CN116519116B - Doped zinc-copper piezoelectric acoustic sensitizer and preparation method and application thereof - Google Patents
Doped zinc-copper piezoelectric acoustic sensitizer and preparation method and application thereof Download PDFInfo
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- CN116519116B CN116519116B CN202310327671.8A CN202310327671A CN116519116B CN 116519116 B CN116519116 B CN 116519116B CN 202310327671 A CN202310327671 A CN 202310327671A CN 116519116 B CN116519116 B CN 116519116B
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- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000011701 zinc Substances 0.000 claims abstract description 18
- 239000010949 copper Substances 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 8
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 53
- 229910052751 metal Inorganic materials 0.000 claims description 22
- 239000002184 metal Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 17
- 239000012266 salt solution Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 150000001879 copper Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 150000003751 zinc Chemical class 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- -1 and is Al 3+ Inorganic materials 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 239000011229 interlayer Substances 0.000 claims description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 2
- 150000004692 metal hydroxides Chemical class 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate group Chemical group [N+](=O)([O-])[O-] NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 230000005536 Jahn Teller effect Effects 0.000 abstract description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002086 nanomaterial Substances 0.000 abstract description 6
- 229910052725 zinc Inorganic materials 0.000 abstract description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052802 copper Inorganic materials 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 description 28
- 238000011282 treatment Methods 0.000 description 16
- 239000008367 deionised water Substances 0.000 description 15
- 229910021641 deionized water Inorganic materials 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- ZKSVYBRJSMBDMV-UHFFFAOYSA-N 1,3-diphenyl-2-benzofuran Chemical compound C1=CC=CC=C1C1=C2C=CC=CC2=C(C=2C=CC=CC=2)O1 ZKSVYBRJSMBDMV-UHFFFAOYSA-N 0.000 description 11
- 239000003642 reactive oxygen metabolite Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 238000005303 weighing Methods 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 8
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 206010027476 Metastases Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000002147 killing effect Effects 0.000 description 5
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- 230000004614 tumor growth Effects 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 238000002604 ultrasonography Methods 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 4
- BNGXYYYYKUGPPF-UHFFFAOYSA-M (3-methylphenyl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].CC1=CC=CC(C[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 BNGXYYYYKUGPPF-UHFFFAOYSA-M 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
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- 238000004519 manufacturing process Methods 0.000 description 3
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- 238000009214 sonodynamic therapy Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
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- 229910009529 yH2 O Inorganic materials 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010056342 Pulmonary mass Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
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- 238000001959 radiotherapy Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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- 210000000689 upper leg Anatomy 0.000 description 1
Classifications
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- 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
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
- A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G9/00—Compounds of zinc
- C01G9/006—Compounds containing, besides zinc, two ore more other elements, with the exception of oxygen or hydrogen
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01H—MEASUREMENT OF MECHANICAL VIBRATIONS OR ULTRASONIC, SONIC OR INFRASONIC WAVES
- G01H11/00—Measuring mechanical vibrations or ultrasonic, sonic or infrasonic waves by detecting changes in electric or magnetic properties
- G01H11/06—Measuring mechanical vibrations or ultrasonic, sonic or infrasonic waves by detecting changes in electric or magnetic properties by electric means
- G01H11/08—Measuring mechanical vibrations or ultrasonic, sonic or infrasonic waves by detecting changes in electric or magnetic properties by electric means using piezoelectric devices
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/20—Two-dimensional structures
- C01P2002/22—Two-dimensional structures layered hydroxide-type, e.g. of the hydrotalcite-type
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
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- Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a doped zinc-copper piezoelectric acoustic sensitizer and a preparation method and application thereof, belonging to the technical field of piezoelectric acoustic sensitizers. The doped zinc-copper piezoelectric acoustic sensitizer has the Jahn-Teller effect, has a layered double hydroxide structure, and has a size of 50nm-200nm, and a chemical composition [(Zn(1‑x‑a)Cua)1‑xMx(OH)2]x+An‑ x/n·yH2O;, wherein M is Al 3+、Fe3+ or Cr 3+; x is 1/1-1/4; a is 0.5-3; a n‑ is Cl ‑、CO3 2‑ or NO 3 ‑; y is 0-10. The doped zinc-copper piezoelectric acoustic sensitizer is based on a zinc-based nanomaterial with piezoelectric performance, and typical copper metal ions capable of causing Jahn-Teller effect are introduced, so that the piezoelectric performance is enhanced, and the ultrasonic availability is improved.
Description
Technical Field
The invention belongs to the technical field of piezoelectric acoustic sensitizers, and particularly relates to a doped zinc-copper piezoelectric acoustic sensitizers, and a preparation method and application thereof.
Background
Today, cancer is the second leading cause of death worldwide, and researchers have been working to find effective methods for treating cancer. The cancer treatment methods clinically applied at the present stage mainly comprise operation, chemotherapy, radiotherapy and immunotherapy, and the treatment methods can cause side effects and adverse reactions while achieving a certain treatment effect. With the rapid development of nanotechnology tumor treatment strategies, various novel non-invasive treatment modes such as photo-thermal treatment, photodynamic treatment, sonodynamic treatment and magnetothermal treatment are emerging, and cancer treatment is pushed to continuously develop and progress towards accurate, effective, safe and low-cost modes.
Among them, sonodynamic therapy (Sonodynamic therapy, SDT) is a novel therapeutic approach that utilizes low-intensity ultrasound to excite sensitizers to generate highly cytotoxic Reactive Oxygen Species (ROS), thereby killing tumor cells. The ultrasound can penetrate deep tissues, accurately focus on tumor areas, activate sonophores, and thus selectively kill tumor cells without damaging surrounding normal organs and tissues, and has good treatment effect on deep tumors.
The widely accepted SDT mechanism is acoustic inertial cavitation theory, mainly ultrasonic wave propagation in liquid, using acoustic sensitizer as nucleation site, thus promoting the formation of many cavitation bubbles, rapid expansion and implosion collapse. Bubble collapse further induces extreme conditions (high temperature, high pressure, and acoustic excitation, etc.). The sonoexcitation-induced ROS production process is similar to photodynamic therapy, but in practical studies the important factor of high pressure (1×10 8 Pa) caused by bubble collapse is always ignored. A method of effectively utilizing pressure is to use a piezoelectric material as an acoustic sensitizer. The piezoelectric material is a dielectric material with a non-centrosymmetric crystal structure, and comprises ZnO, perovskite structure material, two-dimensional ultrathin material and layered bismuth-based material. Under acoustic vibrations, the piezoelectric material polarizes to form a built-in electric field. The piezoelectric potential acts as a strong driving force, promoting charge separation generated by the acoustic wave and suppressing recombination. The separated electrons and holes migrate to the opposite surface and continue the redox reaction. However, the use of piezoelectric acoustic sensitizers in SDT has been rarely reported.
Disclosure of Invention
In order to solve the technical problems, the invention provides a doped zinc-copper piezoelectric acoustic sensitizer, and a preparation method and application thereof. The doped zinc-copper piezoelectric acoustic sensitizer can be used for acoustic power treatment of tumors, has good killing effect on the tumors, and can effectively inhibit tumor metastasis. The use of piezoelectric materials as acoustic sensitizers effectively uses pressure to enhance the availability of ultrasound waves. In addition, piezoelectricity is due to polarization caused by structural distortion, and Jahn-Teller effect, which occurs in transition metal and lone pair cation with steric activity, also provides possibility for designing the composition of piezoelectric material and improving performance.
The first object of the invention is to provide a doped zinc-copper piezoelectric acoustic sensitizer prepared by the method, which has a structure of layered double hydroxide, a size of 50nm-200nm and a chemical composition of [(Zn(1-x-a)Cua)1-xMx(OH)2]x+An- x/n·yH2O;
Wherein M is a doped positively charged trivalent metal ion, and is Al 3+、Fe3+ or Cr 3+;
x is the molar ratio of M/(Zn+Cu) and ranges from 1/1 to 1/4;
a is the mole ratio of Zn/Cu, and the range is 0.5-3;
A n- is an interlayer anion, which is Cl -、CO3 2- or NO 3 -;
y is the amount of crystal water and ranges from 0 to 10.
In one embodiment of the invention, the doped zinc copper piezoelectric acoustic sensitizer has the Jahn-Teller effect.
In one embodiment of the invention, the doped zinc copper piezoelectric acoustic sensitizer exhibits better piezoelectricity due to the Jahn-Teller effect compared to Zn-based piezoelectric materials.
In one embodiment of the invention, the doped zinc copper piezoelectric acoustic sensitizer has an excessively high copper proportion, unstable structure and insignificant Jahn-Teller effect.
The second object of the invention is to provide a preparation method of the doped zinc-copper piezoelectric acoustic sensitizer, which comprises the following steps of mixing a metal salt solution and alkali liquor to react in a solvent to obtain the doped zinc-copper piezoelectric acoustic sensitizer; the mixed metal salt solution is a mixed solution of zinc salt, copper salt, doped metal salt and water.
In one embodiment of the invention, the copper salt is a divalent copper salt.
In one embodiment of the invention, the lye is one or more of sodium hydroxide solution, potassium hydroxide solution and urea solution.
In one embodiment of the invention, the metal salt is a nitrate and/or chloride salt.
In one embodiment of the invention, the molar ratio of the zinc salt, copper salt and metal in the doped metal salt is 0.5-3:1:1. the doped zinc-copper piezoelectric acoustic sensitizer synthesized in the proportion can not only carry out acoustic power treatment, but also induce stronger copper death, regulate tumor immunity microenvironment, promote maturation of DC cells in tumors, and also regulate marrow-derived suppressor cells (MDSCs) and regulatory T cells (tregs) downwards, thereby eradicating tumors more efficiently.
In one embodiment of the invention, the pH is adjusted to 9-10 during the reaction; the reaction temperature is 10-30 ℃; the reaction time is 22-26 h.
In one embodiment of the invention, the solvent is water.
In one embodiment of the invention, after the reaction is finished, the method further comprises the step of separating the doped zinc copper piezoelectric acoustic sensitizer from the reaction solution: and centrifuging to obtain precipitate and washing to obtain the doped zinc-copper piezoelectric sound sensitizer.
In one embodiment of the invention, the rotational speed of the centrifugation is 7800r/min to 8200r/min.
The third object of the invention is to provide the application of the doped zinc-copper piezoelectric acoustic sensitizer in the acoustic power treatment of tumors.
In one embodiment of the invention, the tumor is colon cancer, breast cancer, prostate cancer or melanoma.
In one embodiment of the invention, the ultrasonic power of the sonodynamic therapy is 2W/cm 2-10W/cm2, the frequency is 10kHz-50kHz, and the action time is 10min-30min.
In one embodiment of the invention, under the action of ultrasound, the piezoelectric acoustic sensitizer polarizes under the local high pressure generated by the ultrasonic vibration to form an internal electric field, and the piezoelectric potential acts as a large driving force to excite electrons in a Valence Band (VB) into a Conduction Band (CB) to form holes on the valence band. To be a free electron or hole, the bound electron must acquire enough energy to transition from the valence band to the conduction band. The minimum of this energy is the band gap. The smaller the band gap, the easier the electron transition.
Compared with the prior art, the technical scheme of the invention has the following advantages:
(1) The doped zinc-copper piezoelectric acoustic sensitizer is based on a zinc-based nanomaterial with piezoelectric performance, and typical copper metal ions capable of causing Jahn-Teller effect are introduced, so that the piezoelectric performance is enhanced, and the ultrasonic availability is improved.
(2) The atomic radiuses and electronegativity of zinc and copper in the doped zinc-copper piezoelectric acoustic sensitizer are similar, and the band gap is smaller under the excitation of external energy, so that the doped zinc-copper piezoelectric acoustic sensitizer has higher acoustic sensitization efficiency.
(3) The doped zinc-copper piezoelectric acoustic sensitizer has good killing effect on tumors, can effectively inhibit tumor metastasis, and can excite piezoelectric effect to induce acoustic power under ultrasonic irradiation after reaching focus positions, so that the doped zinc-copper piezoelectric acoustic sensitizer has good acoustic dynamic effect, can obviously inhibit tumor growth, and has great application value in the aspect of cancer treatment.
Drawings
In order that the invention may be more readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings, in which:
FIG. 1 is a transmission electron microscope image of the doped zinc copper piezoelectric acoustic sensitizer of test example 1 of the present invention.
FIG. 2 is a graph showing the detection of ROS release by a DPBF probe under ultrasonic irradiation of the doped zinc copper piezoelectric acoustic sensitizer of example 1.
FIG. 3 is a graph showing the detection of ROS release by the DPBF probe of comparative example 1 under ultrasonic irradiation.
FIG. 4 is a graph showing the detection of ROS release by a DPBF probe in accordance with the present invention under ultrasonic irradiation of the nanomaterial of comparative example 2.
FIG. 5 is a diagram of the piezocatalysis mechanism of the doped zinc copper piezoacoustic sensitizer of example 1 of the present invention.
FIG. 6 is a graph showing the detection of singlet oxygen generated by doped zinc copper piezoelectric acoustic sensitizers under ultrasonic irradiation using ESR and TEMPO probes in test example 2 according to the present invention.
FIG. 7 shows the killing effect of different concentrations of doped zinc copper piezoelectric acoustic sensitizers on colon cancer cells of mice under ultrasonic irradiation in test example 3 according to the present invention.
FIG. 8 shows the effect of various concentrations of doped zinc copper piezoelectric acoustic sensitizers on DC cell maturation in test example 4 of the present invention.
FIG. 9 is a graph showing the tumor growth of the mice in test example 5 according to the present invention.
FIG. 10 is a graph showing the number of pulmonary nodules in mice in test example 5 of the invention.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the invention and practice it.
Example 1
A doped zinc-copper piezoelectric acoustic sensitizer and a preparation method thereof specifically comprise the following steps:
(1) Weighing zinc nitrate, copper nitrate and aluminum nitrate according to the molar ratio of 2:1:1, jointly dissolving in deionized water to prepare a metal salt solution; weighing sodium hydroxide, and dissolving in deionized water to prepare 2M sodium hydroxide solution;
(2) Slowly dripping the metal salt solution and the sodium hydroxide solution into the water phase at normal temperature, stirring, controlling the pH to be about 9.5, and reacting for 24 hours at room temperature after the dripping is finished;
(3) After the reaction is completed, centrifuging at 8000r/min, washing with ethanol for 2 times, washing with deionized water for 2 times, and finally dispersing in water to obtain the doped zinc copper piezoelectric acoustic sensitizer (ZCA), wherein the ZCA has a structure of layered double hydroxide with a size of 50-200 nm and a chemical composition of [(Zn(1-x-a)Cua)1-xMx(OH)2]x+An- x/n·yH2O;
Wherein: m is Al 3+; a is 2/1; x is 1/3; a n- is NO 3 -; y is 0-10.
Example 2
A doped zinc-copper piezoelectric acoustic sensitizer and a preparation method thereof specifically comprise the following steps:
(1) Weighing zinc nitrate, copper nitrate and aluminum nitrate according to the mole ratio of 1:1:1, jointly dissolving in deionized water to prepare a metal salt solution; weighing sodium hydroxide, and dissolving in deionized water to prepare 2M sodium hydroxide solution;
(2) Slowly dripping the metal salt solution and the sodium hydroxide solution into the water phase at normal temperature, stirring, controlling the pH to be about 9.5, and reacting for 24 hours at room temperature after the dripping is finished;
(3) After the reaction is completed, centrifuging at 8000r/min, washing with ethanol for 2 times, washing with deionized water for 2 times, and finally dispersing in water to obtain the doped zinc copper piezoelectric acoustic sensitizer (ZCA). The structure of ZCA is layered double hydroxide with the size of 50nm-200nm and the chemical composition is [(Zn(1-x-a)Cua)1-xMx(OH)2]x+An- x/n·yH2O;
Wherein: m is Al 3+; a is 1/1; x is 1/2; a n- is NO 3 -; y is 0-10.
Example 3
A doped zinc-copper piezoelectric acoustic sensitizer and a preparation method thereof specifically comprise the following steps:
(1) Weighing zinc chloride, copper chloride and aluminum chloride according to the molar ratio of 2:1:1, jointly dissolving in deionized water to prepare a metal salt solution; weighing sodium hydroxide, and dissolving in deionized water to prepare 2M sodium hydroxide solution;
(2) Slowly dripping the metal salt solution and the sodium hydroxide solution into the water phase at normal temperature, stirring, controlling the pH to be about 9.5, and reacting for 24 hours at room temperature after the dripping is finished;
(3) After the reaction is completed, centrifuging at 8000r/min, washing with ethanol for 2 times, washing with deionized water for 2 times, and finally dispersing in water to obtain the doped zinc copper piezoelectric acoustic sensitizer (ZCA). The structure of ZCA is layered double hydroxide with the size of 50nm-200nm and the chemical composition is [(Zn(1-x-a)Cua)1-xMx(OH)2]x+An- x/n·yH2O;
Wherein: m is Al 3+; a is 2/1; x is 1/3; a n- is Cl -; y is 0-10.
Comparative example 1
(1) Weighing zinc chloride and aluminum chloride with the molar ratio of 2:1, jointly dissolving in deionized water to prepare a metal salt solution; weighing sodium hydroxide, and dissolving in deionized water to prepare 2M sodium hydroxide solution;
(2) Slowly dripping the metal salt solution and the sodium hydroxide solution into the water phase at normal temperature, stirring, controlling the pH to be about 9.5, and reacting for 24 hours at room temperature after the dripping is finished;
(3) After the reaction is completed, centrifuging at 8000r/min, washing with ethanol for 2 times, washing with deionized water for 2 times, and finally dispersing in water to obtain the zinc-based piezoelectric acoustic sensitizer, wherein the zinc-based piezoelectric acoustic sensitizer has a structure of layered double metal hydroxide, a size of 50-200 nm and a chemical composition of [ (Zn 1-xMx(OH)2]x+An- x/n·yH2 O);
Wherein: m is Al 3+; x is 1/2; a n- is Cl -; y is 0-10.
Comparative example 2
(1) Weighing magnesium nitrate and aluminum nitrate with the molar ratio of 2:1, jointly dissolving in deionized water to prepare a metal salt solution; weighing sodium hydroxide, and dissolving in deionized water to prepare 2M sodium hydroxide solution;
(2) Slowly dripping the metal salt solution and the sodium hydroxide solution into the water phase at normal temperature, stirring, controlling the pH to be about 9.5, and reacting for 24 hours at room temperature after the dripping is finished;
(3) After the reaction is completed, centrifuging at 8000r/min, washing with ethanol for 2 times, washing with deionized water for 2 times, and finally dispersing in water to obtain the nano material. The nano material has a structure of layered double hydroxide with a size of 50nm-200nm and a chemical composition of [ Mg 1-xMx(OH)2]x+An- x/n·yH2 O ];
wherein: m is Al 3+; x is 1/2; a n- is NO 3 -; y is 0-10.
Test example 1
The doped zinc-copper piezoelectric acoustic sensitizer of example 1 is characterized, and a transmission electron microscope image is shown in fig. 1, wherein the doped zinc-copper piezoelectric acoustic sensitizer has a two-dimensional nano lamellar structure.
Test example 2
(1) The materials prepared in example 1 and comparative examples 1-2 were tested for ROS production by ultrasonic irradiation using 1, 3-Diphenylisobenzofuran (DPBF) at 40kHz,3W/cm 2 and 50 μg/mL concentration of sonosensitizer, and the results are shown in FIGS. 2-4. As can be seen from fig. 2, under the ultrasonic irradiation, the doped zinc copper piezoelectric acoustic sensitizer of example 1 can generate singlet oxygen, so that the characteristic peak of ultraviolet absorption of DPBF at 416nm is reduced, and the DPBF is obviously degraded as the time of ultrasonic irradiation is prolonged. As can be seen from fig. 3, the zinc-based piezoelectricity sensitizer of comparative example 1 can generate singlet oxygen under ultrasonic irradiation, so that the characteristic peak of ultraviolet absorption of DPBF at 416nm is reduced, and the DPBF is slightly degraded as the time of ultrasonic irradiation is prolonged. The ROS production was less effective than in example 1. As can be seen from fig. 4, under the ultrasonic irradiation, the nanomaterial of comparative example 2 can generate singlet oxygen, so that the characteristic peak of ultraviolet absorption of DPBF at 416nm is reduced, and the DPBF is not significantly degraded as the ultrasonic irradiation time is prolonged. In contrast to example 1, no ROS was generated. This is because the doped zinc copper piezoelectric acoustic sensitizer of example 1 acts as a nucleation site, promoting cavitation bubble formation, rapid expansion and implosion collapse. The collapse of the bubbles further induces high voltage (about 1×10 8 Pa), and the doped zinc-copper piezoelectric acoustic sensitizer forms a built-in electric field by high voltage polarization. The piezoelectric potential acts as a strong driving force, promoting charge separation generated by the acoustic wave and suppressing recombination. The separated electrons and holes migrate to the opposite surface and continue to undergo redox reactions, thereby generating a large amount of ROS, resulting in improved acoustic power performance (as shown in fig. 5).
(2) The ESR and TEMPO are used as singlet oxygen capturing agents, singlet oxygen generated by the doped zinc-copper piezoelectric acoustic sensor under ultrasonic irradiation is detected, and as shown in figure 6, the doped zinc-copper piezoelectric acoustic sensor shows a stronger singlet oxygen signal after ultrasonic irradiation.
Test example 3
Based on the doped zinc-copper piezoelectric acoustic sensitizer of example 1, the doped zinc-copper piezoelectric acoustic sensitizer with different concentrations and the mouse colon cancer cells (CT 26) are incubated for 12 hours, and the result is shown in fig. 7, the doped zinc-copper piezoelectric acoustic sensitizer has moderate cytotoxicity to the CT26 cells, however, the CT26 cells after 12 hours of incubation are exposed to an ultrasonic probe with the power of 4.5W/cm 2 for 2 minutes (ZCA+US group), and the doped zinc-copper piezoelectric acoustic sensitizer has a stronger cell killing effect, which indicates that the doped zinc-copper piezoelectric acoustic sensitizer can generate ROS as an acoustic sensitizer to kill tumor cells.
Test example 4
Bone marrow-derived dendritic cells (BMDCs) were extracted from the femur of C57 mice, incubated with the Control group (Control group), the 25ppm and 50ppm doped zinc copper piezoelectric acoustic sensitizers for 12h, and then the DC cell maturity was detected using a flow cytometer, CD80 +、CD86+ was mature DC cells, and the result is shown in FIG. 8, the DC cell maturity of the Control group was 17.3%, and the DC maturity of the doped zinc copper piezoelectric acoustic sensitizers after incubation was significantly increased, and the DC maturity rates of the 25ppm and 50ppm doped zinc copper piezoelectric acoustic sensitizers reached 53.4% and 64.5%, respectively, indicating that the doped zinc copper piezoelectric acoustic sensitizers can promote DC cells and enhance antitumor immune effects.
Test example 5
Four experimental groups were set, namely a Control group (Control group), a US group (ultrasonic irradiation only), a ZCA group and a zca+us group (doped zinc copper piezoelectric acoustic sensitizer combined ultrasonic irradiation treatment). When the tumor volume of the mice reached 100mm 3, treatment was started, and when the tumor volume reached 1000mm 3, the mice were considered dead, and the recording of tumor volume was stopped. The ZCA and ZCA+US groups were prepared by intratumorally injecting the aqueous solution of the doped zinc copper piezoelectric sonosensitizer of example 1 into a subcutaneous colon cancer of a mouse at a concentration of 2mg/mL and an injection dose of 50. Mu.L, and the ZCA+US groups were additionally irradiated at 40kHz,6W/cm 2 for 10min. The US group was also irradiated for 10min under the same conditions. Tumor volumes of mice in different experimental groups were measured at different time points using vernier calipers, tumor growth curves of the mice are shown in fig. 9, and compared with Control groups, the US group has little inhibition effect on tumors; the ZCA group has a certain inhibition effect on tumor growth; however, ZCA+US group shows obvious inhibition effect on tumor growth, which shows that the doped zinc-copper piezoelectric acoustic sensitizer has stronger killing effect on tumor under ultrasonic irradiation.
Then, a mouse subcutaneous breast cancer model is established to observe the influence of the doped zinc-copper piezoelectric acoustic sensitizer on tumor metastasis, as shown in fig. 10, the number of lung nodules of a Control group and a US group is increased, and the number of the nodules of a treatment group which is only injected with the doped zinc-copper piezoelectric acoustic sensitizer is about 40% less than that of a Control group, so that the doped zinc-copper piezoelectric acoustic sensitizer has a certain inhibition effect on tumor lung metastasis. The ZCA+US group has complete inhibition effect on tumor lung metastasis, and the application potential of the doped zinc-copper piezoelectric acoustic sensitizer in tumor treatment and prognosis application is proved again.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations and modifications of the present invention will be apparent to those of ordinary skill in the art in light of the foregoing description. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.
Claims (7)
1. A doped zinc-copper piezoelectric acoustic sensitizer is characterized in that the doped zinc-copper piezoelectric acoustic sensitizer has a structure of layered double metal hydroxide with the size of 50nm-200nm and the chemical composition of [(Zn(1-x-a)Cua)1-xMx(OH)2]x+An- x/n·yH2O;
Wherein M is a doped positively charged trivalent metal ion, and is Al 3+、Fe3+ or Cr 3+;
x is the molar ratio of M/(Zn+Cu) and ranges from 1/1 to 1/4;
a is the mole ratio of Zn/Cu, and the range is 0.5-3;
A n- is an interlayer anion, which is Cl -、CO3 2- or NO 3 -;
y is the amount of crystal water and ranges from 0 to 10.
2. A method for preparing the doped zinc-copper piezoelectric acoustic sensitizer according to claim 1, comprising the steps of mixing a metal salt solution and an alkali solution in a solvent for reaction to obtain the doped zinc-copper piezoelectric acoustic sensitizer; the mixed metal salt solution is a mixed solution of zinc salt, copper salt, doped metal salt and water.
3. The method for preparing a doped zinc copper piezoelectric acoustic sensitizer according to claim 2, wherein the copper salt is a cupric salt.
4. The method for preparing a doped zinc copper piezoelectric acoustic sensitizer according to claim 2, wherein the alkali solution is one or more of sodium hydroxide solution, potassium hydroxide solution and urea solution.
5. The method for preparing a doped zinc copper piezoelectric acoustic sensitizer according to claim 2, wherein the metal salt is nitrate and/or chloride.
6. The method for preparing the doped zinc-copper piezoelectric acoustic sensitizer according to claim 2, wherein the molar ratio of the zinc salt to the copper salt to the metal in the doped metal salt is 0.5-3:1:1.
7. The method for preparing a doped zinc copper piezoelectric acoustic sensitizer according to claim 2, wherein the pH is adjusted to 9-10 during the reaction.
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