CN117379362A - Angiopoietin-like protein 3 loaded hydrogel and preparation method and application thereof - Google Patents
Angiopoietin-like protein 3 loaded hydrogel and preparation method and application thereof Download PDFInfo
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- CN117379362A CN117379362A CN202311309279.7A CN202311309279A CN117379362A CN 117379362 A CN117379362 A CN 117379362A CN 202311309279 A CN202311309279 A CN 202311309279A CN 117379362 A CN117379362 A CN 117379362A
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- angiopoietin
- protein
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- polyethylene glycol
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Classifications
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- Immunology (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides a hydrogel loaded with angiopoietin-like protein 3, which is prepared from a polymer, a solution and the angiopoietin-like protein 3. The invention also provides a preparation method of the hydrogel, a medical dressing, an injection medicament and application of the hydrogel in preparation of the injection medicament or the medical dressing. The hydrogel can be injected, rapidly gel on a wound surface after injection, and can be released stably, so that local delivery and simultaneous release according to needs can be realized. In the preparation method of the hydrogel, the components can react at normal temperature, and the reaction process is not exothermic and is free from toxic component release, so that the hydrogel is suitable for wound healing of different wound surfaces. Solves the problems that the existing medicine containing angiopoietin-like protein 3 can not be injected, can not reach the wound because of insufficient blood supply of the wound surface, can not realize local delivery and simultaneous release according to the needs, and can not be suitable for wound healing of different wound surfaces.
Description
Technical Field
The invention belongs to the technical field of biomedical material engineering, and particularly relates to an angiopoietin-like protein 3 loaded hydrogel and a preparation method and application thereof.
Background
Diabetic foot ulcers are one of the main causes of disability and mortality for diabetics, with an average prevalence of 6.4%, and on a global scale, 1 diabetic patient is amputated every 30 seconds. While the traditional surgical operation method for the ischemia of the lower limbs of the diabetic foot can directly open the blocked blood vessel and can quickly improve the ischemia condition, the traditional surgical operation method has poor effect on the multiple below knee lesions of the diabetic foot, has high restenosis rate, and is often not suitable for the old and the weak patients with the high diabetes, such as operation bypass, vascular intervention treatment and the like. The traditional medicine treatment method improves the collateral circulation of the lower limb ischemia part through the vasodilation effect of the medicine, but because the wound surface is large, the local part is in a high-sugar environment, the infection and the thrombosis are easy to occur, and how to administer the medicine can maintain the local effective medicine concentration and the medicine effect becomes the clinical problem which needs to be solved urgently. With the development of a local drug slow release technology, if the drug is loaded on a degradable polymer biological material and then coated on a wound surface, a stable drug controlled release system can be formed on the local part of the wound surface, so that the stable and controllable release of the drug is ensured, and the treatment effect is achieved; meanwhile, the carrier does not remain along with degradation of biological materials, and has safety. Therefore, the slow-release and controllable drug release system taking the polymer biological material as the carrier for carrying the drug is a great direction of the sugar foot treatment.
Angiopoietin-like protein 3 (ANGPTL 3) belongs to a family of angiopoietin-like proteins, expressed primarily in the liver, produced by hepatocytes and secreted into the blood. The research shows that the ANGPTL3 can activate FAK, MAPK and Akt signal transduction paths through combining with endothelial cell surface integrin alpha v beta 3, promote endothelial cell adhesion, migration and the like so as to induce angiogenesis; ANGPTL3 may also inhibit lipoprotein esterases and regulate triglyceride metabolism. Thus, medicaments containing angiopoietin-like protein 3 can be used to treat diabetic foot ulcers.
However, the existing angiopoietin-like protein 3-loaded drugs are generally oral drugs, cannot be injected, and can hardly reach wounds due to insufficient blood supply of the wound surface. Existing angiopoietin-like protein 3 loaded drugs are difficult to achieve local delivery and simultaneous release on demand. Moreover, the existing medicines have the problems of poor biocompatibility and the like, and cannot be suitable for wound healing of different wound surfaces.
Disclosure of Invention
In view of the above technical problems, the present invention provides a hydrogel loaded with angiopoietin-like protein 3, and a preparation method and application thereof, so as to solve or at least alleviate at least one technical problem existing in the preparation process of the solar cell electrode.
According to a first aspect of the present invention there is provided an angiopoietin-like protein 3 loaded hydrogel formulated from a polymer, a solution and angiopoietin-like protein 3.
Optionally, the mass percentage of the angiopoietin-like protein 3 in the angiopoietin-like protein 3 loaded hydrogel is 0.0001% -0.001%.
Optionally, the mass percentage of the angiopoietin-like protein 3 in the angiopoietin-like protein 3 loaded hydrogel is 0.0001% -0.0005%.
Optionally, the mass percentage of the angiopoietin-like protein 3 in the angiopoietin-like protein 3 loaded hydrogel is 0.0001%.
Optionally, the polymer comprises one of a polyethylene glycol hydrogel system or a modified polyethylene glycol hydrogel system.
Alternatively, the polymer includes amino polyethylene glycol, active ester polyethylene glycol, and aldehyde polyethylene glycol.
Optionally, the mass part ratio of the amino polyethylene glycol to the active ester polyethylene glycol to the aldehyde polyethylene glycol is (7-8): 2-3): 5-6.
Optionally, the solution comprises at least one of polybutylene succinate (PBS) buffer and physiological saline.
In a second aspect, the present invention provides a method for preparing an angiopoietin-like protein 3 loaded hydrogel, comprising the steps of:
dissolving aminopolyethylene glycol in the first solution to form a first component;
dissolving aldehyde polyethylene glycol and active ester polyethylene glycol in a second solution to form a second component;
mixing angiopoietin-like protein 3 and the first component to form a mixture;
mixing said mixture with said second component to obtain said angiopoietin-like protein 3 loaded hydrogel.
Optionally, the first solution comprises at least one of (PBS) buffer and physiological saline.
Optionally, the second solution comprises at least one of (PBS) buffer and physiological saline.
Optionally, the mass ratio of the aminopolyethylene glycol to the first solution in the raw materials for preparing the first component is 1 (5-6); in the raw materials for preparing the second component, the mass ratio of the aldehyde polyethylene glycol to the active ester polyethylene glycol to the second solution is 1 (2-3) (18-20).
In a third aspect, the present invention provides a medical dressing comprising an angiopoietin-like protein 3 loaded hydrogel as defined in any preceding claim and an angiopoietin-like protein 3 loaded hydrogel obtainable by a method of preparation as defined in any preceding claim.
In a fourth aspect, the invention provides an injectable medicament comprising an angiopoietin-like protein 3 loaded hydrogel as defined in any preceding claim and an angiopoietin-like protein 3 loaded hydrogel obtainable by a method as defined in any preceding claim.
In a fifth aspect, the present invention provides the use of an angiopoietin-like protein 3 loaded hydrogel as defined in any preceding claim, and an angiopoietin-like protein 3 loaded hydrogel obtainable by a method of preparation as defined in any preceding claim, in the preparation of a medicament or medical dressing for injection.
Compared with the prior art, the scheme provided by the embodiment of the invention has at least the following beneficial effects:
(1) The angiopoietin-like protein 3 loaded hydrogel can be used by injection, can be rapidly glued on a wound surface after injection and is released stably, and the technical problem that the existing oral medicine is difficult to reach the wound due to insufficient blood supply of the wound surface is solved; furthermore, the angiopoietin-like protein 3-loaded medicament of the invention can realize local delivery and simultaneous release as required.
(2) In the preparation method of the angiopoietin-like protein 3 loaded hydrogel, PEG-CHO, PEG-NHS and PEG-NH2 are used as components, and the PEG-CHO, the PEG-NHS and the PEG-NH2 can rapidly react at normal temperature, and no heat is released and no toxic components are released in the reaction process; the obtained high molecular polymer has good biocompatibility and is suitable for wound healing of different wound surfaces.
(3) By injecting the ANGPTL3 hydrogel in the invention into wounds, the healing of diabetic wounds can be promoted, the healing effect is better than that of the single hydrogel, and a new thought is provided for the treatment of diabetic group ulcers.
The preparation method of the invention has simple operation, the needed raw materials are easy to obtain, and the preparation method is expected to be widely applied in the field of biomedical engineering materials.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments of the present invention will be briefly described below, and it is obvious that the drawings described below are only some embodiments of the present invention, and other drawings may be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing the effect of the angiopoietin-like protein 3-loaded hydrogel of example 1 of the present invention on the cytotoxicity test of effect example 1;
FIG. 2 is a graph showing the effect of the angiopoietin-like protein 3-loaded hydrogel of example 1 according to the invention on the release test of the cytotoxicity test of effect example 2;
FIG. 3 is a graph showing the effect of the angiopoietin-like protein 3-loaded hydrogel of example 1 of the present invention on the in vitro degradation test of effect example 3;
FIG. 4 is a graph showing the effect of the angiopoietin-like protein 3-loaded hydrogel of example 1 of the present invention on the test for promoting healing of diabetic wounds of effect example 4.
Detailed Description
The following describes the technical scheme of the embodiment of the present invention in detail with reference to the drawings.
The following examples are only for more clearly illustrating the technical aspects of the present invention, and thus are merely examples, and are not intended to limit the scope of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In the description of the invention, the terms "comprising" and "having," along with any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, system, article, or apparatus that comprises a list of steps or elements is not limited to only those listed steps or elements but may include other steps or elements not listed or inherent to such process, method, article, or apparatus.
Reference in the specification to "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment may be included in at least one embodiment of the invention. The appearances of such phrases in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments. Those of skill in the art will explicitly and implicitly appreciate that the described embodiments of the invention may be combined with other embodiments.
In the description of the embodiment of the present invention, the symbol "-" means all data including data of two endpoints before and after "-" and all data between the two endpoints, for example, a-B, means all data of a or more and B or less.
The embodiment of the invention provides a hydrogel loaded with angiopoietin-like protein 3, which is prepared from a polymer, a solution and the angiopoietin-like protein 3.
The polymer preferably, but not limited to, comprises one of a polyethylene glycol hydrogel system or a modified polyethylene glycol hydrogel system. More preferably, the polymer comprises aminopolyethylene glycol (PEG-NH 2 ) Active ester polyethylene glycol (PEG-NHS) and aldehyde polyethylene glycol (PEG-CHO). The PEG-NH 2 The mass fraction ratio of the PEG-NHS and the PEG-CHO can be selected according to actual needs, and preferably, the PEG-NH 2 The mass ratio of PEG-NHS to PEG-CHO is (7-8) (2-3) (5-6), the hydrogel loaded with angiopoietin-like protein 3 in the ratio can be injected subcutaneously by a double-gun syringe to rapidly gel, and can be degraded in about 14 days and completely in about 26 days. In this embodiment, the PEG-NH 2 The mass fraction ratio of PEG-NHS to PEG-CHO is 7.48:2.24:5.23.
The solution is used for dissolving the polymer and can be selected according to actual needs. The solution is preferably, but not limited to, polybutylene succinate (PBS) buffer, physiological saline, etc. More preferably, the solution is a PBS buffer. The mass fraction of the solution is preferably, but not limited to, 83-86.
The mass percent of the angiopoietin-like protein 3 in the angiopoietin-like protein 3 loaded hydrogelThe ratio is 0.0001 to 0.001 percent, and the regeneration of blood vessels at ulcer wounds can be better promoted under the condition of the mass concentration range. Preferably, the mass percentage of the angiopoietin-like protein 3 in the angiopoietin-like protein 3 loaded hydrogel is 0.0001% -0.0005%. More preferably, the mass percentage of the angiopoietin-like protein 3 in the angiopoietin-like protein 3 loaded hydrogel is 0.0001%. In this example, the total mass of the angiopoietin-like protein 3-loaded hydrogel was 0.5g, and the PEG-NH contained in the angiopoietin-like protein 3-loaded hydrogel 2 The mass ratio of PEG-NHS to PEG-CHO is (7-8) (2-3) (5-6), the hydrogel with the proportion is loaded with 500ng of ANGPTL3, and the rest is PBS buffer solution, so that the hydrogel of the embodiment can better promote the regeneration of blood vessels at ulcer wounds.
The invention also provides a preparation method of the angiopoietin-like protein 3 loaded hydrogel, which comprises the following steps:
dissolving aminopolyethylene glycol in the first solution to form a first component;
dissolving aldehyde polyethylene glycol and active ester polyethylene glycol in a second solution to form a second component;
mixing angiopoietin-like protein 3 and the first component to form a mixture;
mixing said mixture with said second component to obtain said angiopoietin-like protein 3 loaded hydrogel.
The first solution and the second solution may be the same or different. Preferably, the first solution and the second solution are the same. The solution is preferably, but not limited to, polybutylene succinate (PBS) buffer, physiological saline, etc. More preferably, the solution is a PBS buffer.
The mass ratio of the aminopolyethylene glycol to the first solution in the raw material for preparing the first component is preferably but not limited to 1 (5-6); the mass ratio of the aldehyde polyethylene glycol, the active ester polyethylene glycol and the second solution in the raw materials for preparing the second component is preferably but not limited to 1 (2-3): 18-20.
Preferably, angiopoietin-like protein 3 and the first component are mixed uniformly to form a mixture; and then uniformly mixing the mixture with the second component to obtain the angiopoietin-like protein 3 loaded hydrogel.
The technical scheme and technical effect of the embodiments of the present invention will be described in detail below with reference to specific examples and effect examples.
Example 1:
the present example provides a method for preparing an angiopoietin-like protein 3 loaded hydrogel comprising the steps of:
dissolving 0.0375g of aminopolyethylene glycol in 213 μlpbs buffer to form a first component;
dissolving 0.01125g of aldehyde polyethylene glycol and 0.02625g of active ester polyethylene glycol in 213 mu LPBS buffer to form a second component;
mixing 500ng of angiopoietin-like protein 3 and the first component to form a mixture;
mixing the mixture with the second component to obtain the angiopoietin-like protein 3 loaded hydrogel.
ANGPTL 3-loaded hydrogels of the following effect examples 1 to 4 were each the angiopoietin-like protein 3-loaded hydrogel obtained in example 1.
Effect example 1: cytotoxicity test
Evaluation of toxicity test of ANGPTL 3-loaded hydrogels prepared according to the present invention on mouse fibroblasts (3T 3) using the method of detecting cell activity by CCK-8 test. The specific operation steps are as follows: first, 3T3 cells were seeded at a density of 2000 cells/well in 96-well plates and placed in a carbon dioxide incubator for culture attachment overnight. Subsequently, the original medium was aspirated and replaced with fresh complete medium containing ANGPTL3 loaded hydrogel extract at different concentrations, using ANGPTL3 loaded hydrogels ranging from 0 to 10mg/mL, with 6 samples per concentration. After incubation in an incubator for 24h, the cells were washed once with PBS and 100. Mu.L of fresh medium (containing 10% CCK-8 reagent) was added. The cells were incubated in an incubator for 1h, absorbance at a wavelength of 450nm was detected using a microplate reader, and cell viability was calculated by the following formula, cell viability (%) = (experimental group absorbance-blank group absorbance)/(negative control group absorbance-blank group absorbance) ×100%.
The test results are shown in FIG. 1: the hydrogel loaded with ANGPTL3 has higher cell survival rate under various concentration conditions, does not generate toxicity to 3T3 cells, and has higher cell survival rate than 0 and 1mg/mL groups when the concentration is 10mg/mL, and p is less than 0.0001. The ANGPTL 3-loaded hydrogel has excellent biocompatibility and can be used as a safe gel carrier.
Effect example 2: release test of ANGPTL3 loaded hydrogels
0.5g of the ANGPTL 3-loaded hydrogel sample is placed in a 50mL centrifuge tube, 5.0mL of PBS buffer without calcium ions and magnesium ions is added as a release medium, and the centrifuge tube is placed in a refrigerator at 4 ℃ for oscillation to perform an in vitro release experiment. The oscillation rate was 120r/min. All supernatants were removed at 0.5, 1, 3, 5, 7, 10, 14 days, and supernatant volumes were recorded and fresh 5.0ml pbs buffer was added. All samples were run in parallel 3 times. The content of ANGPTL3 in the supernatant was detected with an Elisa kit, and an in vitro release profile of ANGPTL3 was calculated.
The results of the experiment are shown in figure 2, and the ANGPTL3 loaded hydrogel system was able to maintain sustained release of ANGPTL3 in a 14 day release study. The invention shows that the ANGPTL 3-loaded hydrogel has a better slow release effect.
Effect example 3: in vitro degradation test of ANGPTL3 loaded hydrogels
0.5g of the hydrogel sample loaded with ANGPTL3 is placed in a 50mL centrifuge tube, 5.0mL of PBS buffer without calcium ions and magnesium ions is added as a release medium, and the centrifuge tube is placed in a refrigerator at 4 ℃ for oscillation to carry out in-vitro degradation experiments. The oscillation rate was 120r/min. All supernatants were removed at 0.5, 1, 3, 5, 7, 10, 14 days, the hydrogels were carefully removed, and after fixed height photographing on a background plate, fresh 5.0ml pbs buffer was added.
The test results are shown in fig. 3, and ANGPTL3 loaded hydrogels gradually degrade over 14 days, and have failed to retain a complete shape at day 14.
Effect example 4: ANGPTL3 loaded hydrogels to promote healing assays of diabetic wounds
8-week-old C57BL6J male mice are selected, 1% streptozotocin is injected into the abdominal cavity (80 mg/kg, 3 times of continuous injection) to establish a diabetic mouse model, and random blood sugar is greater than 16.7 mmol/L to enter a selected experimental group. After the blood sugar is qualified, dividing animals of an experimental group into a blank hydrogel group, carrying out an ANGPTL 3-loaded hydrogel group, after each group is anesthetized by isoflurane, preparing skin on the back of a mouse by using dehairing paste, cutting off the whole skin with a fixed area and the diameter of about 1cm on the back by using a skin tissue sampling device, taking the skin tissue sampling device as 0 day (D0), injecting hydrogel on the skin around a wound by using a double-gun injector the next day, injecting an equal dose PBS (phosphate buffer solution) into a model group, taking a photo by using a digital camera to record the healing condition of the wound, taking tissue around the wound on the 15 th day (D15), carrying out an immunohistochemical test of HE staining, and detecting corresponding indexes.
As shown in fig. 4, the wound healing effect of the ANGPTL 3-loaded hydrogel group animals was better than that of the blank hydrogel group, and HE staining results showed that the thickness of the new granulation tissue of the ANGPTL 3-loaded hydrogel group and the blank hydrogel group was thicker than that of the model group, and the epidermis structure was continuous and complete, and Xu Xinsheng hair follicles could be observed in the wound center. For the model group, it was seen that the epidermis structure was incomplete, the granulation tissue thickness was thin, no new hair follicle was observed at the center of the wound, and inflammatory cell infiltration was seen around the wound. Vascular endothelial cells were labeled with CD31, a-SMA immunohistochemistry, as indicated by the arrow, and the results showed that both ANGPTL3 loaded hydrogel groups and blank hydrogel groups were seen to have more small vessel hyperplasia. The ANGPTL3 loaded hydrogel group showed significantly increased VEGF positive expression compared to the model group. Taken together, the results demonstrate that ANGPTL3 loaded hydrogels can promote healing of diabetic wounds.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention, and are intended to be included within the scope of the appended claims and description. In particular, the technical features mentioned in the respective embodiments may be combined in any manner as long as there is no structural conflict. The invention is not limited to the specific embodiments of the invention herein, but encompasses all technical solutions falling within the scope of the claims.
Claims (12)
1. A hydrogel loaded with angiopoietin-like protein 3, wherein the hydrogel is formulated from a polymer, a solution, and angiopoietin-like protein 3.
2. The angiopoietin-like protein 3 loaded hydrogel of claim 1, wherein the mass percent of angiopoietin-like protein 3 in the angiopoietin-like protein 3 loaded hydrogel is 0.0001% to 0.001%.
3. The angiopoietin-like protein 3 loaded hydrogel of claim 1, wherein the polymer comprises one of a polyethylene glycol hydrogel system or a modified polyethylene glycol hydrogel system.
4. The angiopoietin-like protein 3 loaded hydrogel of claim 3, wherein said polymer comprises an amino polyethylene glycol, an active ester polyethylene glycol, and an aldehyde polyethylene glycol.
5. The angiopoietin-like protein 3 loaded hydrogel of claim 4, wherein the mass ratio of amino polyethylene glycol, active ester polyethylene glycol, and aldehyde polyethylene glycol is (7-8): 2-3): 5-6.
6. The angiopoietin-like protein 3 loaded hydrogel of any one of claims 1-5, wherein the solution comprises at least one of polybutylene succinate (PBS) buffer and physiological saline.
7. A method for preparing an angiopoietin-like protein 3 loaded hydrogel, comprising the steps of:
dissolving aminopolyethylene glycol in the first solution to form a first component;
dissolving aldehyde polyethylene glycol and active ester polyethylene glycol in a second solution to form a second component;
mixing angiopoietin-like protein 3 and the first component to form a mixture;
mixing said mixture with said second component to obtain said angiopoietin-like protein 3 loaded hydrogel.
8. The method of claim 7, wherein the first solution and/or the second solution comprises at least one of a (PBS) buffer and physiological saline.
9. The method for producing an angiopoietin-like protein 3 loaded hydrogel according to claim 7, wherein the mass ratio of said aminopolyethylene glycol to the first solution in the raw material for producing said first component is 1 (5-6); in the raw materials for preparing the second component, the mass ratio of the aldehyde polyethylene glycol to the active ester polyethylene glycol to the second solution is 1 (2-3) (18-20).
10. A medical dressing comprising the angiopoietin-like protein 3-loaded hydrogel of any one of claims 1 to 6 and the angiopoietin-like protein 3-loaded hydrogel obtained by the method of any one of claims 7 to 9.
11. An injectable pharmaceutical agent comprising the angiopoietin-like protein 3-loaded hydrogel according to any one of claims 1 to 6 and the angiopoietin-like protein 3-loaded hydrogel obtained by the method according to any one of claims 7 to 9.
12. Use of the angiopoietin-like protein 3 loaded hydrogel of any one of claims 1-6 in the preparation of an injectable medicament or medical dressing, the angiopoietin-like protein 3 loaded hydrogel obtained by the method of any one of claims 7-9.
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