CN117338928A - Magnesium alloy and preparation method and application thereof - Google Patents
Magnesium alloy and preparation method and application thereof Download PDFInfo
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- CN117338928A CN117338928A CN202311414917.1A CN202311414917A CN117338928A CN 117338928 A CN117338928 A CN 117338928A CN 202311414917 A CN202311414917 A CN 202311414917A CN 117338928 A CN117338928 A CN 117338928A
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- magnesium alloy
- peroxide coating
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- 229910000861 Mg alloy Inorganic materials 0.000 title claims abstract description 127
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000576 coating method Methods 0.000 claims abstract description 68
- 239000011248 coating agent Substances 0.000 claims abstract description 67
- 150000002978 peroxides Chemical class 0.000 claims abstract description 36
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 31
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 30
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 30
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 27
- 239000002840 nitric oxide donor Substances 0.000 claims abstract description 23
- 238000011065 in-situ storage Methods 0.000 claims abstract description 13
- 235000018102 proteins Nutrition 0.000 claims description 28
- 239000007853 buffer solution Substances 0.000 claims description 20
- SPAGIJMPHSUYSE-UHFFFAOYSA-N Magnesium peroxide Chemical compound [Mg+2].[O-][O-] SPAGIJMPHSUYSE-UHFFFAOYSA-N 0.000 claims description 15
- 229960004995 magnesium peroxide Drugs 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 15
- 239000007943 implant Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 11
- DLINORNFHVEIFE-UHFFFAOYSA-N hydrogen peroxide;zinc Chemical compound [Zn].OO DLINORNFHVEIFE-UHFFFAOYSA-N 0.000 claims description 10
- 229920000724 poly(L-arginine) polymer Polymers 0.000 claims description 10
- 229940105296 zinc peroxide Drugs 0.000 claims description 10
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 9
- 229940098773 bovine serum albumin Drugs 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 239000004343 Calcium peroxide Substances 0.000 claims description 6
- LHJQIRIGXXHNLA-UHFFFAOYSA-N calcium peroxide Chemical compound [Ca+2].[O-][O-] LHJQIRIGXXHNLA-UHFFFAOYSA-N 0.000 claims description 6
- 235000019402 calcium peroxide Nutrition 0.000 claims description 6
- 238000000151 deposition Methods 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- UHCGLDSRFKGERO-UHFFFAOYSA-N strontium peroxide Chemical compound [Sr+2].[O-][O-] UHCGLDSRFKGERO-UHFFFAOYSA-N 0.000 claims description 6
- 230000012010 growth Effects 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- KWTQSFXGGICVPE-UHFFFAOYSA-N 2-amino-5-(diaminomethylideneamino)pentanoic acid;hydron;chloride Chemical compound Cl.OC(=O)C(N)CCCN=C(N)N KWTQSFXGGICVPE-UHFFFAOYSA-N 0.000 claims description 4
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- 102000008100 Human Serum Albumin Human genes 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 3
- 229930064664 L-arginine Natural products 0.000 claims description 3
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- 239000011777 magnesium Substances 0.000 claims description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 5
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 239000001301 oxygen Substances 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract description 5
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- 101710185544 Maltose-binding periplasmic protein Proteins 0.000 description 17
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- 239000007789 gas Substances 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 230000002980 postoperative effect Effects 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 206010052428 Wound Diseases 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 4
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- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 2
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- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
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- 239000004246 zinc acetate Substances 0.000 description 2
- 239000011787 zinc oxide Substances 0.000 description 2
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 125000002059 L-arginyl group Chemical class O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
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- 238000003384 imaging method Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/40—Peroxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- 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
- A61K9/0012—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
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides a magnesium alloy, a preparation method and application thereof, wherein the magnesium alloy comprises a magnesium alloy body and a peroxide coating coated on the surface of the magnesium alloy body; the surface of the peroxide coating is adsorbed with a protein carrier, and the surface of the protein carrier is loaded with an NO donor. The magnesium alloy body can generate hydrogen in situ in the tumor acidic microenvironment, and can down regulate the expression of tumor cell heat shock proteins, so that tumor cells are sensitive to temperature, and the tumor cells are killed under a low-intensity alternating magnetic field. Meanwhile, the peroxide coating can excite the NO donor to release NO in the tumor acidic microenvironment, and the magnesium alloy body can promote the inside of cancer cells to generate thermoactive oxygen substances which further generate active nitrogen substances with stronger toxicity with the NO, so that the tumor cells are further killed.
Description
Technical Field
The invention belongs to the technical field of magnesium alloy preparation, and particularly relates to a magnesium alloy and a preparation method and application thereof.
Background
Currently, surgical resection remains the primary means of clinical treatment of tumors. However, the margins of many invasive tumors are difficult to distinguish intraoperatively, and the residual tumor tissue after surgery can lead to a significant risk of postoperative recurrence. Currently, post-operative radiotherapy and chemotherapy remain the main methods of clinically eliminating residual tumor tissue, but the therapeutic effect is still not ideal due to its higher systemic toxicity and lower sensitivity.
Currently, among many treatment methods for preventing postoperative tumor recurrence, magnetocaloric therapy is a method for eliminating tumor by using heat generated by magnetic nanoparticles under the action of alternating magnetic field, and is attracting attention due to the advantages of non-invasiveness, safety, unrestricted penetration depth, and the like. As CN 114949266A discloses a breast cancer responsive multimode imaging diagnosis and treatment integrated magnetic nano-probe, which has the characteristics of magnetocaloric temperature rise and controllable drug carrying release; CN 115317606B discloses a magnetic nano-droplet for increasing the penetrability of solid tumor and having the efficacy of magnetocaloric sensitization immunotherapy, which has a certain penetrability of solid tumor and the property of magnetocaloric induction of thermal ablation of tumor cells. However, the magnetic nanoparticles as magnetocaloric agents inevitably accumulate in normal tissues while passing through the systemic blood circulation, resulting in thermal damage to the normal tissues. In addition, high temperatures promote the expression of heat shock proteins by tumor cells, which repair damaged proteins in cancer cells, rendering the tumor cells insensitive to high temperatures, and therefore, it is generally necessary to apply higher temperatures to thermally damage the tumor cells.
Magnesium alloys are expected to be a potential magnetocaloric therapeutic agent due to their inherent eddy current thermal properties and good degradation properties. The use of implantable metals as accurate and efficient magnetocaloric therapeutic agents for tumors is disclosed, for example, in CN111449830a, which suggests that implantable metals can be used in alternating magnetic fieldsThe heat energy generated by the eddy current heat effect realizes the magnetocaloric treatment of tumor, wherein the applied alternating magnetic field intensity is 0.1-10 multiplied by 10 9 A·m -1 ·s -1 . CN116254445a discloses that Mg-Al-Ca ternary magnesium alloys can be used as anti-tumor implant materials or as magnetic hyperthermia media. However, if the metal implant is simply applied to the postoperative wound, the high temperature generated by the metal implant such as magnesium alloy under the alternating magnetic field and capable of achieving the therapeutic effect of killing tumor cells can further cause the thermal damage to normal tissues with larger surrounding areas, so that certain side effects are brought to prevent the postoperative recovery of patients. Therefore, there is an urgent need to explore a method for safely and effectively eliminating residual tumor tissues after operation and continuously inhibiting in-situ recurrence of tumor tissues after operation under the action of a low-intensity alternating magnetic field.
Disclosure of Invention
In view of the above, the present invention aims to provide a magnesium alloy, and a preparation method and application thereof. The magnesium alloy can be subjected to low-strength alternating magnetic field (0.1X10) 8 ～0.9×10 8 A·m -1 ·s -1 ) The tumor cells are killed by thermal therapy at a milder temperature, thereby further protecting surrounding normal tissues.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a magnesium alloy, comprising a magnesium alloy body and a peroxide coating coated on the surface of the magnesium alloy body;
the surface of the peroxide coating is adsorbed with a protein carrier, and the surface of the protein carrier is loaded with an NO donor.
Preferably, the peroxide coating comprises any one or more of a magnesium peroxide coating, a zinc peroxide coating, a calcium peroxide coating, or a strontium peroxide coating.
Preferably, the proteinaceous carrier is selected from any one or more of bovine serum albumin, human serum albumin, rabbit serum albumin or egg white albumin.
Preferably, the NO donor is selected from any one or more of poly L-arginine hydrochloride, poly L-arginine or L-arginine.
Preferably, the magnesium alloy comprises Mg and any one or more of Zn, ca, Y, nd, gd, gd, sm or Zr.
In a second aspect, the present invention provides a method for preparing the magnesium alloy, comprising the following steps:
mixing and reacting the magnesium alloy body coated with the peroxide coating on the surface with a buffer solution of a protein carrier, and mixing and reacting the obtained product with the buffer solution of an NO donor to obtain the magnesium alloy.
Preferably, the buffer solution of the protein-based carrier and the buffer solution of the NO donor are neutral in acid-base.
Preferably, the magnesium alloy body with the peroxide coating coated on the surface is prepared by an in-situ growth method or a surface deposition method.
In a third aspect, the present invention provides a metal implant for inhibiting tumor growth or inhibiting local recurrence of a tumor, comprising the magnesium alloy described above.
Preferably, the metal implant (i.e. magnesium alloy) is placed in a tumor cell wound after operation, and alternating magnetic field stimulation is applied to obtain the implant.
Preferably, the alternating magnetic field has a strength of 0.1X10 8 ～0.9×10 8 A·m -1 ·s -1 。
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a magnesium alloy which comprises a magnesium alloy body and a peroxide coating coated on the surface of the magnesium alloy body, wherein a protein carrier is adsorbed on the surface of the peroxide coating, and an NO donor is loaded on the surface of the protein carrier. The magnesium alloy body in the invention can generate hydrogen in situ in the tumor acidic microenvironment, down regulate the expression of tumor cell heat shock protein, make tumor cells sensitive to temperature, and make the tumor cells under low-intensity alternating magnetic field (0.1 multiplied by 10) 8 ～0.9×10 8 A·m -1 ·s -1 ) The tumor cells are killed by the thermotherapy at a milder temperature, so as to realize the milder magnetocaloric therapy and further protect the surroundingIs a normal tissue of (a). At the same time, the peroxide coating can decompose and generate H in the tumor acidic microenvironment 2 O 2 ，H 2 O 2 The NO donor can be stimulated to release NO gas molecules, and the mild magnetocaloric therapy can promote the generation of thermoactive oxygen substances inside cancer cells, so that the generated active oxygen substances can further generate active nitrogen substances with stronger toxicity with the released NO gas molecules, thereby further killing the tumor cells. Therefore, the magnesium alloy provided by the invention can realize the cooperative treatment of the moderate magnetocaloric therapy and the gas therapy, and further thoroughly remove the residual tumor cells.
It should be noted that the magnesium alloy provided by the invention can be implanted in situ in a tumor cell wound after operation, does not pass through blood circulation, can not be enriched in normal tissues, and the excitation source is an alternating magnetic field with lower intensity, so that the penetration depth is not limited, the treatment application range is wider, and the effect of the magnesium alloy on killing residual tumor tissues is greatly improved while the influence of magnetocaloric therapy on surrounding normal cells is reduced. In addition, the magnesium alloy is slowly degraded, can be used as an auxiliary treatment material after tumor surgical excision, and has great potential in continuously inhibiting local recurrence of tumor.
Drawings
FIG. 1 is a scanning electron microscope image of a surface-modified magnesium alloy prepared in example 1 of the present invention;
FIG. 2 is an X-ray diffraction chart of a surface-modified magnesium alloy prepared in example 1 of the present invention;
FIG. 3 is a thermogravimetric analysis spectrum of the surface modified magnesium alloy prepared in example 1 of the present invention;
FIG. 4 is a graph showing the effect of the surface-modified magnesium alloy prepared in example 1 of the present invention on killing tumor cells;
FIG. 5 is a scanning electron microscope image of a magnesium alloy coated with a zinc peroxide coating layer on the surface prepared in example 2 of the present invention;
FIG. 6 is an X-ray energy dispersive spectrum of a magnesium alloy coated with a zinc peroxide coating prepared in example 2 of the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. 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.
Aiming at the problems that in the prior art, a magnesium alloy is used as a magnetic therapy medium, and the high temperature generated under an alternating magnetic field and capable of achieving the therapeutic effect of killing tumor cells can further cause thermal damage to normal tissues with larger surrounding areas and prevent postoperative recovery of patients, the invention provides a magnesium alloy which comprises a magnesium alloy body and a peroxide coating coated on the surface of the magnesium alloy body, wherein a protein carrier is adsorbed on the surface of the peroxide coating, and an NO donor is loaded on the surface of the protein carrier.
The source of the magnesium alloy body is not particularly limited, and the magnesium alloy body can be a general commercial magnesium alloy body without toxic or harmful elements. The magnesium alloy body preferably includes Mg and any one or more of Zn, ca, Y, nd, gd, gd, sm or Zr. Generally, the content range of metallic Zn in the magnesium alloy body is: 0.1 to 80wt percent; the content range of Ca is as follows: 0.1 to 10wt percent; the content range of Y is as follows: 0.1 to 20wt percent; the content range of Nd is: 0.1 to 20wt percent; the content range of Gd is as follows: 0.1 to 20wt percent; the content range of Sm is as follows: 0.1 to 20wt percent; the Zr content range is as follows: 0.1 to 2 weight percent.
In the present invention, the peroxide coating preferably includes any one or more of a magnesium peroxide coating, a zinc peroxide coating, a calcium peroxide coating, or a strontium peroxide coating, more preferably a magnesium peroxide coating. In the present invention, the protein carrier is adsorbed on the surface of the peroxygen coating by coordination, and the NO donor is adsorbed on the surface of the protein carrier by electrostatic adsorption, for example, when the NO donor is selected from any one or more of poly-L-arginine hydrochloride, poly-L-arginine or L-arginine, the protein carrier may be selected from any one or more of bovine serum albumin, human serum albumin, rabbit serum albumin or egg serum albumin. In some embodiments of the invention, the NO donor is preferably poly-L-arginine hydrochloride and the proteinaceous carrier is preferably bovine serum albumin.
The magnesium alloy provided by the invention comprises a magnesium alloy body and a peroxide coating coated on the surface of the magnesium alloy body, wherein a protein carrier is adsorbed on the surface of the peroxide coating, and an NO donor is loaded on the surface of the protein carrier. Wherein, the magnesium alloy body can generate hydrogen in situ in the tumor acidic microenvironment, down regulate the expression of tumor cell heat shock protein, make tumor cells sensitive to temperature, and make the tumor cells under low-intensity alternating magnetic field (0.1×10) 8 ～0.9×10 8 A·m -1 ·s -1 ) The tumor cells are killed by the thermotherapy at a milder temperature, so that the moderate magnetocaloric therapy is realized, and the surrounding normal tissues are further protected. At the same time, the peroxide coating can decompose and generate H in the tumor acidic microenvironment 2 O 2 ，H 2 O 2 The NO donor can be stimulated to release NO gas molecules, and the mild magnetocaloric therapy can promote the generation of thermoactive oxygen substances inside cancer cells, so that the generated active oxygen substances can further generate active nitrogen substances with stronger toxicity with the released NO gas molecules, thereby further killing the tumor cells. Therefore, the magnesium alloy provided by the invention can realize the cooperative treatment of the moderate magnetocaloric therapy and the gas therapy, and further thoroughly remove the residual tumor cells.
The invention also provides a preparation method of the magnesium alloy, which comprises the following steps:
mixing and reacting the magnesium alloy body coated with the peroxide coating on the surface with a buffer solution of a protein carrier, and mixing and reacting the obtained product with the buffer solution of an NO donor to obtain the magnesium alloy.
According to the present invention, first, a magnesium alloy body coated with a peroxide coating on the surface is mixed with a buffer solution of a protein carrier and reacted. In the invention, the magnesium alloy body with the surface coated with the peroxide coating is prepared by adopting different methods according to different peroxide coatings. Generally, the preparation can be carried out by an in-situ growth method or a surface deposition method.
In some embodiments of the present invention, when the peroxide coating is a magnesium peroxide coating, the magnesium alloy body with the surface coated with the magnesium peroxide coating is preferably obtained by an in-situ growth method, and specifically comprises the following steps:
immersing the magnesium alloy body in saturated sodium bicarbonate solution for reaction for 5-15 h, preferably 12h, so as to obtain magnesium alloy a; calcining the magnesium alloy a at 300-600 ℃, preferably 500 ℃ for 2-6 hours, preferably 3 hours to obtain a magnesium alloy b; and (3) soaking the magnesium alloy b in hydrogen peroxide solution to react for 5-15 h, preferably 12h, so as to obtain the magnesium alloy body with the surface growing with the magnesium peroxide coating. Wherein the calcination is preferably carried out in a muffle furnace.
In some embodiments of the present invention, when the peroxide coating is a zinc peroxide coating, a calcium peroxide coating or a strontium peroxide coating, the surface deposition method is preferably adopted, and the present invention takes as an example a magnesium alloy body with a zinc peroxide coating coated on the surface, and specifically includes the following steps:
immersing the magnesium alloy body in a solution of polyvinylpyrrolidone or polyvinyl alcohol, and depositing and adsorbing for 0.5-3 h, preferably 2h; immersing the obtained product in an aqueous solution of zinc acetate, and shaking and mixing for 2-5 h, preferably 4h in a shaking table; then adding hydrogen peroxide solution, preferably 3mL of 30wt% hydrogen peroxide solution, to the obtained solution, and placing the hydrogen peroxide solution on a heating plate with the temperature of 200-500 ℃ and the temperature of 300 ℃ to heat for 5-20 min, preferably 15min, so as to obtain the magnesium alloy body with the zinc peroxide coating on the surface.
It should be noted that, when the peroxide coating is a calcium peroxide coating or a strontium peroxide coating, the magnesium alloy body with the surface of which is grown with the calcium peroxide coating or the strontium peroxide coating can be prepared by the above method, and will not be described in detail herein.
When the magnesium alloy body coated with the peroxide coating on the surface is obtained, the magnesium alloy body is preferably mixed and reacted with a buffer solution of a protein carrier. Wherein, the buffer solution of the protein carrier is preferably phosphate buffer solution of the protein carrier, and the acid-base property of the buffer solution is preferably neutral so as to avoid degradation of the peroxide coating. In some embodiments of the present invention, it is preferable to mix the magnesium alloy body coated with the peroxide coating on the surface with 1.0 to 2.0g/L, preferably 1.6g/L of buffer solution of protein carrier, and react for 8 to 20 hours, preferably 12 hours at room temperature to obtain the magnesium alloy body loaded with protein carrier after the peroxide coating grows on the surface.
And then mixing and reacting the magnesium alloy body with the protein carrier loaded after the peroxide coating grows on the surface with a buffer solution of the NO donor to obtain the magnesium alloy. Wherein, the buffer solution of the NO donor is preferably phosphate buffer solution of the NO donor, and the acid-base property is preferably neutral, so as to avoid degradation of the peroxide coating. In some embodiments of the present invention, it is preferable to mix the magnesium alloy body loaded with the protein carrier after the peroxide coating is grown on the surface with 0.3 to 1.0g/L, preferably 0.6g/L buffer solution to obtain NO donor, and react for 8 to 20 hours, preferably 12 hours at room temperature to obtain magnesium alloy.
In the present invention, the room temperature means a temperature of "20 to 30 ℃, preferably 25 ℃.
The preparation method of the magnesium alloy provided by the invention is simple and convenient and is easy to realize.
The invention also provides a metal implant for inhibiting the growth of the tumor or inhibiting the local recurrence of the tumor, and the metal implant is the magnesium alloy related to the technical scheme.
In the invention, the application process of the metal implant, namely the magnesium alloy, is simple, and the following steps can be adopted:
placing the metal implant, namely magnesium alloy, in a tumor cell wound after operation, and applying alternating magnetic field stimulation to obtain the magnesium alloy.
In the present invention, the alternating magnetic field has a low intensity, specifically 0.1X10 8 ～0.9×10 8 A·m -1 ·s -1 。
In conclusion, the magnesium alloy provided by the invention can be implanted in situ in a tumor cell wound after operation, does not pass through blood circulation, cannot be enriched in normal tissues, has an excitation source of a low-intensity alternating magnetic field, has unlimited penetration depth and wider treatment application range, and greatly improves the killing effect of the magnesium alloy on residual tumor tissues while reducing the influence of magnetocaloric therapy on surrounding normal cells. In addition, the magnesium alloy is slowly degraded, can be used as an auxiliary treatment material after tumor surgical excision, and has great potential in continuously inhibiting local recurrence of tumor.
In order to further illustrate the present invention, the following examples are provided. The experimental materials used in the following examples of the present invention are all generally commercially available. Wherein, the magnesium alloy body is purchased from Suzhou Jinjun technology Co., ltd, and the mass ratio of the magnesium alloy elements is as follows: mg: zn: ca (97.7:2.0:0.3); mouse breast cancer cells were supplied by Shanghai Fuhe Biotechnology Co.
Example 1
The embodiment provides a surface-modified magnesium alloy, wherein magnesium peroxide is generated in situ on the surface of the magnesium alloy, and bovine serum albumin is further utilized to load poly-L-arginine hydrochloride. The preparation method comprises the following steps:
(1) Immersing a magnesium alloy body (MgA for short) in saturated sodium bicarbonate solution for reaction for 12 hours, and taking out a magnesium alloy body a;
(2) Calcining the magnesium alloy body a in the step (1) in a muffle furnace at 500 ℃ for 3 hours to obtain a magnesium alloy body b;
(3) Soaking the magnesium alloy body b in the step (2) in hydrogen peroxide solution at room temperature for reaction for 12 hours to obtain a magnesium alloy body (called as MM for short) with magnesium peroxide grown on the surface;
(4) Mixing MM in the step (3) with 1.6g/L bovine serum albumin buffer solution with neutral acid and alkali at room temperature, and reacting for 12 hours to obtain a magnesium alloy body (MMB) loaded with bovine serum albumin after magnesium peroxide grows on the surface;
(5) And (3) mixing the MMB in the step (4) with a poly L-arginine salt buffer solution with neutral pH value of 0.6g/L, and reacting for 12 hours to obtain a magnesium alloy body (MMBP) with the surface growing magnesium peroxide, loading bovine serum albumin and finally agglomerating the L-arginine hydrochloride, thus obtaining the final surface-modified magnesium alloy.
As a result of scanning electron microscope detection on MgA, MM, MMB and MMBP described above, as shown in fig. 1, MM, MMB and MMBP were significantly roughened compared with MgA metal surfaces, indicating that the magnesium alloy body surfaces were significantly modified.
As a result of performing an X-ray diffraction test on MMBP, as shown in FIG. 2, it can be seen that diffraction peaks (JCPDS card No. 19-0771) of magnesium peroxide appear at 37.1 DEG and 53.8 DEG on an X-ray diffraction pattern of MMBP, which indicates that the magnesium peroxide successfully grows in situ on the surface of the obtained magnesium alloy.
As shown in FIG. 3, the results of thermogravimetric analysis and detection of the above MgA, MM, MMB and MMBP show that the MMs, MMB and MMBP have obvious weight loss compared with MgA, and the weight loss of MMBP, MMB, MM is gradually increased, which indicates that on the basis of growing magnesium peroxide on the surface of magnesium alloy in situ, bovine serum albumin and poly L-arginine hydrochloride are successfully loaded, and the successful synthesis of the surface modified magnesium alloy MMBP is proved.
Tumor cell killing effect test
Mouse breast cancer cells were inoculated in 96-well plates for 24h incubation, then MgA, MM and MMBP (diameter d=0.5 MM, length l=6 MM) were added to the 96-well plates containing 1640 medium solution at pH 6.5, respectively, and the material and cells were incubated for 12h. Then alternating magnetic field (Alternating Magnetic Field, abbreviated as AMF) (magnetic field strength: H) appl ×f appl ＝0.9×10 8 A·m·- 1 ·s -1 ) I.e. + AMF, wherein only the AMF group (as a Control group) to which an alternating magnetic field is applied, i.e., only cells and a 1640 medium solution having a pH of 6.5 are present in the well plate; on the basis of the Control group, mgA is additionally added into the pore plate to form an MgA group; on the basis of the Control group, MM is additionally added into the pore plate to be an MM group; on the basis of Control group, MMBP group is added in the pore plate, AMF is applied for 6min, CCK-8 is added in the pore plate according to the instruction of the kit, and the cell activity after incubation with the material is detected.
In addition, the invention inoculates the breast cancer cells of the mice in a 96-well plate for 24 hours, and then respectively incubates the breast cancer cells in the 96-well plate with pH of 6.5MgA, MM and MMBP (diameter d=0.5 MM, length l=6 MM) were added to 96-well plates of 1640 medium solution and the material and cells were incubated for 12h. No longer carries out alternating magnetic field (Alternating Magnetic Field, abbreviated as AMF) (magnetic field strength: H appl ×f appl ＝0.9×10 8 A·m·- 1 ·s -1 ) Namely AMF, wherein an AMF group (as a Control group) without applying an alternating magnetic field, namely 1640 culture medium solution with the pH of 6.5 and cells only in the pore plate, and MgA is additionally added into the pore plate on the basis of the Control group to form an MgA group; on the basis of the Control group, MM is additionally added into the pore plate to be an MM group; on the basis of the Control group, MMBP is additionally added into the pore plate to form an MMBP group, and finally CCK-8 is added into the pore plate according to the instruction of the kit, so that the activity of cells incubated with the materials is detected.
The test results are shown in fig. 4, and it can be seen that the magnesium alloy alone, that is, mgA group magnesium alloy, caused partial death of cells by generating a large amount of hydrogen under an acidic condition without applying an alternating magnetic field, and that the ratio of cell death was further increased by the combined treatment of hydrogen and nitric oxide when MMBP group was obtained after the magnesium alloy was coated with magnesium peroxide and loaded with a drug. However, when the alternating magnetic field is applied, the cell death ratio of the MgA group, the MM group and the MMBP group is greatly increased under the combined action of the magnetocaloric treatment and the gas treatment, and especially the MMBP+AMF group, namely the final treatment group, has the cell survival ratio lower than 20 percent, which proves that the surface modified magnesium alloy has excellent killing effect on tumor cells.
Example 2
The embodiment provides a magnesium alloy with a zinc oxide coating grown on the surface, and the specific preparation method comprises the following steps:
(1) Immersing the magnesium alloy body in polyvinylpyrrolidone solution, and depositing and adsorbing for 2h;
(2) Immersing the product in the step (1) in a zinc acetate aqueous solution, and shaking and mixing for 4 hours in a shaking table;
(3) Adding 3ml of 30% hydrogen peroxide solution to the solution of step (2);
(4) And (3) placing the product obtained in the step (3) on a heating plate at 300 ℃ and heating for 10min to obtain the magnesium alloy with the zinc peroxide coating growing on the surface.
Scanning electron microscope and X-ray energy dispersion spectrum tests were carried out on the magnesium alloy with zinc oxide coating grown on the surface obtained in example 2, and the results are shown in fig. 5 and 6, wherein the surface of the magnesium alloy rod in the scanning electron microscope is roughened, which indicates that the coating is attached; and the X-ray energy dispersion spectrogram shows that a large amount of zinc elements are uniformly distributed on the surface of the magnesium alloy, and the feasibility of modification of the zinc peroxide coating on the surface of the magnesium alloy is proved.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. The magnesium alloy is characterized by comprising a magnesium alloy body and a peroxide coating coated on the surface of the magnesium alloy body;
the surface of the peroxide coating is adsorbed with a protein carrier, and the surface of the protein carrier is loaded with an NO donor.
2. The magnesium alloy of claim 1, wherein the peroxide coating comprises any one or more of a magnesium peroxide coating, a zinc peroxide coating, a calcium peroxide coating, or a strontium peroxide coating.
3. The magnesium alloy according to claim 1, wherein the protein carrier is selected from any one or more of bovine serum albumin, human serum albumin, rabbit serum albumin or egg albumin.
4. The magnesium alloy according to claim 1, wherein the NO donor is selected from any one or more of poly L-arginine hydrochloride, poly L-arginine or L-arginine.
5. The magnesium alloy of claim 1, wherein the magnesium alloy comprises Mg and any one or more of Zn, ca, Y, nd, gd, gd, sm or Zr.
6. A method for producing the magnesium alloy according to any one of claims 1 to 5, comprising the steps of:
mixing and reacting the magnesium alloy body coated with the peroxide coating on the surface with a buffer solution of a protein carrier, and mixing and reacting the obtained product with the buffer solution of an NO donor to obtain the magnesium alloy.
7. The method according to claim 6, wherein the buffer solution for the protein carrier and the buffer solution for the NO donor are neutral in acid-base.
8. The method according to claim 6, wherein the magnesium alloy body coated with the peroxide coating on the surface is prepared by an in-situ growth method or a surface deposition method.
9. A metal implant for inhibiting tumor growth or inhibiting local recurrence of tumor, comprising the magnesium alloy according to claims 1 to 5 or the magnesium alloy prepared by the preparation method according to any one of claims 6 to 8.
10. The metal implant of claim 9, wherein the metal implant is placed in a tumor cell wound after surgery, and alternating magnetic field stimulation is applied to obtain the metal implant;
the strength of the alternating magnetic field is 0.1×10 8 ～0.9×10 8 A·m -1 ·s -1 。
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