of chemotherapy because the physical environment of the body causes obstacles and toxic and side effects to anticancer drugs. In recent years, the rapid development of a nano drug delivery system greatly improves the efficiency of the drug reaching the focus, and brings new opportunities for tumor treatment. Therefore, designing and preparing a novel nano drug delivery system gradually becomes one of effective ways for treating tumors.
In a series of novel nano drug-carrying systems, the functional hybrid nano material combines the characteristics of inorganic nano materials and organic materials, has the advantages of good biocompatibility, high efficient treatment rate and the like, and has good application prospect. However, when the nano-assembly is used as a nano-carrier, it is required to load drug molecules and controllably release the drug molecules into tumor cells or tissues. However, the nanoparticle assembly prepared by the existing method can well coat the drug molecules, but the drug molecules in the nanoparticle assembly are difficult to controllably release, thereby limiting the application range of the nanoparticle assembly.
Disclosure of Invention
The invention solves the technical problem that the release of the coated molecules by the nanoparticle assembly in the prior art is uncontrollable.
To achieve the above object, according to a first aspect of the present invention, there is provided a nanoparticle grafted with a photo-responsive polymer, the nanoparticle surface being grafted with a photo-responsive polymer; the photoresponsive polymer is an amphiphilic block copolymer; the amphiphilic block copolymer contains a hydrophilic chain segment and a hydrophobic chain segment; the photoresponsive molecules are connected to the main chain of the amphiphilic block copolymer in a covalent bond mode, or the photoresponsive molecules are connected to the side chains of the hydrophilic chain segment or the hydrophobic chain segment in a covalent bond mode; the photoresponsive polymer is connected with the nano particles through coordination, host-guest interaction or covalent bonds; the nanoparticles are inorganic nanoparticles.
Preferably, the inorganic nanoparticles are metal nanoparticles, oxide nanoparticles, sulfide nanoparticles or up-conversion nanoparticles; the volume of the inorganic nano particles is 0.5nm3-550000nm3(ii) a The shape of the inorganic nano-particle is spherical, rod-shaped, star-shaped, polygonal or Janus structure; the photoresponse molecule is azobenzene or spiroAt least one of pyran, azonaphthoquinone, diarylethene, o-nitrobenzoyl, coumarin, coca-m-diacid, azobenzene derivatives, spiropyran derivatives, azonaphthoquinone derivatives, diarylethene derivatives, o-nitrobenzoyl derivatives, coumarin derivatives, and coca-m-diacid derivatives; the photoresponsive polymer is connected with the nano-particles through at least one of disulfide bonds, sulfydryl, carboxyl, amino, pyridine, carbonyl, ethylenediamine, thiocyanate, isothiocyanide, cyclodextrin and azobenzene;
preferably, the inorganic nanoparticles are at least one of gold nanoparticles, silver nanoparticles, nickel nanoparticles, silica nanoparticles, ferroferric oxide nanoparticles, gadolinium oxide nanoparticles, cerium oxide nanoparticles and copper sulfide nanoparticles.
Preferably, the molar mass of the hydrophilic segment is between 1kg/mol and 50kg/mol, and the molar mass of the hydrophobic segment is between 10kg/mol and 1000 kg/mol; the mass ratio of the hydrophilic chain segment to the hydrophobic chain segment is 1 (1-20); the hydrophilic chain segment is at least one of polyvinyl alcohol, polyacrylic acid, polyacrylamide, poly-4-vinylpyridine, polyvinylpyrrolidone, polyvinyl alcohol derivatives, polyacrylic acid derivatives, polyacrylamide derivatives, poly-4-vinylpyridine derivatives and polyvinylpyrrolidone derivatives; the hydrophobic chain segment is at least one of polystyrene, polymethyl methacrylate, levorotatory polylactic acid, dextrorotatory polylactic acid, polypropylene, polyethylene, polybutadiene, polystyrene derivatives, polymethyl methacrylate derivatives, levorotatory polylactic acid derivatives, dextrorotatory polylactic acid derivatives, polypropylene derivatives, polyethylene derivatives and polybutadiene derivatives;
preferably, the hydrophilic segment has a molar mass of from 3kg/mol to 10 kg/mol; the mass ratio of the hydrophilic chain segment to the hydrophobic chain segment is 1 (3-10).
According to another aspect of the present invention, there is provided a method for preparing the nanoparticle grafted with the photo-responsive polymer, comprising the steps of:
(1) preparation of photoresponsive Polymer: preparing hydrophilic polymer and hydrophobic polymer by using living polymerization or anionic polymerization; connecting a photoresponsive molecule to either end of the hydrophilic polymer or the hydrophobic polymer to obtain an intermediate hydrophilic polymer and an intermediate hydrophobic polymer; then connecting groups which can generate coordination, host-guest interaction or chemical reaction with the nano particles to any end of the intermediate hydrophilic polymer or the intermediate hydrophobic polymer to obtain the modified hydrophilic polymer and the modified hydrophobic polymer; connecting the modified hydrophobic polymer and the hydrophilic polymer, and connecting the photoresponse molecules between the hydrophilic polymer and the hydrophobic polymer in a covalent bond mode to form the photoresponse polymer containing the photoresponse molecules between the hydrophilic chain segment and the hydrophobic chain segment;
or the step (1) is the following technical scheme: preparing an amphiphilic block copolymer by utilizing living polymerization, connecting an optical response molecule at the tail end of the amphiphilic block copolymer, and then connecting a group capable of generating coordination, host-guest interaction or chemical reaction with nanoparticles on the optical response molecule to obtain an optical response polymer of which the tail end contains the optical response molecule;
or the step (1) is the following technical scheme: preparing an amphiphilic block copolymer with the tail end containing a group capable of performing coordination, host-guest interaction or chemical reaction with the nanoparticles by utilizing living polymerization, and connecting the photoresponse molecules to the side chain of the hydrophilic chain segment or the hydrophobic chain segment of the amphiphilic block copolymer by utilizing organic synthesis reaction to obtain the photoresponse polymer containing the photoresponse molecules on the side chain of the hydrophilic chain segment or the hydrophobic chain segment;
(2) preparing the non-nano particles: preparing inorganic nanoparticles by a hydrothermal method, a seed growth method, a vapor deposition method, a precipitation method, a sol-gel method or an emulsion method;
(3) preparation of nanoparticles grafted with photoresponsive polymer: and (3) carrying out coordination, host-guest interaction or chemical reaction on the photoresponsive polymer obtained in the step (1) and the non-nano particles obtained in the step (2) to obtain the nano particles grafted with the photoresponsive polymer.
According to another aspect of the present invention, a method for preparing a light-controlling nanoparticle assembly is provided, in which the light-controlling nanoparticle assembly is obtained by self-assembly of the nanoparticles grafted with the light-responsive polymer.
According to another aspect of the present invention, there is provided a light-controlling nanoparticle assembly prepared by the method for preparing a light-controlling nanoparticle assembly, wherein the light-controlling nanoparticle assembly is at least one of a vesicular shape, a spherical shape, a hemi-bowl shape, a rod shape, a cake shape, a layered shape, a linear shape and a planetary shape; the volume of the light-operated nano particle assembly is 525nm3-6.5×1010nm3。
According to another aspect of the present invention, there is provided a method for preparing a light-controlled nanoparticle assembly coated with drug molecules, wherein the light-controlled nanoparticle assembly coated with drug molecules is obtained by self-assembling the nanoparticles grafted with a light-responsive polymer and the drug molecules; the nano particles of the grafted photoresponsive polymer are connected with drug molecules through hydrophilic and hydrophobic acting forces.
Preferably, the drug molecule is a hydrophilic drug molecule or a hydrophobic drug molecule;
preferably, the drug molecule is at least one of an anti-cancer drug, an antipyretic drug, a cardiac arrest preventing drug, an analgesic, a hypotensive drug, a monoclonal antibody, an epidermal growth factor, an interferon, a growth hormone, bovine serum albumin, insulin, a vaccine, lisinopril and nimesulide.
Preferably, the anticancer drug is at least one of adriamycin, paclitaxel, camptothecin, taxus chinensis polysaccharide, garlicin and daunorubicin; the drug for preventing cardiac arrest is at least one of lidocaine, nitroglycerin, dopamine, norepinephrine and epinephrine; the analgesic is at least one of paracetamol, phenylbutazone, rofecoxib and morphine.
According to another aspect of the present invention, there is provided a drug molecule-coated light-controlled nanoparticle assembly prepared by the method for preparing a drug molecule-coated light-controlled nanoparticle assembly, wherein the drug molecule-coated light-controlled nanoparticle assembly is characterized in that the drug molecule is coated by the light-controlled nanoparticle assemblyThe light-controlled nano particle assembly of the object molecule is at least one of vesicular, spherical, half bowl-shaped, rod-shaped, cake-shaped, layered, linear and planetary; the volume of the light-operated nano particle assembly is 525nm3-6.5×1010nm3。
According to another aspect of the present invention, there is provided a use of the nanoparticle grafted with a photoresponsive polymer in the preparation of a light-controlled release drug.
Generally, compared with the prior art, the above technical solution conceived by the present invention mainly has the following technical advantages:
(1) the invention prepares the nanoparticle assembly for controlling the release of the responsive medicament by selecting the specific type of response groups. The nanoparticle assembly can controllably release the drug molecules coated therein under the stimulation of light. The nanoparticle assembly can be used at a specific time or under specific conditions in the using process, and the photoresponse operation is simple, easy to control and reusable. If the photoresponse group is positioned in the middle of the main chain, the photoresponse group is dissociated under the condition of illumination, and the hydrophilic and hydrophobic sections of the polymer are separated. The polymer chain structure is changed, the assembly body is disassembled, and the loaded drug molecules are controllably released, so that the drug only acts at the focus position. If the photoresponse group is positioned at the tail end of the main chain, the photoresponse group is dissociated under the illumination condition, the polymer chain is broken, the polymer chain is separated from the nano particles, the assembly body is disassembled, and the loaded drug molecules are controllably released, so that the drug only acts at the focus position. If the photoresponse group is positioned on the side chain, the hydrophilicity and the hydrophobicity of the photoresponse group are reversed under the illumination condition, the hydrophilicity and the hydrophobicity of the polymer chain are changed, the assembly body is disassembled, and the loaded drug molecules are controllably released, so that the drug only acts on the focus position. Solves the problem that the nano-carrier prepared by the prior art is difficult to intelligently regulate and control the drug release at a specific time or under a specific condition.
(2) The invention provides a preparation method of a nanoparticle assembly, which comprises the steps of selecting a specific block copolymer and nanoparticles, preparing the assembly in a blending system by utilizing the selectivity of a surfactant to different blocks, and adjusting the appearance of the assembly by regulating and controlling factors such as the block ratio, the block length, the size of the nanoparticles and the like.
(3) The nano particle assembly prepared by the invention can be controllably disassembled, assembled and released to release drugs, and the inorganic nano particles have certain potential application value in the fields of biological imaging, photoelectric devices, high-density storage, biosensing and the like due to the photothermal effect, the surface Raman enhancement effect, the photoacoustic effect and the like of the inorganic nano particles, and the photothermal property of the nano particles also has certain effect on tumor cells.
Drawings
FIG. 1 is a flow chart of example 1.
FIG. 2 is the structure of the gold nanoparticle assembly for releasing drugs in response to UV light of example 1; FIG. 2(a) is a transmission electron microscope image of the gold nanoparticle assembly, and FIG. 2(b) is a scanning electron microscope image of the gold nanoparticle assembly.
Fig. 3 is hydrodynamic diameter change (DLS) data of the uv-responsive drug-releasing gold nanoparticle assembly after 3 irradiation times, 10min uv each time.
FIG. 4 is a graph showing the photothermal effect of the gold nanoparticle assembly releasing the drug in response to ultraviolet light in example 1. The gold nanoparticle assemblies were dispersed in water and tested for photothermal effects at 0. mu.g/mL, 25. mu.g/mL, 50. mu.g/mL, 75. mu.g/mL, 100. mu.g/mL, respectively.
Fig. 5 is a drug controlled release curve of the uv-responsive drug-releasing au nanoparticle assembly of example 1 after 3 times of uv irradiation without uv irradiation and 10min each time.
FIG. 6 is the drug distribution profile of the doxorubicin-loaded UV-responsive drug-releasing gold nanoparticle assemblies of example 1 in HELA cells; FIG. 6(a) is a drug profile of HELA cells incubated for 2h in the absence of UV radiation; FIG. 6(b) is a drug profile of HELA cells incubated for 2h after 3min of UV irradiation; fig. 6(c) is a drug profile of HELA cells incubated for 2h after 10min of uv irradiation.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1 preparation method of gold nanoparticle vesicles with ultraviolet light-controlled drug release
The preparation method mainly comprises the following steps:
1. synthesis of photoresponsive Polymer: it is worth noting that the photoresponsive group in the photoresponsive polymer takes coca-diacid as an example, and under the ultraviolet radiation with the wavelength of less than 260nm, the four-membered ring of the coca-diacid can be broken, so that the hydrophilic and hydrophobic chain segments are separated, the chain structure of the polymer is changed, and the purpose of optically controlled drug release is further achieved.
1.1, synthesis of photoresponsive group: cinnamic acid is closed under 365nm ultraviolet irradiation to form an ultraviolet light response group coca-m-diacid.
1.2 Synthesis of a Polymer containing (S-S) bonds and coca-isophthalic acid:
1.2.1 Synthesis of coca-m-diacid terminated polystyrene (PS-coca-m-diacid):
(a) monohydroxy-terminated Polystyrene (PS)20kOH, 20kg/mol) can be synthesized or purchased by anionic polymerization or living polymerization.
(b) 1g of the above PS20kdissolving-OH, 0.1g Dicyclohexylcarbodiimide (DCC) and 0.06g 4-Dimethylaminopyridine (DMAP) in 4mL dichloromethane, slowly dropping the solution into a dichloromethane solution containing 0.2mL triethylamine and 0.146g cocatalytic m-diacid, stirring for 24h at room temperature, and carrying out esterification reaction to obtain PS20k-cocaine diacid. Then PS is put in20kAnd (3) precipitating a-coca-m-diacid dichloromethane solution in absolute ethyl alcohol, filtering, drying in vacuum at 30 ℃ for 48 hours, and sealing for storage for later use.
1.2.2 Synthesis of cystamine-terminated polyvinyl alcohol (PEG-cystamine):
(a) 5g of monohydroxy-terminated polyvinyl alcohol (PEG) having a molecular weight of 5kg/mol was placed in a clean flask5kOH), succinic anhydride 0.4g, dichloromethane 4mL, pyridine 4.5mL, stirred at room temperature for 24h to give monocarboxylic end-capped polyvinyl alcohol (PEG)5k-COOH). Mixing PEG5kAnd (3) after the dichloromethane solution of-COOH is separated out in anhydrous ether, carrying out suction filtration, carrying out vacuum drying at 30 ℃ for 48h, and carrying out sealed storage for later use.
(b) Mixing 1g of the above PEG5k-COOH, 0.1g 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI. HCl), 0.06g N-hydroxysuccinimide (NHS) were dissolved in 5mL dichloromethane and slowly added dropwise to a solution of 0.45g cystamine and 0.63mL triethylamine in dichloromethane, stirred at room temperature for 24h, and PEG was obtained by amidation reaction5k-cystamine. Mixing PEG5kAnd (3) separating out a cystamine dichloromethane solution in anhydrous ether, carrying out suction filtration, carrying out vacuum drying at 30 ℃ for 48h, and carrying out sealed storage for later use.
1.2.3 containing (S-S) bond and coca-isophthalic acid PS20k-b-PEG5kThe synthesis of (2):
1g of PS was added to a clean flask20k-coca-diacid, 0.25g PEG5k-cystamine, 0.1g EDCI.HCL, 0.06g NHS, 0.08mL triethylamine and 5mL dichloromethane, stirring at room temperature for 24h, and performing amidation reaction again to obtain a compound containing (S-S) bond and coca-m-diacid PS20k-b-PEG5k. Mixing PS20k-b-PEG5kAnd (3) after the dichloromethane solution is separated out in absolute ethyl alcohol, carrying out suction filtration, carrying out vacuum drying at 30 ℃ for 48h, and sealing and storing for later use. The molecular weight and molecular weight distribution of the polymer were determined by gel permeation chromatography coupled with multi-angle laser light scattering (GPC-MALLS), and the structural information of the polymer was determined by infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR).
(1) Preparation of a photoresponsive polymer containing photoresponsive molecules between a hydrophilic segment and a hydrophobic segment: preparing hydrophilic polymer and hydrophobic polymer by using living polymerization or anionic polymerization; forming a photoresponsive polymer containing photoresponsive molecules between the hydrophilic chain segment and the hydrophobic chain segment by adopting a scheme A, a scheme B, a scheme C, a scheme D, a scheme E or a scheme F;
scheme A: connecting a photoresponse molecule to the tail end of the hydrophilic polymer, and connecting a group capable of carrying out coordination, host-guest interaction or chemical reaction with the nanoparticles to the tail end of the hydrophobic polymer; connecting the obtained hydrophobic polymer and hydrophilic polymer, and connecting the photoresponsive molecules between the hydrophilic polymer and the hydrophobic polymer in a covalent bond mode to form the photoresponsive polymer containing the photoresponsive molecules between the hydrophilic chain segment and the hydrophobic chain segment;
scheme B: connecting a photoresponse molecule to the tail end of the hydrophobic polymer, and connecting a group capable of carrying out coordination, host-guest interaction or chemical reaction with the nanoparticles to the tail end of the hydrophilic polymer; connecting the obtained hydrophobic polymer and hydrophilic polymer, and connecting the photoresponsive molecules between the hydrophilic polymer and the hydrophobic polymer in a covalent bond mode to form the photoresponsive polymer containing the photoresponsive molecules between the hydrophilic chain segment and the hydrophobic chain segment;
scheme C: respectively connecting the photoresponse molecules and groups which can generate coordination, host-guest interaction or chemical reaction with the nanoparticles to two ends of the hydrophilic polymer; the hydrophobic polymer remains unchanged; connecting the obtained hydrophobic polymer and hydrophilic polymer, and connecting the photoresponsive molecules between the hydrophilic polymer and the hydrophobic polymer in a covalent bond mode to form the photoresponsive polymer containing the photoresponsive molecules between the hydrophilic chain segment and the hydrophobic chain segment;
scheme D: respectively connecting the photoresponse molecules and groups which can generate coordination, host-guest interaction or chemical reaction with the nanoparticles to two ends of the hydrophobic polymer; the hydrophilic polymer remains unchanged; connecting the obtained hydrophobic polymer and hydrophilic polymer, and connecting the photoresponsive molecules between the hydrophilic polymer and the hydrophobic polymer in a covalent bond mode to form the photoresponsive polymer containing the photoresponsive molecules between the hydrophilic chain segment and the hydrophobic chain segment;
scheme E: connecting a photoresponse molecule to one end of a hydrophilic polymer, and then connecting a group capable of generating coordination, host-guest interaction or chemical reaction with the nanoparticles to the photoresponse molecule; the hydrophobic polymer remains unchanged; connecting the obtained hydrophobic polymer and hydrophilic polymer, and connecting the photoresponsive molecules between the hydrophilic polymer and the hydrophobic polymer in a covalent bond mode to form the photoresponsive polymer containing the photoresponsive molecules between the hydrophilic chain segment and the hydrophobic chain segment;
scheme F: connecting a photoresponse molecule to one end of a hydrophobic polymer, and then connecting a group capable of carrying out coordination, host-guest interaction or chemical reaction with the nanoparticles to the photoresponse molecule; the hydrophilic polymer remains unchanged; and connecting the obtained hydrophobic polymer and the hydrophilic polymer, and connecting the photoresponsive molecules between the hydrophilic polymer and the hydrophobic polymer in a covalent bond mode to form the photoresponsive polymer containing the photoresponsive molecules between the hydrophilic chain segment and the hydrophobic chain segment.
(2) Preparation of a photoresponsive polymer containing photoresponsive molecules at the ends of the amphiphilic block copolymer: preparing an amphiphilic block copolymer by utilizing living polymerization, connecting an optical response molecule at the tail end of the amphiphilic block copolymer, and then connecting a group capable of generating coordination, host-guest interaction or chemical reaction with nanoparticles on the optical response molecule to obtain an optical response polymer of which the tail end contains the optical response molecule.
(3) Preparation of photoresponsive Polymer containing photoresponsive molecules in the side chains of the hydrophilic segment or the hydrophobic segment: preparing an amphiphilic block copolymer with the tail end containing a group capable of performing coordination, host-guest interaction or chemical reaction with the nanoparticles by utilizing living polymerization, and connecting the photoresponse molecules to the side chain of the hydrophilic chain segment or the hydrophobic chain segment of the amphiphilic block copolymer by utilizing organic synthesis reaction to obtain the photoresponse polymer containing the photoresponse molecules on the side chain of the hydrophilic chain segment or the hydrophobic chain segment.
2. And (3) synthesis of gold nanoparticles: can select a seed growth method or a hydrothermal method to synthesize goldThe nanoparticle will be described by taking a seed growth method as an example. Firstly, sequentially adding H into a 20mL sample bottle2O(19mL)、HAuCl4(0.5mL,10mM) and sodium citrate (0.5mL,10mM) were mixed well; add freshly prepared NaBH rapidly with stirring4Ice water solution (0.6mL,0.1M) which instantly turns bright orange red in color, is continuously stirred for 2-5min and then is kept standing at room temperature for 3h to ensure that residual NaBH is left4The hydrolysis was completed to obtain gold species of 3.5nm in size. Next, H was sequentially added to a 100mL Erlenmeyer flask2O (28.5mL), CTAB (24mL,0.2M) and HAuCl4(1.5mL,10mM) and mixed well; adding freshly prepared ascorbic acid solution (0.4mL,0.1M) under vigorous stirring, after the solution turns colorless, rapidly adding 20mL of newly prepared gold seed solution, continuously stirring for 1h, and standing at room temperature for 12h to obtain gold nanoparticles of 8 nm. By adjusting gold seed and HAuCl4The proportion can adjust the size of the gold nano particles.
3. Light-responsive polymer grafted gold nanoparticles: the PS containing S-S bond and coca-diacid synthesized in the step 120k-b-PEG5kDissolve in 200mL chloroform solution (. about.0.25 mg/mL). And 200mL of the above 8nm gold nanoparticle solution was added dropwise thereto. Stirring for 1h at room temperature, standing and curing for 24h to obtain a layered mixed solution. Discarding the upper layer of transparent aqueous solution, collecting the lower layer of deep red organic phase, centrifuging, purifying, removing free polymer, and collecting PS20k-b-PEG5kThe modified gold nanoparticles were dispersed in THF (2mg/mL) for use.
The photoresponsive polymer is connected with the nano-particles through groups of coordination, host-guest interaction or chemical reaction. Wherein the groups connected with the nanoparticles through coordination are disulfide bonds, sulfydryl, pyridine carbonyl, ethylenediamine, thiocyanogen and isothiocyanates; the group connected with the nano particles through the interaction of the host and the object is cyclodextrin or azobenzene; the groups attached to the nanoparticles by chemical reaction are amino or carboxyl groups.
4. Preparation of gold nanoparticle assembly and loading of hydrophobic anticancer drugs: the method comprises the following steps: dispersing the gold nanoparticles with the surface grafted with the photoresponse polymer in an organic solvent (2mg/mL) which can be mutually dissolved with water, taking 50 mu L of the gold nanoparticles, quickly adding the gold nanoparticles into 200 mu L of aqueous solution containing a surfactant (5mg/mL), shaking up for dispersion, standing for 12h, centrifuging twice after the organic solvent is completely volatilized, and purifying to obtain the gold nanoparticle assembly. The required surfactant is polyvinyl alcohol; the organic solvent which is required to be mutually soluble with water is tetrahydrofuran.
Adding 5 μ L (10mg/mL adriamycin N, N-dimethylformamide solution) into 200 μ L polyvinyl alcohol (5mg/mL) water solution, mixing, adding 50 μ L gold nanoparticles dispersed in tetrahydrofuran into the polyvinyl alcohol water solution dissolved with adriamycin rapidly with a liquid-transferring gun, shaking for dispersing, standing for 12h, after tetrahydrofuran is completely volatilized, centrifuging at 10000rpm for 5min, discarding supernatant, and dispersing with deionized water. Repeating the centrifugation-dispersion step for 2 times to obtain the gold nanoparticle assembly coated with the anticancer drug. Fig. 2(a) and 2(b) are a transmission electron microscope image and a scanning electron microscope image of the gold nanoparticle assembly, respectively, and it can be known that the morphology of the gold nanoparticle assembly constructed by the method is a vesicle structure.
FIG. 1 is a flow chart of example 1. Firstly, nano particles grafted with a photoresponse polymer and drug molecules are used as assembly primitives, a photoresponse assembly body coating the drug molecules is prepared by a nano precipitation method, and the assembly body can be disassembled and assembled under ultraviolet irradiation, so that the coated drug molecules are released, and the purpose of drug release is achieved.
The ultraviolet light response gold nanoparticle vesicle prepared in the embodiment has the drug loading rate of 15% and the ultraviolet response wavelength of 254 nm.
Examples 2-5 photo-responsive drug-releasing nanoparticle assemblies of varying performance parameters.
By changing the type and molecular weight of the photoresponsive polymer, the photoresponsive group, the type of the drug, the type and size of the nanoparticle in example 1, a plurality of nanoparticle assemblies with different parameters and photoresponsive release of the drug can be obtained, and the specific conditions and parameters adopted in examples 2-5 and the performance parameters of the correspondingly prepared nanoparticle assemblies are shown in table 1. Wherein PLLA10K-b-PAA10KRepresents L-polylactic acid10kB-polyacrylic acid10k、PS50K-b-PEG1KDenotes polystyrene50k-b-polyvinyl alcohol1k、PMMA100K-b-PAN5KRepresents polymethyl methacrylate100k-b-polyacrylamide5k、PDLA1000K-b-P4VP50KRepresents poly (D-lactic acid)1000kB-poly-4-vinylpyridine50k. The photo-responsive polymer nano particles can wrap the drugs in the prior art, hydrophobic drug molecules are connected with the hydrophobic chain segments in the photo-responsive polymer through hydrophilic and hydrophobic effects, and hydrophilic drugs are connected with the hydrophilic chain segments in the photo-responsive polymer through hydrophilic and hydrophobic effects.
The assembling method comprises a manual membrane extrusion emulsification method, a self-organization precipitation method, a thin film hydration method, a nano precipitation method or a selective solution assembling method. The surfactants required in the manual membrane extrusion emulsification method and the nano precipitation method comprise anionic surfactants, cationic surfactants, zwitterionic surfactants and nonionic surfactants. The preparation method specifically comprises higher fatty acid salt, sulfate, sulfonate, benzalkonium chloride, benzalkonium bromide, lecithin, fatty glyceride, sorbitan fatty acid (span), polyvinyl alcohol (PVA), Cetyl Trimethyl Ammonium Bromide (CTAB), Sodium Dodecyl Sulfate (SDS), and polysorbate-80 (Tween-80); the organic solvent which is mutually soluble with water and is required by the self-organizing precipitation method, the nano precipitation method and the solution method comprises Tetrahydrofuran (THF), dioxane, N-Dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).
Figure BDA0001874242270000121
Example 6 deassembly test of uv-responsive drug-releasing gold nanoparticle vesicles
The gold nanoparticle vesicles with the ultraviolet-responsive drug release described in example 1 were dispersed in water, and the gold nanoparticle vesicle disassembly process was detected in real time using Dynamic Light Scattering (DLS). The particle size changes of the gold nanoparticle vesicles after ultraviolet irradiation for 0min, 10min, 20min and 30min are respectively monitored, and fig. 3 is shown. The result shows that the size of the vesicle is gradually reduced after each ultraviolet irradiation, so that the vesicle disassembly and assembly process can be further controlled by adjusting the ultraviolet irradiation time.
Example 7 photothermal Effect testing of nanoparticle vesicles with UV-responsive drug release
The UV-light-responsive drug-releasing gold nanoparticle vesicles described in example 1 were dispersed in water and measured for photothermal effects at 0. mu.g/mL, 25. mu.g/mL, 50. mu.g/mL, 75. mu.g/mL, 100. mu.g/mL, FIG. 4. The result shows that the photothermal effect of the gold nanoparticle vesicle is better and better along with the increase of the concentration, which indicates that the gold nanoparticle vesicle has better photothermal effect.
Example 8 controlled drug Release of gold nanoparticles with UV-light response to drug Release
The ultraviolet-light-responsive drug-releasing gold particle vesicles described in example 1 were placed in a centrifuge tube containing 25mL of phosphate buffered saline (PBS solution, pH 7.4) and in a water bath shaker at 37 ℃, and the experiment was divided into a blank control group and an experimental group, the blank group did not radiate ultraviolet light for 72 hours, and the experimental group irradiated with ultraviolet light for three times for 10min each time within 72 hours. And taking out 2mL of the LPBS solution from the centrifuge tube at certain time intervals in each group, supplementing 2mL of fresh PBS solution, respectively measuring the content of the adriamycin in the taken-out solution, and calculating the release rate of the adriamycin at different time points. The experimental results show that the adriamycin maintains a slow release rate within 72 hours in the absence of ultraviolet irradiation, and can only be released to about 50 percent finally. The doxorubicin release rate increased after each uv irradiation, and after 30min of cumulative irradiation, about 80% was released within 72h, fig. 5. As can be seen in fig. 5, the coated drug doxorubicin maintained a slow release rate for 72 hours and eventually only released about to 50% in the absence of uv light. The doxorubicin release rate increased after each uv irradiation, and after 30min of cumulative irradiation, it was released to about 80% in 72 h. The gold nanoparticle vesicle capable of releasing the medicament in the programmed way realizes the programmed medicament release of the medicament.
Example 9 controlled drug release of UV-light-responsive drug-releasing gold nanoparticle vesicles in cancer cells
The gold nano-particle vesicle for releasing the drug in response to the ultraviolet light described in example 1 is loaded with 10 μ g of adriamycin, and the HELA cells are treated at 5 × 104And (3) paving the cells/hole in a 24-well plate, incubating the adriamycin-loaded gold nanoparticle vesicles (-0.2 nM) and HELA cells for 0.5h after overnight culture, removing the culture solution, washing the cells for 3 times by using PBS (phosphate buffer solution), radiating ultraviolet light for different samples for different durations, and continuously incubating for 0.5h,1h and 2 h. Then fixed with 4% paraformaldehyde for 15min and stained with 5 μ g/ml DAPI for 15min before imaging with a laser confocal microscope. DAPI passage Ex＝334nm、EmObservations were made on 350nm filters and doxorubicin was passed through Ex＝488nm、EmObservations were made on 560nm filters. As shown in fig. 6(a), the adriamycin fluorescence of the HELA cells without ultraviolet irradiation is very weak, only a small amount of adriamycin is distributed in the cytoplasm after 2h of incubation, while the adriamycin fluorescence of the HELA cells after 3min of ultraviolet irradiation is enhanced, but most of the adriamycin still stays in the cytoplasm after 2h of incubation, fig. 6(b), the adriamycin fluorescence of the HELA cells after 10min of ultraviolet irradiation is stronger, and most of the adriamycin enters the nucleus after 2h of incubation, fig. 6(c), which shows that the gold nanoparticles capable of releasing the drug in response to ultraviolet irradiation can effectively release the drug by ultraviolet irradiation and can adjust the drug release rate by adjusting the duration of ultraviolet irradiation. Besides the gold nanoparticles used in the above embodiments, the nanoparticles suitable for the present invention include silica nanoparticles, ferroferric oxide nanoparticles, gadolinium oxide nanoparticles, cerium oxide nanoparticles, and nickel nanoparticles. The shape of the nanoparticles may be spherical, rod-like, star-shaped, polygonal, Janus's structure.
The nanoparticle assembly of the present invention is an assembly formed of nanoparticle particles, and the size of the nanoparticle assembly can be adjusted by adjusting the concentration of the nanoparticles; the morphology of the nanoparticle assembly can be adjusted by adjusting the hydrophilic and hydrophobic blocks of the amphiphilic block copolymer grafted on the surfaces of the nanoparticles, the size ratio of the nanoparticles and the types of the polymers.
The nano particle assembly for releasing the medicine in the photoresponse can be used for a human body or other animal bodies, for example, the medicine is loaded into the photoresponse nano particle assembly in advance and is injected into the body together, when the nano particle assembly reaches a focus part, the medicine is released and plays a drug effect by externally giving light stimulation, the action time of the medicine is effectively shortened, and the optimal treatment time is grasped. The invention can also utilize the self photo-thermal, surface enhanced Raman scattering and cell imaging effects of the nano particles, take the gold nano particle assembly as an example, because the gold nano particle assembly has good photo-thermal effect, under the irradiation of the near infrared laser, the gold nano particle assembly has the photo-thermal effect, can generate heat and has certain effect on tumor cells.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (15)

1. A method for preparing a light-operated nanoparticle assembly is characterized in that nanoparticles grafted with a light-responsive polymer are self-assembled, and the self-assembly specifically comprises the following steps: dispersing the nano particles of the grafted photoresponsive polymer in an organic solvent which can be mutually dissolved with water, adding the organic solvent into an aqueous solution containing a surfactant, standing the mixture after dispersion, and centrifugally purifying the mixture after the organic solvent is volatilized to obtain a light-controlled nano particle assembly;
the surface of the nano particle grafted with the light-responsive polymer is grafted with the light-responsive polymer; the photoresponsive polymer is an amphiphilic block copolymer; the amphiphilic block copolymer contains a hydrophilic chain segment and a hydrophobic chain segment; the hydrophilic chain segment is polyvinyl alcohol, and the hydrophobic chain segment is polystyrene; the photo-responsive molecule cocaine diacid is connected to the main chain of the amphiphilic block copolymer in a covalent bond mode, or the photo-responsive molecule cocaine diacid is connected to the side chain of the hydrophilic chain segment or the hydrophobic chain segment in a covalent bond mode; the photoresponsive polymer is connected with the nano particles through coordination, host-guest interaction or covalent bonds; the nanoparticles are inorganic nanoparticles.
2. The method of making a light-controlling nanoparticle assembly according to claim 1, wherein the inorganic nanoparticles are metal nanoparticles, oxide nanoparticles, sulfide nanoparticles, or upconversion nanoparticles; the volume of the inorganic nano particles is 0.5nm3-550000nm3(ii) a The shape of the inorganic nano-particle is spherical, rod-shaped, star-shaped, polygonal or Janus structure; the photo-responsive polymer is connected with the nanoparticles through at least one of disulfide bonds, sulfydryl, carboxyl, amino, pyridine, carbonyl, ethylenediamine, thiocyanate, isothiocyanide, cyclodextrin and azobenzene.
3. The method of claim 2, wherein the inorganic nanoparticles are at least one of gold nanoparticles, silver nanoparticles, nickel nanoparticles, silica nanoparticles, ferroferric oxide nanoparticles, gadolinium oxide nanoparticles, cerium oxide nanoparticles, and copper sulfide nanoparticles.
4. The method of making a light management nanoparticle assembly of claim 1, wherein the hydrophilic segment has a molar mass of 1kg/mol to 50kg/mol and the hydrophobic segment has a molar mass of 10kg/mol to 1000 kg/mol; the mass ratio of the hydrophilic chain segment to the hydrophobic chain segment is 1 (1-20).
5. The method of making a light controlling nanoparticle assembly according to claim 4, wherein the hydrophilic segment has a molar mass of from 3kg/mol to 10 kg/mol; the mass ratio of the hydrophilic chain segment to the hydrophobic chain segment is 1 (3-10).
6. The method of claim 1, wherein the light-controlling nanoparticle assembly is in the form of a vesicle, sphere, half-bowl, rod, cake, layer, line, or stripAt least one of a planetary shape; the volume of the light-operated nano particle assembly is 525nm3-6.5×1010nm3。
7. A preparation method of a light-operated nanoparticle assembly body coated with drug molecules is characterized in that the light-operated nanoparticle assembly body coated with the drug molecules is obtained by self-assembling nanoparticles grafted with a light-responsive polymer and the drug molecules; the nano particles of the grafted photoresponsive polymer are connected with drug molecules through hydrophilic and hydrophobic acting forces; the self-assembly specifically comprises the following steps: adding the medicine into an organic solvent which can be mutually dissolved with water, adding the nano particles grafted with the photoresponsive polymer, dispersing, standing, and centrifuging after the organic solvent is volatilized to obtain a light-controlled nano particle assembly;
the surface of the nano particle grafted with the light-responsive polymer is grafted with the light-responsive polymer; the photoresponsive polymer is an amphiphilic block copolymer; the amphiphilic block copolymer contains a hydrophilic chain segment and a hydrophobic chain segment; the hydrophilic chain segment is polyvinyl alcohol, and the hydrophobic chain segment is polystyrene; the photo-responsive molecule cocaine diacid is connected to the main chain of the amphiphilic block copolymer in a covalent bond mode, or the photo-responsive molecule cocaine diacid is connected to the side chain of the hydrophilic chain segment or the hydrophobic chain segment in a covalent bond mode; the photoresponsive polymer is connected with the nano particles through coordination, host-guest interaction or covalent bonds; the nanoparticles are inorganic nanoparticles.
8. The method of claim 7, wherein the inorganic nanoparticles are metal nanoparticles, oxide nanoparticles, sulfide nanoparticles, or upconversion nanoparticles; the volume of the inorganic nano particles is 0.5nm3-550000nm3(ii) a The shape of the inorganic nano-particle is spherical, rod-shaped, star-shaped, polygonal or Janus structure; the photoresponsive polymer is prepared by disulfide bond, sulfhydryl, carboxyl, amino, pyridine, carbonyl, ethylenediamine, thiocyanogen, isothiocyanato, and cyclodextrinAt least one of a fine and azobenzene is attached to the nanoparticles.
9. The method of claim 8, wherein the inorganic nanoparticles are at least one of gold nanoparticles, silver nanoparticles, nickel nanoparticles, silica nanoparticles, ferroferric oxide nanoparticles, gadolinium oxide nanoparticles, cerium oxide nanoparticles, and copper sulfide nanoparticles.
10. The method of claim 7, wherein the hydrophilic segment has a molar mass of 1kg/mol to 50kg/mol, and the hydrophobic segment has a molar mass of 10kg/mol to 1000 kg/mol; the mass ratio of the hydrophilic chain segment to the hydrophobic chain segment is 1 (1-20).
11. The method of preparing the light-controlling nanoparticle assembly coated with a drug molecule according to claim 10, wherein the hydrophilic segment has a molar mass of 3kg/mol to 10 kg/mol; the mass ratio of the hydrophilic chain segment to the hydrophobic chain segment is 1 (3-10).
12. The method of claim 7, wherein the drug molecule is a hydrophilic drug molecule or a hydrophobic drug molecule.
13. The method of claim 12, wherein the drug molecule is at least one of an anti-cancer drug, an anti-pyretic drug, a cardiac arrest drug, an analgesic, a hypotensive drug, a monoclonal antibody, an epidermal growth factor, an interferon, a growth hormone, bovine serum albumin, insulin, a vaccine, lisinopril, and nimesulide.
14. The method of claim 13, wherein the anti-cancer drug is at least one of doxorubicin, paclitaxel, camptothecin, taxus chinensis polysaccharide, allicin, and daunorubicin; the drug for preventing cardiac arrest is at least one of lidocaine, nitroglycerin, dopamine, norepinephrine and epinephrine; the analgesic is at least one of paracetamol, phenylbutazone, rofecoxib and morphine.
15. The drug molecule-coated light-controlled nanoparticle assembly prepared by the method for preparing a drug molecule-coated light-controlled nanoparticle assembly according to any one of claims 7 to 14, wherein the drug molecule-coated light-controlled nanoparticle assembly is at least one of a vesicular shape, a spherical shape, a hemi-bowl shape, a rod shape, a cake shape, a layered shape, a linear shape and a planetary shape; the volume of the light-operated nano particle assembly is 525nm3-6.5×1010nm3。
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