CN117258131A - Microneedle patch loaded with sparfloxacin and manganese-based nano-drugs and application of microneedle patch in-situ triple negative breast cancer and lung metastasis treatment - Google Patents
Microneedle patch loaded with sparfloxacin and manganese-based nano-drugs and application of microneedle patch in-situ triple negative breast cancer and lung metastasis treatment Download PDFInfo
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- CN117258131A CN117258131A CN202311492476.7A CN202311492476A CN117258131A CN 117258131 A CN117258131 A CN 117258131A CN 202311492476 A CN202311492476 A CN 202311492476A CN 117258131 A CN117258131 A CN 117258131A
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- manganese
- sparfloxacin
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- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 title claims abstract description 55
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 26
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Classifications
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
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- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
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- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a microneedle patch carrying sparfloxacin and manganese-based nano-drugs and application thereof in-situ triple negative breast cancer and lung metastasis treatment. According to the invention, the clinical main antibacterial agent sparfloxacin is combined into the microneedle for the first time, and the obtained drug-loaded microneedle can effectively inhibit the growth and metastasis of tumors, effectively prevent the recurrence of the tumors, and realize the efficient killing of triple negative breast cancer.
Description
Technical Field
The invention belongs to the technical field of medical instrument preparation, and particularly relates to a microneedle patch for in-situ triple negative breast cancer and lung metastasis treatment.
Background
Breast cancers are classified according to the presence or absence of receptors, such as Estrogen Receptor (ER), progestogen Receptor (PR) and human epidermal growth factor receptor 2 (HER 2/neu). Triple Negative Breast Cancers (TNBC) lack expression of the above receptors, accounting for only 10-20% of the total number of breast cancer cases. However, TNBC is markedly invasive, and metastasis of brain and internal organs is most common, particularly in the lungs. The current conventional treatment method of TNBC in clinic mainly comprises operation, radiotherapy and chemotherapy, wherein the operation treatment is basic stone, and the chemotherapy and the radiotherapy are used as auxiliary treatments. However, TNBC shows increased resistance and risk of early recurrence due to molecular heterogeneity in its progression. Throughout the tumor growth process, cancer cells need to withstand oxidative stress during proliferation, matrix detachment, circulation, remote colonization, and therapy, with redox homeostasis critical to cancer cells. Reactive Oxygen Species (ROS) have a bi-directional effect on cancer, and appropriate concentrations stimulate tumorigenesis and support the progression of cancer cells, while excessive concentrations can lead to cell death. The up-regulated antioxidant system in cancer cells limits ROS to levels that promote tumors. In cancer, redox regulation interacts with tumor initiation, proliferation, metastasis, programmed cell death, autophagy, metabolic reprogramming, tumor microenvironment, treatment, and resistance to promote the progression of cancer. Therefore, by promoting the activation of the cGAS-STING pathway and activating innate immunity, the combination of the acquired immune effect which is possibly generated after the redox balance steady state is broken, and further, the lung metastasis of tumor cells is more strongly inhibited, and the treatment scheme has a very broad treatment prospect.
In tumor response, the natural immune system cGAS-STING signaling pathway activates Dendritic Cells (DCs), tumor-specific CD8 + T cells and natural killer (natural killer cell, NK) cells, thereby initiating systemic anti-tumor immunity, killing cancer cells. In recent years, studies have shown Mn 2+ Can effectively promote the activation of cGAS and STING as an agonist. Mn is reported in immunology (Immunity, 2018, volume 48, pages 675-687) 2+ Play a critical role in host defense against DNA viruses. Mn (Mn) 2+ Released from membrane-encapsulated organs after viral infection, accumulate in the cytoplasm and bind directly to cGAS, enhancing the sensitivity of cGAS to double-stranded DNA (dsDNA) and its enzymatic activity, enabling cGAS to produce cGAMP in the presence of low concentrations of dsDNA, thereby activating STING and allowing the body to produce type I IFN and host antiviral capacity. As the study goes deep, mn has been reported in Cell Research (2020, volume 30, pages 966-979) 2+ Can also directly activate cGAS (without depending on dsDNA at all), and Mn 2+ Catalysis and Mn 2 + The process by which dsDNA catalyzes cGAS to synthesize cGAMP differs significantly. Mn (Mn) 2+ cGAS binding results in a change in cGAS conformation similar to DNA-cGAS binding, but the structure of the catalytic center is significantly different, resulting in a large change in cGAMP synthesis at the cGAS enzyme catalytic center. This study further demonstrates Mn 2+ Is a second cGAS activator outside of DNA. Thus, mn 2+ At the time of activating cGAS-STING messageThe number pathway has great potential in generating anti-tumor immune responses. In addition, sparfloxacin as a fluoroquinolone drug can damage the DNA of tumor cells and inhibit the activity of reductase, which is similar to Mn 2+ The mediated cGAS-STING pathway has potential synergy and can enhance its effect. At present, the clinical sparfloxacin is mainly used as an antibacterial drug.
Disclosure of Invention
The invention provides a microneedle patch carrying sparfloxacin and manganese-based nano-drugs and application thereof in-situ triple negative breast cancer and lung metastasis treatment, and aims to solve the technical problems that: construction of transdermal drug delivery System to achieve Mn 2+ And the accurate release of sparfloxacin, reduction of toxic and side effects, improvement of tumor microenvironment and activation of cGAS-STING signal channels to realize the immunotherapy of tumors.
The invention adopts the following technical scheme to solve the technical problems:
the microneedle patch carrying sparfloxacin and manganese-based nano-drugs is characterized in that: the microneedle patch comprises a back weighting layer and a needle array arranged on the back weighting layer; the back-weighting layer is formed by polymer solution, and the needle array is formed by hyaluronic acid added with sparfloxacin and manganese-based nano-drugs. The preparation method of the microneedle patch comprises the following steps:
adding sparfloxacin and a manganese-based nano-drug into hyaluronic acid hydrogel together, and stirring at room temperature in dark overnight until the mixture becomes a uniform light yellow mixed solution; dropwise adding the mixed solution to a microneedle mould by using a suction pipe, pumping air under a vacuumizing environment together with the mould, filling gel under the bottom into micropores of a needle body of the microneedle mould, removing redundant parts except the micropores, and drying; and adding a polymer solution above the mould to form a backing layer, then placing the mould in a drying oven, drying overnight in a dark place, and demoulding to obtain the microneedle patch carrying sparfloxacin and manganese-based nano-drugs.
Further, the mass ratio of sparfloxacin to manganese-based nano-drug is 1:2-10, and the mass ratio of sparfloxacin to hyaluronic acid is 1:100.
Further, the preparation method of the manganese-based nano-drug comprises the following steps: adding zinc salt and sodium oleate into a mixed solution composed of ethanol, deionized water and cyclohexane, carrying out reflux reaction for 4 hours at 70 ℃, and taking supernatant to obtain zinc salt oleic acid compound; adding manganese salt and sodium oleate into a mixed solution composed of ethanol, deionized water and cyclohexane, carrying out reflux reaction for 4 hours at 70 ℃, and taking supernatant to obtain a manganese salt oleic acid compound; mixing zinc salt oleic acid compound and manganese salt oleic acid compound, adding sublimed sulfur and octadecene, heating to 300 ℃, preserving heat for 1h, cooling to 60 ℃, taking out the product, and centrifugally washing with a mixed solution of cyclohexane and ethanol to obtain the manganese-based nano-drug.
Further, the zinc salt is at least one of zinc chloride, zinc nitrate and zinc sulfate, and the manganese salt is at least one of manganese chloride, manganese nitrate and manganese sulfate.
Further: in preparing the zinc salt oleic acid compound, the molar ratio of zinc salt to sodium oleate is 1:2; in preparing the manganese salt oleic acid compound, the molar ratio of manganese salt to sodium oleate is 1:2; the molar ratio of the zinc salt to the sublimed sulfur is 1:2; the volume ratio of the total volume of the zinc salt oleic acid compound and the manganese salt oleic acid compound to the volume of the octadecene is 1:4.
further, in the mixed solution, the volume ratio of ethanol, deionized water and cyclohexane is 6:7:8.
further, the polymer solution is at least one of polyvinylpyrrolidone, hyaluronic acid and polyvinyl alcohol, and the concentration is 1-2 g/mL.
Further, the backing layer of the microneedle patch may be a square with a side length of 0.8-3.0cm or a circular patch with a radius of 0.4-1.5 cm.
Further, each microneedle head in the needle body array is conical with the height of 400-1000 mu m and the bottom diameter of 150-400 mu m.
The micro-needle patch loaded with sparfloxacin and manganese-based nano-drugs can be used for preparing drugs for transdermal drug delivery for treating in-situ triple negative breast cancer and inhibiting metastasis.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention prepares the soluble microneedle loaded with sparfloxacin and manganese-based nano-drugs for the first time, has simple preparation method, mild reaction conditions, uniform appearance of the obtained product and lower production cost, and is suitable for industrialized amplified production.
2. The micro-needle loaded with sparfloxacin and manganese-based nano-drugs can realize rapid dissolution, realizes more accurate drug release by transdermal drug delivery above tumor parts, has smaller drug delivery amount and better biocompatibility.
3. The invention constructs a biological response polymer micro-needle drug release system loaded manganese-based nano-drug and sparfloxacin for activating innate immunity and breaking redox balance to treat triple negative breast cancer. The microneedle can release Mn 2+ Thereby depleting the intratumoral over-expressed GSH and generating OH; at the same time, the cGAS-STING signal pathway can be activated, and the immunotherapy can be enhanced. Released metal ions (Zn) 2+ 、Mn 2+/4+ ) H may be produced in cells 2 S gas affects the mitochondrial respiratory chain, further inducing ROS production. Inhibit proliferation and migration of tumor cells under a plurality of synergistic effects.
4. According to the invention, sparfloxacin is released through local transdermal by the microneedle, so that the dosage and toxic and side effects of sparfloxacin are obviously reduced, stronger immune effect can be caused, and better curative effect is reflected.
Drawings
Fig. 1 is an optical picture of the microneedle prepared in example 5.
Fig. 2 is a TEM photograph of the manganese-based nano-drug used in example 5 ((a) in fig. 2) and an HRTEM photograph ((b) in fig. 2).
Fig. 3 is a bright field side view image ((a) in fig. 3) and an SEM image ((b) in fig. 3) of an inverted fluorescence microscope of the microneedle patch prepared in example 5.
Fig. 4 is the effect of the change in concentration of the selected functional components (metered in example 3 with sparfloxacin SP, metered in example 2 with manganese-based nano-drug ZMS, metered in example 4 with the total amount of sparfloxacin and manganese-based nano-drug) in the cell system in the microneedles of examples 3 (a in fig. 4), 2 (b in fig. 4) and 4 (c in fig. 4) in example 7 on the viability of 4T1 cells.
FIG. 5 is the effect of the micro-scale of example 1 (control) and examples 4, 5, 6 on 4T1 cell viability.
FIG. 6 is a view of the tumor dissected from each treatment group of example 8.
Fig. 7 is a comparison of the number of nodules in the anatomically removed lung map for each treatment group of example 8.
Detailed Description
The following describes in detail the examples of the present invention, which are implemented on the premise of the technical solution of the present invention, and detailed embodiments and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following examples.
The preparation method of the manganese-based nano-drug used in the following examples comprises the following steps:
adding 4mmol of zinc chloride and 8mmol of sodium oleate into a mixed solution composed of 6mL of ethanol, 7mL of deionized water and 8mL of cyclohexane, transferring into a 50mL three-neck flask, carrying out reflux reaction for 4h at 70 ℃, and taking a supernatant to obtain a zinc salt oleic acid compound; 4mmol of manganese chloride and 8mmol of sodium oleate are added into a mixed solution composed of 6mL of ethanol, 7mL of deionized water and 8mL of cyclohexane, the mixed solution is transferred into a 50mL three-neck flask, reflux reaction is carried out for 4 hours at 70 ℃, and a supernatant is taken to obtain a manganese salt oleic acid compound.
Mixing zinc salt oleic acid compound and manganese salt oleic acid compound, adding 8mmol of sublimed sulfur and octadecene (the volume of which is 4 times of the total volume of the zinc salt oleic acid compound and the manganese salt oleic acid compound), heating to 300 ℃, preserving heat for 1h, cooling to 60 ℃, taking out the product, and centrifugally washing with a mixed solution with the volume ratio of cyclohexane to ethanol being 4:1 to prepare the manganese-based nano-drug.
Example 1
The present example prepares a hyaluronic acid microneedle patch free of a mixture of manganese-based nanomaterials and sapafloxacin:
300mg of hyaluronic acid was weighed and added to 10mL of deionized water, and stirred for 24 hours in a dark place to obtain hyaluronic acid hydrogel. Dropwise adding the hydrogel onto a microneedle mould by using a suction pipe, then carrying out vacuumizing treatment together with the mould until air is completely extracted, filling gel under-ground into micropores of a needle body of the microneedle mould, removing redundant parts except the micropores, and drying at 40 ℃ for 1h; then, 1.5g/mL PVP solution was added over the mold, and then the mold was dried overnight in an oven at 40℃in the absence of light, and the mold was released to obtain a microneedle patch.
Example 2
The present example prepares hyaluronic acid microneedles containing only manganese-based nanomaterials:
25mg of the manganese-based nano-drug and 250mg of hyaluronic acid are weighed and added into 10mL of deionized water, and the mixture is stirred for 24 hours in a dark place, so as to obtain a pale yellow uniform gelatinous mixture. Dropwise adding the mixture onto a microneedle mould by using a suction pipe, then carrying out vacuumizing treatment together with the mould until air is completely extracted, filling gel under-deposition into micropores of a needle body of the microneedle mould, removing redundant parts except the micropores, and drying at 40 ℃ for 1h; then 1g/mL of hyaluronic acid solution is added above the mold, then the mold is placed in an oven at 40 ℃ to be dried overnight in a dark place, and the mold is removed from the mold, so that the microneedle patch is obtained.
Example 3
The present example prepared hyaluronic acid microneedles containing sparfloxacin only:
5mg of sparfloxacin and 300mg of hyaluronic acid are weighed and added into 10mL of deionized water, and the mixture is stirred for 24 hours in a dark place, so as to obtain a light yellow uniform colloidal mixture. Dropwise adding the mixture onto a microneedle mould by using a suction pipe, then carrying out vacuumizing treatment together with the mould until air is completely extracted, filling gel under-deposition into micropores of a needle body of the microneedle mould, removing redundant parts except the micropores, and drying at 40 ℃ for 1h; then 1g/mL of hyaluronic acid solution is added above the mold, then the mold is placed in an oven at 40 ℃ to be dried overnight in a dark place, and the mold is removed from the mold, so that the microneedle patch is obtained.
Example 4
The hyaluronic acid microneedle patch loaded with sparfloxacin and manganese-based nano-drugs according to the mass ratio of 1:2 is prepared in the embodiment:
5mg of sparfloxacin, 10mg of manganese-based nano-drug and 270mg of hyaluronic acid are weighed and added into 10mL of deionized water, and the mixture is stirred for 24 hours in a dark place, so as to obtain a pale yellow uniform gelatinous mixture. Dripping a mixture containing 100 mug of sparfloxacin and manganese-based nano-drug on a microneedle mould by using a suction pipe, then carrying out vacuumizing treatment together with the mould until air is completely extracted, filling gel under-ground into micropores of a needle body of the microneedle mould, removing redundant parts outside the micropores, and drying at 40 ℃ for 1h; then 1g/mL of hyaluronic acid solution is added above the mold, then the mold is placed in an oven at 40 ℃ to be dried overnight in a dark place, and the mold is removed from the mold, so that the microneedle patch is obtained.
Example 5
The hyaluronic acid microneedle patch loaded with sparfloxacin and manganese-based nano-drugs according to the mass ratio of 1:5 is prepared in the embodiment:
5mg of sparfloxacin, 25mg of manganese-based nano-drug and 270mg of hyaluronic acid are weighed and added into 10mL of deionized water, and the mixture is stirred for 24 hours in a dark place, so as to obtain a pale yellow uniform gelatinous mixture. Dripping a mixture containing 100 mug of sparfloxacin and manganese-based nano-drug on a microneedle mould by using a suction pipe, then carrying out vacuumizing treatment together with the mould until air is completely extracted, filling gel under-ground into micropores of a needle body of the microneedle mould, removing redundant parts outside the micropores, and drying at 40 ℃ for 1h; then 1g/mL of hyaluronic acid solution is added above the mold, then the mold is placed in an oven at 40 ℃ to be dried overnight in a dark place, and the mold is removed from the mold, so that the microneedle patch is obtained.
Fig. 1 is an optical image of the microneedle patch prepared in example 5, from which it can be seen that the microneedle patch is a 15 x 15 array with a square shape with a 9mm side of the corresponding backing layer.
Fig. 2 shows TEM images (fig. 2 (a)) and HRTEM images (fig. 2 (b)) of the manganese-based nano-drug used in example 5, and it can be seen that the synthesized manganese-based nano-drug has a particle size of about 10 nm.
Fig. 3 is a bright field side view image ((a) in fig. 3) and SEM image ((b) in fig. 3) of an inverted fluorescence microscope of the microneedle patch prepared in example 5, from which the overall morphology of the microneedle can be clearly seen.
Example 6
Preparation of sparfloxacin and manganese-based nano-drug in this example hyaluronic acid microneedle patch loaded according to a mass ratio of 1:10:
5mg of sparfloxacin, 50mg of manganese-based nano-drug and 270mg of hyaluronic acid are weighed and added into 10mL of deionized water, and the mixture is stirred for 24 hours in a dark place, so as to obtain a pale yellow uniform gelatinous mixture. Dripping a mixture containing 100 mug of sparfloxacin and manganese-based nano-drug on a microneedle mould by using a suction pipe, then carrying out vacuumizing treatment together with the mould until air is completely extracted, filling gel under-ground into micropores of a needle body of the microneedle mould, removing redundant parts outside the micropores, and drying at 40 ℃ for 1h; then 1g/mL of hyaluronic acid solution is added above the mold, then the mold is placed in an oven at 40 ℃ to be dried overnight in a dark place, and the mold is removed from the mold, so that the microneedle patch is obtained.
Example 7
This example tested the therapeutic effect of the micro-scale prepared in examples 1-6 on mouse breast cancer cells (4T 1) as follows:
and (3) resuscitating the 4T1 cells, culturing until the 4T1 cells are full of the cell bottle and are in a logarithmic phase, adding the control group and experimental group materials into the culture overnight, incubating for 24 hours, and performing cell viability test detection.
Fig. 4 is the effect of the variation in concentration of the selected microneedles of example 3 (a in fig. 4), example 2 (b in fig. 4) and example 4 (c in fig. 4) in the cell system with the functional components (sparfloxacin in example 3, manganese-based nanomaterials in example 2, and total sparfloxacin and manganese-based nanomaterials in example 4) on 4T1 cell viability. FIG. 5 is the effect of the micro-scale of example 1 (control) and examples 4, 5, 6 on 4T1 cell viability.
In fig. 4, it can be analyzed that the experimental group microneedles (1:2 group) exhibited a certain effect of inhibiting the tumor cell viability compared to the control group without the sapafloxacin or manganese-based nano-drug. And as shown in fig. 5, in the microneedles of the experimental groups of different proportions, 1: the group 5 shows the best inhibition, which shows that different ratios of sparfloxacin and manganese-based nano-drugs have different effects, and also shows that sparfloxacin and manganese-based nano-drugs have mutual synergistic effect.
Example 8
The micro-negative breast cancer model treatment effect prepared in examples 1-3 and 5 was tested according to the following steps:
mice were randomly grouped: control microneedle groups, experimental groups with test microneedles were selected, 5 mice per group. The molding method is to inject 4T1 into the fourth pair of breast subcutaneous breast parts to construct a 4T1 in-situ tumor implantation model. The treatment method is that when the tumor volume is about 100mm 3 At this time, microneedle patches were attached to tumor sites of mice and treated in each group, once every other day.
Control group: the pure hyaluronic acid microneedles of example 1 were administered to the molded mice.
Manganese-based nano-drug group: the microneedle of example 2 containing only manganese-based nanomaterials was administered to a molded mouse.
Sparfloxacin group: the microneedle of example 3 containing only sapafloxacin was administered to the model mice.
1: group 5: the manganese-based nanomaterials of example 5 were administered to model mice at a mass ratio to sapafloxacin of 1: 5.
The tumor volume size of the mice was measured daily, calculated according to the calculation formula of volume=length×width/2 and recorded. Until the end of 14 days, the mice are sacrificed and the tumors and lung tissues are taken out, the treatment effect and the number of the metastasis nodes of the tumors and the lung metastasis tissues are monitored, and the killing effect of the micro-needles loaded with sparfloxacin and manganese-based nano-drugs on the tumors in the animal bodies is verified.
Fig. 6 is a tumor map of each treatment group dissected and removed in example 8, illustrating that the microneedles prepared based on the manganese-based nano-drug and sparfloxacin have a certain anti-tumor capability due to the interaction between the manganese-based nano-drug and sparfloxacin.
Fig. 7 is a comparison of the number of nodules in the dissected lung map of each treatment group of example 8, demonstrating that microneedles prepared based on manganese-based nanomaterials and sparfloxacin have some anti-metastatic capacity due to the interaction between the manganese-based nanomaterials and sparfloxacin.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (9)
1. The microneedle patch carrying sparfloxacin and manganese-based nano-drugs is characterized in that: the microneedle patch comprises a back weighting layer and a needle array arranged on the back weighting layer; the back-weighting layer is formed by polymer solution, and the needle array is formed by hyaluronic acid added with sparfloxacin and manganese-based nano-drugs.
2. The sparfloxacin and manganese-based nano-drug loaded microneedle patch according to claim 1, wherein: the mass ratio of sparfloxacin to manganese-based nano-drug is 1:2-10, and the mass ratio of sparfloxacin to hyaluronic acid is 1:100.
3. The microneedle patch carrying sparfloxacin and a manganese-based nano-drug according to claim 1, wherein the preparation method of the manganese-based nano-drug is as follows:
adding zinc salt and sodium oleate into a mixed solution composed of ethanol, deionized water and cyclohexane, carrying out reflux reaction for 4 hours at 70 ℃, and taking supernatant to obtain zinc salt oleic acid compound; adding manganese salt and sodium oleate into a mixed solution composed of ethanol, deionized water and cyclohexane, carrying out reflux reaction for 4 hours at 70 ℃, and taking supernatant to obtain a manganese salt oleic acid compound;
mixing zinc salt oleic acid compound and manganese salt oleic acid compound, adding sublimed sulfur and octadecene, heating to 300 ℃, preserving heat for 1h, cooling to 60 ℃, taking out the product, and centrifugally washing with a mixed solution of cyclohexane and ethanol to obtain the manganese-based nano-drug.
4. A microneedle patch carrying sparfloxacin and manganese-based nano-drugs according to claim 3, wherein: the zinc salt is at least one of zinc chloride, zinc nitrate and zinc sulfate, and the manganese salt is at least one of manganese chloride, manganese nitrate and manganese sulfate.
5. A microneedle patch carrying sparfloxacin and manganese-based nano-drugs according to claim 3, wherein: in preparing the zinc salt oleic acid compound, the molar ratio of zinc salt to sodium oleate is 1:2; in preparing the manganese salt oleic acid compound, the molar ratio of manganese salt to sodium oleate is 1:2; the molar ratio of the zinc salt to the sublimed sulfur is 1:2; the volume ratio of the total volume of the zinc salt oleic acid compound and the manganese salt oleic acid compound to the volume of the octadecene is 1:4.
6. a microneedle patch carrying sparfloxacin and manganese-based nano-drugs according to claim 3, wherein: in the mixed solution, the volume ratio of ethanol, deionized water and cyclohexane is 6:7:8.
7. the sparfloxacin and manganese-based nano-drug loaded microneedle patch according to claim 1, wherein: the polymer solution is at least one of polyvinylpyrrolidone, hyaluronic acid and polyvinyl alcohol, and the concentration is 1-2 g/mL.
8. The sparfloxacin and manganese-based nano-drug loaded microneedle patch according to claim 1, wherein: each microneedle head in the needle body array is conical with the height of 400-1000 mu m and the bottom diameter of 150-400 mu m.
9. Use of a microneedle patch carrying sparfloxacin and manganese-based nano-drugs according to any one of claims 1 to 8 for the preparation of a medicament for transdermal administration for the treatment of in situ triple negative breast cancer and for inhibiting metastasis.
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