CN110124032B - Anti-tumor implant with local chemotherapy and photothermal treatment functions and preparation method thereof - Google Patents
Anti-tumor implant with local chemotherapy and photothermal treatment functions and preparation method thereof Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- 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
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- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- 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
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses an anti-tumor implant with local chemotherapy and photothermal treatment functions and a preparation method thereof, and relates to the technical field of medicine preparation. The preparation method of the anti-tumor implant with the functions of local chemotherapy and photothermal therapy comprises the following steps: mixing the drug-loaded polydopamine particle dispersion liquid with a water-soluble polymer solution to obtain an internal phase spinning solution; dissolving gelatin or chitosan to form external phase spinning solution; carrying out coaxial electrostatic spinning on the internal phase spinning solution and the external phase spinning solution; wherein the water-soluble polymer is selected from one of polyvinyl alcohol, polyvinylpyrrolidone and polyethylene oxide, and the drug in the drug-loaded polydopamine granule is an anti-tumor drug. The anti-tumor implant comprises nano-fibers with a core-shell structure, and drug-loaded nano-poly-dopamine particles are loaded in the core-shell structure, and the fiber implant has the effects of local chemotherapy and photothermal therapy, and is a biodegradable implant with good biocompatibility.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to an anti-tumor implant with local chemotherapy and photothermal treatment functions and a preparation method thereof.
Background
Malignant tumor still seriously threatens human health, in the aspect of tumor treatment, systemic chemotherapy (accompanied by surgical excision, radiotherapy and the like) is still the current main means, the toxic and side effects brought by the malignant tumor are large, and patients need to suffer great pain. In order to improve the administration mode, some researchers begin to wrap the drug by various nano-carriers to reduce the toxic and side effects of the chemotherapeutic drug and improve the drug effect, but most of the nano-carriers enter the body by systemic administration, so that the following problems still exist in the process of reaching tumor tissues, such as: clearance by the reticuloendothelial system, excessive enrichment at non-targeted tissues, high permeability and retention effects that are overly dependent on solid tumors, and insufficient accumulation at tumors in clinical or animal experiments.
In contrast, topical delivery systems are effective in overcoming these problems. Because it can make the local medicine concentration be maintained at higher level in a certain period of time, so that it can raise therapeutic effect, at the same time it can effectively reduce toxic side effect of medicine to normal organ and tissue, and has no need of repeatedly administering medicine, and can reduce pain of patient. At present, various non-degradable materials (such as ethylene-vinyl acetate copolymer) and degradable materials (such as polyether-polyanhydride copolymer, polyether-polyester copolymer, degradable hydrogel material and the like) are all used for preparing various anti-tumor implants for locally transmitting various anti-tumor drugs and factors (such as paclitaxel, adriamycin and other therapeutic drugs, anti-angiogenesis factors, endostatin genes and the like).
With some of the currently reported topical drug delivery systems, there still remain some problems, such as some of the topically injected micro/nano drug carriers, easily escaping out of the lesion; some semisolid drug delivery systems for local injection have difficulty in forming gel in vivo in real use, thereby causing the burst release of the drug; some of the locally implanted block drug delivery systems have difficulty in adjusting their degradation properties and effectively controlling the release of the drug. Therefore, there is still a need to develop new topical drug delivery systems. An anti-tumor implant, particularly a fibrous implant, is a very effective local delivery system and would be a class of delivery systems that are implanted locally in an operational manner. It can be used for treating tumor directly, and can also be used as filler after operation, and can effectively prevent tumor recurrence.
However, the conventional antitumor implants (including some existing fibrous implants) still have some of the aforementioned problems. Moreover, most of the drugs carried by the implant are directly released by the degradation of the carrier, but the released drugs are small molecules, are easy to diffuse to other tissues, can be eliminated, and have poor targeting property, so the improvement is needed. In addition, the existing anti-tumor implant also has the problems of immunological rejection after operation, toxicity, difficult degradation and the like.
Disclosure of Invention
The invention aims to provide a preparation method of an anti-tumor implant with local chemotherapy and photothermal therapy functions, and aims to prepare the anti-tumor implant with the local chemotherapy and photothermal therapy functions.
It is another object of the present invention to provide an anti-tumor implant having local chemotherapy and photothermal therapy functions.
The technical problem to be solved by the invention is realized by adopting the following technical scheme.
The invention provides a preparation method of an anti-tumor implant with local chemotherapy and photothermal therapy functions, which comprises the following steps:
mixing the drug-loaded polydopamine particle dispersion liquid with a water-soluble polymer solution to obtain an internal phase spinning solution;
dissolving gelatin or chitosan to form external phase spinning solution;
carrying out coaxial electrostatic spinning on the internal phase spinning solution and the external phase spinning solution;
wherein the water-soluble polymer is selected from one of polyvinyl alcohol, polyvinylpyrrolidone and polyethylene oxide, and the drug in the drug-loaded polydopamine granule is an anti-tumor drug.
The invention also provides an anti-tumor implant with local chemotherapy and photothermal therapy functions, which comprises nano fibers with a core-shell structure, wherein drug-loaded nano poly dopamine particles are loaded in the core-shell structure;
wherein, the drug loaded in the drug-loaded nano poly dopamine particles is an anti-tumor drug, and the anti-tumor drug is adriamycin or camptothecin;
preferably, the particle size of the drug-loaded nano polydopamine particles is 40-130 nm;
more preferably, the antitumor implant is prepared by the above preparation method.
The embodiment of the invention provides a preparation method of an anti-tumor implant with local chemotherapy and photothermal therapy functions, which has the beneficial effects that: the preparation method comprises the steps of mixing a drug-loaded polydopamine particle dispersion liquid with a water-soluble polymer solution to form an inner phase spinning solution, dissolving gelatin or chitosan to form an inner phase spinning solution, mixing the inner phase spinning solution and an outer phase spinning solution, and carrying out coaxial electrostatic spinning to prepare the nano-fiber with the core-shell structure, wherein nano-polydopamine particles are loaded in the inner core of the nano-fiber. The anti-tumor implant prepared by the preparation method provided by the invention has the functions of local chemotherapy and photothermal therapy, and is a novel anti-tumor implant.
The invention also provides an anti-tumor implant with local chemotherapy and photothermal treatment functions, which comprises the nano-fiber with the core-shell structure, and the drug-loaded nano-poly-dopamine particles are loaded in the core-shell structure, so that the fiber implant has the effects of local chemotherapy and photothermal treatment, and is a nontoxic and degradable implant.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a transmission electron micrograph of an anti-tumor implant according to an embodiment of the present invention;
FIG. 2 is a temperature rise curve of 44nm particles at different concentrations;
FIG. 3 is a temperature increase curve for 44nm particles at different concentrations;
FIG. 4 is a temperature rise curve of 137nm particles at different concentrations;
FIG. 5 is an in vitro photothermal cytotoxicity test of electrospun fibers carrying polydopamine particles.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The following is a detailed description of the anti-tumor implant and the preparation method thereof provided by the embodiments of the present invention.
The preparation method of the anti-tumor implant with the functions of local chemotherapy and photothermal therapy provided by the embodiment of the invention comprises the following steps:
s1 preparation of internal phase spinning solution
Mixing the drug-loaded polydopamine particle dispersion liquid with a water-soluble polymer solution to obtain an internal phase spinning solution; the drug in the drug-loaded polydopamine particles is an anti-tumor drug. Among them, the water-soluble polymer is selected from any one of polyvinyl alcohol, polyvinylpyrrolidone and polyethylene oxide, and is preferably polyvinyl alcohol.
The water-soluble polymer is a main part of the internal phase spinning solution, the water-soluble polymer is a solid matrix after spinning, the drug-loaded polydopamine particles can be dispersed in the solid matrix, and the water-soluble polymer can be dissolved in water in the subsequent use process. Preferably, the particle size of the drug-loaded polydopamine particles is 40-130 nm.
Preferably, the process of mixing the drug-loaded polydopamine particle dispersion liquid and the polyvinyl alcohol solution is to drop the drug-loaded polydopamine particle dispersion liquid into the polyvinyl alcohol solution, and the drug-loaded polydopamine particle dispersion liquid and the polyvinyl alcohol solution are mixed in a dropping manner, so that the drug-loaded polydopamine particles can be uniformly dispersed into the polyvinyl alcohol solution, and the uniformity of the finally obtained product is improved.
Preferably, the drug-loaded polydopamine particles have a drug loading of 10-30%. The concentration of the polyvinyl alcohol in the internal phase spinning solution is 80-120g/L, and the mass ratio of the drug-loaded polydopamine particles to the polyvinyl alcohol is 1: 5-20. The uniformity and stability of the final product are controlled by controlling the mass ratio of the drug-loaded polydopamine particles to the polyvinyl alcohol, and if the dosage of the polyvinyl alcohol is too small, the dispersion uniformity of the drug-loaded polydopamine particles is influenced, and the drug effect of the product is influenced.
In some embodiments, the concentration of the polyvinyl alcohol solution is 150-250g/L, and the concentration of the polyvinyl alcohol is adjusted by deionized water after the drug-loaded polydopamine particle dispersion is mixed with the polyvinyl alcohol solution. The concentration of the polyvinyl alcohol solution is slightly greater than that of polyvinyl alcohol in the internal phase spinning solution, so that the operation is more convenient and easier, and after a suspension formed by the drug-loaded polydopamine particles and water is dripped into the polyvinyl alcohol solution, deionized water is needed to adjust the concentration of the polyvinyl alcohol to a specified range.
Specifically, the drug-loaded polydopamine particles can be prepared by preparing drug-loaded dopamine particles by means of adsorption after commercially available polydopamine particles are prepared. Preferably, the drug-loaded polydopamine particle dispersion liquid is obtained by mixing drug-loaded polydopamine particles with water and then concentrating, and the drug-loaded polydopamine particle suspension liquid with higher concentration is adopted for mixing, so that the subsequent regulation and control of the use amount of each component are facilitated, for example, the concentration of polyvinyl alcohol is regulated to a specified range, and the spinning work is facilitated.
The preparation process of the drug-loaded polydopamine particles comprises the following steps: mixing polydopamine particles with polyethylene glycol with a tumor targeting molecule modified at one end, and reacting at 15-25 ℃ for 20-30h to obtain targeted polydopamine particles; mixing the targeted polydopamine particles, the antitumor drugs and the tris buffer solution, stirring for 20-30h in the dark, and dialyzing and rotary-steaming.
In some embodiments, the process for preparing polydopamine particles comprises: mixing ammonia water, an organic solvent and water to obtain a first mixed solution, dropwise adding a dopamine hydrochloride solution into the first mixed solution, reacting for 20-30h at the temperature of 15-25 ℃, and then separating out polydopamine particles;
in further embodiments, the process for preparing polydopamine particles comprises: dropping the aqueous solution of sodium hydroxide into the aqueous solution of dopamine hydrochloride, reacting for 3-10h at the temperature of 30-70 ℃, and then separating out the polydopamine particles. Particle size can be adjusted by adjusting the concentration of dopamine hydrochloride, the amount of sodium hydroxide and the temperature, with particle size decreasing with decreasing dopamine hydrochloride concentration, increasing sodium hydroxide amount or increasing reaction temperature.
Specifically, the organic solvent used in the preparation process of the polydopamine particles can be a water-miscible solvent, such as ethanol, methanol, dimethyl sulfoxide, acetone, tetrahydrofuran, and the like. When the particle size of the polydopamine particles is larger than 100nm, the separation of the polydopamine particles is realized by adopting a centrifugal separation mode; preferably, the particles obtained after centrifugation are redispersed with water and recentrifuged; when the particle size of the polydopamine particles is less than 100nm, the separation of the polydopamine particles is realized by adopting a dialysis and rotary evaporation mode; preferably, the dialysis process is carried out by dialysis for 30-40h with a dialysis bag with molecular weight of 13500-14500 and rotary evaporation temperature of 25-35 ℃. The particle size of the final product is controlled by the using amount of the ammonia water, and the larger the using amount of the ammonia water is, the smaller the particle size of the product is.
In some embodiments, the polyethylene glycol terminally modified with a tumor targeting molecule can be a commercially available product, such as a Sigma-Aldrich vendor.
In another embodiment, the process for preparing a polyethylene glycol with a single-end modified tumor targeting molecule comprises: mixing and dissolving the polyethylene glycol modified by ammonia at the two ends and the tumor targeting molecules, carrying out an amide reaction under the action of a catalyst, and then separating, purifying, freezing and drying. Specifically, the tumor targeting molecule is selected from any one of folic acid, phenylboronic acid, aptamers and RGD polypeptide, and the catalyst is a mixture formed by N-hydroxysuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
Specifically, the antitumor drug is selected from adriamycin or camptothecin, and the two antitumor drugs can be adsorbed with the targeted polydopamine particles, so that the antitumor drug is loaded on the targeted polydopamine particles.
S2 preparation of external phase spinning solution
Gelatin or chitosan is dissolved to form an external phase spinning solution, and the gelatin or chitosan can be used for forming an outer shell structure in electrostatic spinning.
In some embodiments, the external phase spinning dope is a mixed solution (i.e., a first spinning dope) formed by dissolving gelatin and genipin; the genipin is added into the raw materials of the external-phase spinning solution, so that the genipin and the gelatin can be crosslinked, the mechanical property of the product is improved, and the product is easy to degrade.
In another embodiment, the external phase spinning solution is a mixed solution (i.e., the second spinning solution) formed by dissolving chitosan and polyethylene oxide. Preferably, the ratio of chitosan: the mass ratio of the polyoxyethylene is 1:0.8-1.2, and the total concentration of the chitosan and the polyoxyethylene is 50-70 g/L. More preferably, when the second spinning solution is used as the external phase spinning solution, after spinning, washing the fiber filaments for 5-15 times by using an ethanol solution of genipin, then soaking the fiber filaments in the ethanol solution of genipin for 10-24 hours, and then soaking the fiber filaments in absolute ethanol for 2 hours; further preferably, the concentration of the ethanol solution of genipin is 0.2-1% by mass/volume.
Preferably, the solvent of the external phase spinning solution is acetic acid and water, and the volume ratio of the acetic acid to the water is 7-11: 1; preferably, the external phase dope is stirred for 8-15h before electrospinning. The mixed solvent formed by acetic acid and water is used as the raw material, so that the spinning effect can be enhanced, and the stability and the uniformity of spinning in the spinning process are better.
Further, the total concentration of gelatin and genipin in the external phase spinning solution is 200-250g/L, and the mass ratio of the gelatin to the genipin is 25-35: 3. The dosage of the gelatin and the genipin needs to be controlled, the gelatin is a main raw material for spinning, and the dosage of the gelatin and the genipin is controlled within the range, so that the uniformity and the strength of a spinning product can be effectively improved, and meanwhile, the product is endowed with good degradability.
S3, coaxial electrospinning
And carrying out coaxial electrostatic spinning on the internal phase spinning solution and the external phase spinning solution. The specific operation of coaxial spinning can be referred to the prior art, and generally speaking, the coaxial electrospinning process comprises: respectively placing the internal phase spinning solution and the external phase spinning solution into an injector, connecting the injector to an internal inlet and an external inlet of a coaxial spinning needle head, and horizontally fixing the injector on a micro-flow injection pump; a roller wrapped with aluminum foil paper is fixed at a position 10-20cm from the needle point as a fiber receiver, and the rotating speed is about 80-120 rpm. In the coaxial electrostatic spinning process, the operating voltage is 12-20kv, the pushing speed is 0.1-0.2mL/h, the receiving distance is 10-20cm, the operating temperature is 15-25 ℃, and the operating humidity is preferably controlled within 40%.
The embodiment of the invention also provides an anti-tumor implant, which comprises nano fibers with a core-shell structure, wherein drug-loaded nano poly dopamine particles are loaded in an inner core of the core-shell structure; wherein, the drug loaded in the drug-loaded nano poly dopamine particles is an anti-tumor drug, and the anti-tumor drug is adriamycin or camptothecin; preferably, the particle size of the drug-loaded nano poly dopamine particles is 40-130 nm.
The anti-tumor implant is a nanofiber with a core-shell structure, and drug-loaded nano poly dopamine particles are loaded in an inner core, and the implant has tumor targeting and photothermal treatment effects.
Preferably, the anti-tumor implant can be prepared by the preparation method.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
This embodiment provides a method for preparing an anti-tumor implant, which includes the following steps:
firstly, preparing medicine-carrying polydopamine particles:
(1) and (3) preparing polydopamine particles. (a) 5mL of aqueous ammonia, 40mL of absolute ethanol and 90mL of deionized water were mixed together and stirred for about 30 minutes to mix them uniformly. (b) 0.5g dopamine hydrochloride was weighed and dissolved completely in 30mL deionized water. (c) Dropwise adding the dopamine hydrochloride solution in the (b) into the mixed solution in the (a), and continuously stirring for 24 hours. It was found that the color of the mixed solution gradually became dark brown during the dropping. (d) After reacting for 20 hours at 15 ℃, centrifugally collecting the generated poly-dopamine particles, and washing the particles for three times by using a distilled water redispersion and recentrifugation method to obtain the dopamine particles with better monodispersity.
(2) Preparing the polyethylene glycol molecule with the tumor targeting molecule modified at one end. 10g of a double-terminal ammonia-modified polyethylene glycol (NH)2-PEG-NH2) With 1g of folic acid molecule, dissolved in 80mL of dimethyl sulfoxide solvent, and reacted by amide reaction (15 ℃ for 20h) catalyzed by 0.5g N-hydroxysuccinimide and 1g of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride to attach the folic acid molecule to NH2-PEG-NH2On the single-terminal amino group of (1). Then separating, purifying and freeze-drying to obtain the single-end folic acid modified polyethylene glycol molecule.
(3) 20mg of polydopamine particles and 10mg of adriamycin are weighed and added into 20mL of TIRS buffer solution (pH8.5), stirred for 20 hours in the dark, dialyzed for 30 hours by a 1500 molecular weight dialysis bag, and then rotary-evaporated at 30 ℃ to obtain a concentrated solution.
Next, preparation of the internal phase spinning solution:
and (2) concentrating a dispersion liquid formed by mixing the drug-loaded polydopamine particles and water in a centrifugal collection and redispersion mode, then dropwise adding the high-concentration dispersion liquid into a pre-dissolved polyvinyl alcohol aqueous solution with the concentration of 150g/L, supplementing deionized water to the mixed solution to enable the concentration of the polyvinyl alcohol to be 80g/L, and uniformly stirring. The mass ratio of the drug-loaded polydopamine particles to the polyvinyl alcohol is controlled to be 1: 5.
Then, preparation of external phase spinning solution:
the external phase spinning solution is formed by dissolving gelatin and genipin in a mixed solvent formed by acetic acid and water, the total concentration of solutes in the external phase spinning solution is 200g/L, the mass ratio of the gelatin to the genipin is 25:3, and the volume ratio of the acetic acid to the water is 7: 1. The external phase spinning solution was stirred for about 8 hours before electrospinning, so that the gelatin therein was crosslinked with genipin and was dark blue overall.
Finally, coaxial electrospinning
Equal volumes of the internal phase spinning solution and the external phase spinning solution were placed in 5mL syringes, respectively, and connected to the internal and external inlets of the coaxial spinning needles, and then the syringes were horizontally fixed to a micro-flow injection pump. A clean and grounded aluminum foil wrapped cylinder was fixed at about 10cm from the needle tip as a fiber receiver at about 80rpm (low speed). During spinning, an electrostatic high voltage of about 12kV is applied between the needle head and the receiving plate, and the pushing speeds of the internal and external phase spinning solutions are controlled to be 0.1 mL/h. All operations are completed at about 15 ℃, and after the fibers are collected, the fibers are placed in a vacuum drying oven for vacuum drying for standby so as to remove the solvent which is not completely volatilized.
Example 2
This embodiment provides a method for preparing an anti-tumor implant, which includes the following steps:
firstly, preparing medicine-carrying polydopamine particles:
(1) and (3) preparing polydopamine particles. (a) 9mL of aqueous ammonia, 40mL of absolute ethanol, and 90mL of deionized water were mixed together and stirred for about 30 minutes to mix them uniformly. (b) 0.5g dopamine hydrochloride was weighed and dissolved completely in 30mL deionized water. (c) Dropwise adding the dopamine hydrochloride solution in the (b) into the mixed solution in the (a), and continuously stirring for 24 hours. It was found that the color of the mixed solution gradually became dark brown during the dropping. (d) After 30h reaction at 25 ℃, the polydopamine granules are dialyzed for 30 hours by a 13500 molecular weight dialysis bag and then are obtained by rotary evaporation at 25 ℃. Thus obtaining the dopamine granule concentrated solution with better monodispersity.
(2) Preparing the polyethylene glycol molecule with the tumor targeting molecule modified at one end. 4g of amino-terminated polyethylene glycol (NH)2-PEG-NH2) With 0.3g of phenylboronic acid monohydrate, dissolved in 50mL of dimethyl sulfoxide solvent in 0.2g N-hydroxyAttachment of folate molecules to NH by amide reaction (reaction at 25 ℃ C. for 48h followed by addition of 5mL deionized water) catalyzed by phenylsuccinimide and 4g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride2-PEG-NH2On the single-terminal amino group of (1). Filtering to remove solid, dialyzing the filtrate with dialysis bag (MWCO 1000) for 3 days, and lyophilizing the residue to obtain single-end folic acid modified polyethylene glycol molecule.
(3) 20mg of polydopamine particles and 10mg of adriamycin are weighed and added into 20mL of TIRS buffer solution (pH8.5), stirred for 30 hours in the dark, dialyzed for 40 hours by a 1500 molecular weight dialysis bag, and then rotary-evaporated at 30 ℃ to obtain a concentrated solution.
Next, preparation of the internal phase spinning solution:
and (2) concentrating a dispersion liquid formed by mixing the drug-loaded polydopamine particles and water in a centrifugal collection and redispersion mode, then dropwise adding the high-concentration dispersion liquid into a polyvinyl alcohol aqueous solution with the concentration of 250g/L dissolved in advance, supplementing deionized water to the mixed solution to enable the concentration of the polyvinyl alcohol to be 120g/L, and uniformly stirring. The mass ratio of the drug-loaded polydopamine particles to the polyvinyl alcohol is controlled to be 1: 20.
Then, preparation of external phase spinning solution:
the external phase spinning solution is formed by dissolving gelatin and genipin in a mixed solvent formed by acetic acid and water, the total concentration of solutes in the external phase spinning solution is 250g/L, the mass ratio of the gelatin to the genipin is 35:3, and the volume ratio of the acetic acid to the water is 11: 1. The external phase spinning solution was stirred for about 15 hours before electrospinning, so that the gelatin therein was crosslinked with genipin and was dark blue overall.
Finally, coaxial electrospinning
Equal volumes of the internal phase spinning solution and the external phase spinning solution were placed in 5mL syringes, respectively, and connected to the internal and external inlets of the coaxial spinning needles, and then the syringes were horizontally fixed to a micro-flow injection pump. A clean and grounded aluminum foil wrapped cylinder was mounted about 20cm from the needle tip as a fiber receiver at about 120rpm (low speed). During spinning, an electrostatic high voltage of about 20kV is applied between the needle head and the receiving plate, and the pushing speeds of the internal and external phase spinning solutions are controlled to be 0.2 mL/h. All operations are completed at about 30 ℃, and after the fibers are collected, the fibers are placed in a vacuum drying oven for vacuum drying for standby so as to remove the solvent which is not completely volatilized.
Example 3
This embodiment provides a method for preparing an anti-tumor implant, which includes the following steps:
firstly, preparing medicine-carrying polydopamine particles:
(1) and (3) preparing polydopamine particles. (a) 9mL of aqueous ammonia, 40mL of absolute ethanol, and 90mL of deionized water were mixed together and stirred for about 30 minutes to mix them uniformly. (b) 0.5g dopamine hydrochloride was weighed and dissolved completely in 30mL deionized water. (c) Dropwise adding the dopamine hydrochloride solution in the (b) into the mixed solution in the (a), and continuously stirring for 24 hours. It was found that the color of the mixed solution gradually became dark brown during the dropping. (d) Reacting at 25 deg.C for 30h, dialyzing the polydopamine granules with 14500 molecular weight dialysis bag for 40 hr, and rotary steaming at 35 deg.C. Thus obtaining the dopamine granule concentrated solution with better monodispersity.
(2) Preparing the polyethylene glycol molecule with the tumor targeting molecule modified at one end. 4g of amino-terminated polyethylene glycol (NH)2-PEG-NH2) 0.3g of phenylboronic acid monohydrate, dissolved in 50mL of dimethylsulfoxide, was reacted with 0.2g N-hydroxysuccinimide and 0.4g of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride to link the folic acid molecule to NH by amide reaction (reaction at 20 ℃ C. for 24h)2-PEG-NH2On the single-terminal amino group of (1). Then separating, purifying and freeze-drying to obtain the single-end folic acid modified polyethylene glycol molecule.
(3) 20mg of polydopamine particles and 10mg of adriamycin are weighed and added into 20mL of TIRS buffer solution (pH8.5), stirred for 30 hours in the dark, dialyzed for 36 hours by a 1500 molecular weight dialysis bag, and then rotary-evaporated at 30 ℃ to obtain a concentrated solution.
Next, preparation of the internal phase spinning solution:
and (2) concentrating a dispersion liquid formed by mixing the drug-loaded polydopamine particles and water in a centrifugal collection and redispersion mode, then dropwise adding the high-concentration dispersion liquid into a previously dissolved polyvinyl alcohol aqueous solution with the concentration of 200g/L, supplementing deionized water to the mixed solution to enable the concentration of the polyvinyl alcohol to be 100g/L, and uniformly stirring. The mass ratio of the drug-loaded polydopamine particles to the polyvinyl alcohol is controlled to be 1: 10.
Then, preparation of external phase spinning solution:
the external phase spinning solution is formed by dissolving gelatin and genipin in a mixed solvent formed by acetic acid and water, the total concentration of solutes in the external phase spinning solution is 220g/L, the mass ratio of the gelatin to the genipin is 30:3, and the volume ratio of the acetic acid to the water is 9: 1. Before electrospinning, the external-phase spinning solution is stirred for about 10 hours, so that the gelatin is crosslinked by genipin, and the whole spinning solution is dark blue.
Finally, coaxial electrospinning
Equal volumes of the internal phase spinning solution and the external phase spinning solution were placed in 5mL syringes, respectively, and connected to the internal and external inlets of the coaxial spinning needles, and then the syringes were horizontally fixed to a micro-flow injection pump. A clean and grounded aluminum foil wrapped cylinder was fixed at about 14cm from the tip as a fiber receiver at about 100rpm (low speed). During spinning, an electrostatic high voltage of about 18kV is applied between the needle head and the receiving plate, and the pushing speeds of the internal and external phase spinning solutions are controlled to be 0.15 mL/h. All operations were completed at about 27 ℃ and after the fibers were collected, they were placed in a vacuum oven for vacuum drying to remove the solvent that was not completely volatilized.
Example 4
This example provides a method for preparing an anti-tumor implant, which comprises the following steps: the solute in the external phase spinning solution comprises gelatin only and the amount is equal to the sum of the gelatin and genipin.
Example 5
This example provides a method for preparing an anti-tumor implant, which comprises the following steps: (1) the solute in the external phase spinning solution is chitosan and polyethylene oxide, the total concentration of the chitosan and the polyethylene oxide is 50g/L, and the mass ratio of the chitosan to the polyethylene oxide is 1: 1. After successful spinning, washing the fiber yarn for 5-10 times by using an ethanol solution of genipin, and then soaking the fiber yarn in the solution for 24 hours to achieve the purpose of cross-linked chitosan. And then soaked in absolute ethyl alcohol for 2 hours. The concentration of the ethanol solution of genipin is 0.5 percent of mass/volume percent. (2) The polydopamine particles of the inner phase are pure polydopamine particles without drug (doxorubicin).
Example 6
This example provides a method for preparing an anti-tumor implant, which comprises the following steps:
the preparation method of the polydopamine particles comprises the following steps: (a) dopamine hydrochloride 180mg was added to 90mL of deionized water and mixed together and stirred for about 30 minutes to mix well. (b) Dropping a corresponding sodium hydroxide aqueous solution (37.6mg of sodium hydroxide dissolved in 1mL of water) into the mixed solution in the step (a) according to the molar ratio of dopamine hydrochloride to hydroxide of 1:0.8, continuously stirring for 5 hours at 50 ℃, centrifugally collecting generated polydopamine particles, re-dispersing the polydopamine particles by using distilled water, and washing the polydopamine particles for three times by using a centrifugal method, so as to obtain the dopamine particles with good monodispersity.
Example 7
This example provides a method for preparing an anti-tumor implant, which comprises the following steps:
the preparation method of the polydopamine particles comprises the following steps: (a) dopamine hydrochloride 120mg was added to 90mL of deionized water and mixed together and stirred for about 30 minutes to mix well. (b) The corresponding aqueous sodium hydroxide solution (31.34mg sodium hydroxide dissolved in 1mL water) was added dropwise to the mixed solution in (a) with the molar dopamine hydrochloride: hydroxide 1:1, stirring was continued at 70 ℃ for 5 hours, and the resulting polydopamine particles were dialyzed with a 13500 molecular weight dialysis bag for 30 hours and then rotary evaporated at 25 ℃. Thus obtaining the dopamine granule concentrated solution with better monodispersity.
Comparative example 1
The comparative example provides a preparation method of an anti-tumor implant, which has the same specific steps as example 3, except that: the push speed in coaxial electrostatic spinning is 0.05 mL/h.
Comparative example 2
The comparative example provides a preparation method of an anti-tumor implant, which has the same specific steps as example 3, except that: the push speed in coaxial electrostatic spinning is 0.3 mL/h.
Comparative example 3
The comparative example provides a preparation method of an anti-tumor implant, which has the same specific steps as example 3, except that: the internal phase contained polydopamine nanoparticles of 400nm in size.
Test example 1
The transmission electron micrograph of the antitumor implant prepared in test example 5 is shown in fig. 1. As can be seen from FIG. 1, it can be seen by transmission electron microscopy that the entire fiber is indeed in a core-shell structure, the interior is darker, and the contrast is more obvious under the lens than the outer shell, probably because polydopamine is carried.
In comparative example 1, the liquid outlet part of the needle head is easy to block due to too low pushing speed, and in comparative example 2, the raw material loss is large and the fibers are not uniform due to too high pushing speed; in comparative example 3, the particles are too large to be completely entrapped by the fibers and are not easily diffused into the depth of the tumor tissue. Thus, although the method of coaxial spinning is about the same as the prior art method, parameter control in the spinning process has a significant impact on the stability of the spinning process and the uniformity of the product.
Test example 2
The particle size of the polydopamine particles prepared in example 3 is approximately 44nm, the polydopamine particles are mixed with water to form suspensions with different concentrations, and the photo-thermal heating effect of the polydopamine particle suspensions with different concentrations is tested, and the test results are shown in fig. 2-3. The particle size of the polydopamine particles prepared in example 1 is approximately 137nm, and the polydopamine particles are mixed with water to form suspensions with different concentrations, and the photo-thermal heating effect of the polydopamine particle suspensions with different concentrations is tested, and the test results are shown in fig. 4.
The test method comprises the following steps: taking 44nm polydopamine particles as an example, 3mL of deionized water is placed in a centrifugal tube with the capacity of 5mL to serve as a control group, and the concentration of 3mL of polydopamine particles is adjustedPolydopamine/water dispersions of 50. mu.g/mL, 100. mu.g/mL, 200. mu.g/mL and 400. mu.g/mL were respectively contained in 5mL centrifuge tubes as experimental groups at 808nm (1W/cm)2Or 2W/cm2) Irradiating with near infrared laser for 600s, and recording temperature once every 30s by using infrared thermometer. The test procedure of the photothermal heating effect of the poly-dopamine particles with the particle size of 137nm is approximately the same.
As can be seen from FIGS. 2-4, the temperature rise of the particles with different concentrations increases with the increase of the illumination time; under the same illumination condition, the higher the concentration is, the larger the temperature rise of the nanoparticles is, namely, the stronger the photothermal conversion capability is. Under the same size condition (fig. 2 and 3), the larger the illumination power, the larger the temperature rise. Same laser (808nm, 1W/cm)2) Under irradiation conditions (fig. 2 and 4), the larger the particle size, the larger the temperature rise, and the stronger the photothermal conversion ability.
Test example 3
Co-culture of mouse breast cancer cells with the antitumor implant prepared in example 5, and examination of the antitumor implant on a near-infrared laser (1.5W/cm)2) The results of the in vitro antitumor effect of irradiation for different periods of time under irradiation conditions are shown in FIG. 5.
The test method comprises the following steps: mouse breast cancer cells were seeded in 48-well plates and cultured for 24 hours (5.0X 10 per well)4Individual cells, 800 μ L of medium), and then the anti-tumor implant (fiber membrane) prepared in example 5 was gently transferred into a well plate. The sample was exposed to 808nm laser at 1.5W/cm2The irradiation was continued for 5, 10, 15 or 20 minutes, respectively, and then the cell viability was determined by Alamar-Blue method. The Alamar-Blue method can be specifically referred to in the Alamar-Blue reagent specification.
As can be seen from FIG. 5, the survival rate of the tumor cells of the group without light is about 100%, and the normal activity of the cells is not affected, which indicates that the anti-tumor implant agent has no toxicity to the tumor cells under the conditions of no drug loading and no light; the survival rate of the tumor cells after the irradiation of light is only about 20 percent, which shows that the anti-tumor implant can realize good anti-tumor effect after the short-time irradiation without drug loading.
In summary, according to the preparation method of the anti-tumor implant with local chemotherapy and photothermal therapy functions provided by the invention, the drug-loaded polydopamine particle dispersion liquid and the water-soluble polymer solution are mixed to form the inner phase spinning solution, the gelatin or chitosan is dissolved to form the inner phase spinning solution, the inner phase spinning solution and the outer phase spinning solution are mixed to perform coaxial electrostatic spinning, so that the nano-fiber with the core-shell structure is prepared, and the nano-polydopamine particles are loaded in the inner core of the nano-fiber. The anti-tumor implant prepared by the preparation method provided by the invention has the functions of local chemotherapy and photothermal therapy.
The invention also provides an anti-tumor implant which comprises the nano-fibers with the core-shell structure, and drug-loaded nano-poly dopamine particles are loaded in the core-shell structure, and the fiber implant has the effects of local chemotherapy and photothermal therapy.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (14)
1. A preparation method of an anti-tumor implant with local chemotherapy and photothermal therapy functions is characterized by comprising the following steps:
mixing the drug-loaded polydopamine particle dispersion liquid with a water-soluble polymer solution to obtain an internal phase spinning solution;
dissolving gelatin or chitosan to form external phase spinning solution;
carrying out coaxial electrostatic spinning on the internal phase spinning solution and the external phase spinning solution;
wherein the water-soluble polymer is selected from any one of polyvinyl alcohol, polyvinylpyrrolidone and polyethylene oxide, and the drug in the drug-loaded polydopamine particles is an anti-tumor drug;
the particle size of the drug-loaded polydopamine particles is 40-130 nm;
the water-soluble polymer is polyvinyl alcohol, the concentration of the polyvinyl alcohol in the internal phase spinning solution is 80-120g/L, and the mass ratio of the drug-loaded polydopamine particles to the polyvinyl alcohol is 1: 5-20;
the external-phase spinning solution is a first spinning solution or a second spinning solution, the first spinning solution is a mixed solution formed by dissolving gelatin and genipin, and the second spinning solution is a mixed solution formed by dissolving chitosan and polyethylene oxide;
in the first spinning solution, the total concentration of gelatin and genipin is 200-250g/L, and the mass ratio of gelatin to genipin is 25-35: 3;
and (3) chitosan in the second spinning solution: the mass ratio of the polyoxyethylene is 1:0.8-1.2, and the total concentration of the chitosan and the polyoxyethylene is 50-70 g/L;
in the coaxial electrostatic spinning process, the operating voltage is 12-20kv, the pushing speed is 0.1-0.2mL/h, the receiving distance is 10-20cm, and the operating temperature is 15-30 ℃.
2. The method for preparing an anti-tumor implant with local chemotherapy and photothermal therapy functions as claimed in claim 1, wherein the process of mixing the drug-loaded polydopamine particle dispersion with the polyvinyl alcohol solution is dropping the drug-loaded polydopamine particle dispersion into the polyvinyl alcohol solution.
3. The preparation method of the anti-tumor implant with local chemotherapy and photothermal therapy functions as claimed in claim 1, wherein the drug-loaded polydopamine particles have a drug loading of 10% -30%.
4. The method for preparing the anti-tumor implant with local chemotherapy and photothermal therapy functions according to claim 1, wherein the process for preparing the drug-loaded polydopamine particles comprises the following steps:
mixing polydopamine particles and polyethylene glycol with a tumor targeting molecule modified at one end, and reacting at the temperature of 15-25 ℃ for 20-30h to obtain targeted polydopamine particles with a tumor targeting function;
mixing the targeted polydopamine particles, the antitumor drugs and the tris buffer solution, stirring in the dark for 20-30h, and dialyzing and steaming to obtain drug-loaded nanoparticles with a tumor targeting function;
wherein the antitumor drug is selected from adriamycin or camptothecin.
5. The method for preparing the antitumor implant with local chemotherapy and photothermal therapy functions as claimed in claim 4, wherein the polydopamine particle is prepared by a process comprising: mixing ammonia water, an organic solvent and water to obtain a first mixed solution, dropwise adding a dopamine hydrochloride solution into the first mixed solution, reacting for 20-30h at the temperature of 15-25 ℃, and then separating out polydopamine particles.
6. The method for preparing the antitumor implant with local chemotherapy and photothermal therapy functions as claimed in claim 4, wherein the polydopamine particle is prepared by a process comprising: dropping the aqueous solution of sodium hydroxide into the aqueous solution of dopamine hydrochloride, reacting for 3-10h at the temperature of 30-70 ℃, and then separating out the polydopamine particles.
7. The method for preparing an anti-tumor implant with local chemotherapy and photothermal therapy functions as claimed in claim 6, wherein when the particle size of the polydopamine particles is greater than 100nm, the separation of the polydopamine particles is performed by centrifugation; re-dispersing the particles obtained after centrifugal separation with water and re-centrifuging to remove free drug;
when the particle size of the polydopamine particles is less than 100nm, the polydopamine particles are separated and concentrated in a dialysis and rotary evaporation mode; during dialysis, dialyzing with a dialysis bag with molecular weight of 13500-14500 at rotary evaporation temperature of 25-35 deg.C for 30-40 h.
8. The method for preparing the antitumor implant with local chemotherapy and photothermal therapy functions as claimed in claim 4, wherein the preparation process of the polyethylene glycol with the tumor targeting molecule modified at the single end comprises: mixing and dissolving the polyethylene glycol modified by ammonia at the two ends and the tumor targeting molecules, carrying out an amide reaction under the action of a catalyst, and then separating, purifying, freezing and drying.
9. The method for preparing an antitumor implant with local chemotherapy and photothermal therapy functions according to claim 8, wherein the tumor targeting molecule is selected from any one of folic acid, phenylboronic acid, aptamers and RGD polypeptide, and the catalyst is a mixture of N-hydroxysuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
10. The method for preparing an antitumor implant having local chemotherapy and photothermal therapy effects according to claim 1, wherein the external phase spinning solution is stirred for 8-15 hours before electrospinning.
11. The method for preparing an anti-tumor implant having local chemotherapy and photothermal therapy functions according to claim 1, wherein the solvent of the external phase spinning solution is acetic acid and water, and the volume ratio of acetic acid to water is 7-11: 1.
12. The method for preparing the antitumor implant with local chemotherapy and photothermal therapy functions according to claim 1, wherein when the second spinning solution is used as the external phase spinning solution, after spinning, the fiber filaments are washed with genipin ethanol solution for 5-15 times, then soaked in genipin ethanol solution for 10-24 hours, and then soaked in absolute ethanol for 2 hours; the concentration of the ethanol solution of genipin is 0.2-1% of mass/volume percent.
13. The method for preparing the antitumor implant with local chemotherapy and photothermal therapy functions as claimed in claim 1, wherein the coaxial electrospinning process comprises: respectively placing the internal phase spinning solution and the external phase spinning solution into an injector, connecting the injector to an internal inlet and an external inlet of a coaxial spinning needle, and horizontally fixing the injector on a micro-flow injection pump; and fixing a roller wrapped by the aluminum foil paper at a position 10-20cm away from the needle point as a fiber receiver, wherein the rotating speed is 80-120 rpm.
14. An anti-tumor implant with local chemotherapy and photothermal therapy functions, which is prepared by the preparation method of any one of claims 1 to 13, and comprises nanofibers with a core-shell structure, wherein drug-loaded nano poly dopamine particles are loaded in the inner core of the core-shell structure.
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