CN115465853B - Orange light carbon dot based on citric acid and chiral 2-amino-1, 2-diphenyl ethanol and preparation method and application thereof - Google Patents
Orange light carbon dot based on citric acid and chiral 2-amino-1, 2-diphenyl ethanol and preparation method and application thereof Download PDFInfo
- Publication number
- CN115465853B CN115465853B CN202211099781.5A CN202211099781A CN115465853B CN 115465853 B CN115465853 B CN 115465853B CN 202211099781 A CN202211099781 A CN 202211099781A CN 115465853 B CN115465853 B CN 115465853B
- Authority
- CN
- China
- Prior art keywords
- amino
- citric acid
- carbon
- rcds
- photon
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 title claims abstract description 90
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- GEJJWYZZKKKSEV-UHFFFAOYSA-N 2-amino-1,2-diphenylethanol Chemical compound C=1C=CC=CC=1C(N)C(O)C1=CC=CC=C1 GEJJWYZZKKKSEV-UHFFFAOYSA-N 0.000 title claims abstract description 11
- GEJJWYZZKKKSEV-UONOGXRCSA-N (1r,2s)-2-amino-1,2-diphenylethanol Chemical compound C1([C@@H](O)[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-UONOGXRCSA-N 0.000 claims abstract description 13
- GEJJWYZZKKKSEV-KGLIPLIRSA-N (1s,2r)-2-amino-1,2-diphenylethanol Chemical compound C1([C@H](O)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-KGLIPLIRSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000004440 column chromatography Methods 0.000 claims abstract description 8
- 238000003384 imaging method Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000003746 solid phase reaction Methods 0.000 claims abstract description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 33
- 230000005284 excitation Effects 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 12
- 238000000482 two photon fluorescence microscopy Methods 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 239000000975 dye Substances 0.000 claims description 5
- 238000012632 fluorescent imaging Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 239000000523 sample Substances 0.000 claims description 5
- 238000000799 fluorescence microscopy Methods 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000001963 growth medium Substances 0.000 claims description 3
- 239000007790 solid phase Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000001218 confocal laser scanning microscopy Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002070 Raman circular dichroism spectroscopy Methods 0.000 abstract description 65
- 206010028980 Neoplasm Diseases 0.000 abstract description 31
- 238000002438 flame photometric detection Methods 0.000 abstract description 26
- 238000011282 treatment Methods 0.000 abstract description 25
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 239000002086 nanomaterial Substances 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 230000004614 tumor growth Effects 0.000 abstract description 4
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 35
- 241000699670 Mus sp. Species 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- 238000001126 phototherapy Methods 0.000 description 15
- 238000002428 photodynamic therapy Methods 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 230000005540 biological transmission Effects 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000002189 fluorescence spectrum Methods 0.000 description 6
- 238000002173 high-resolution transmission electron microscopy Methods 0.000 description 6
- 238000005286 illumination Methods 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 239000003642 reactive oxygen metabolite Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 229910052724 xenon Inorganic materials 0.000 description 4
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 4
- XDFNWJDGWJVGGN-UHFFFAOYSA-N 2-(2,7-dichloro-3,6-dihydroxy-9h-xanthen-9-yl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1C2=CC(Cl)=C(O)C=C2OC2=CC(O)=C(Cl)C=C21 XDFNWJDGWJVGGN-UHFFFAOYSA-N 0.000 description 3
- 238000004435 EPR spectroscopy Methods 0.000 description 3
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 230000001678 irradiating effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- -1 hydroxyl radicals Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 210000003712 lysosome Anatomy 0.000 description 2
- 230000001868 lysosomic effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 238000005424 photoluminescence Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- VCUVETGKTILCLC-UHFFFAOYSA-N 5,5-dimethyl-1-pyrroline N-oxide Chemical compound CC1(C)CCC=[N+]1[O-] VCUVETGKTILCLC-UHFFFAOYSA-N 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 238000011262 co‐therapy Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 210000001703 glandular epithelial cell Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 239000012221 photothermal agent Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B32/00—Carbon; Compounds thereof
- C01B32/15—Nano-sized carbon materials
-
- 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
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nanotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Composite Materials (AREA)
- Manufacturing & Machinery (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the field of fluorescent nano materials, and particularly relates to an orange fluorescent carbon dot based on citric acid and chiral 2-amino-1, 2-diphenylethanol, and a preparation method and application thereof. The method comprises the steps of taking citric acid and chiral 2-amino-1, 2-diphenyl ethanol as raw materials, performing high-temperature solid-phase reaction without adding any solvent, and separating and purifying target fluorescent carbon points through column chromatography, wherein the carbon points prepared by (1R, 2S) -2-amino-1, 2-diphenyl ethanol are named RCDs, and the carbon points prepared by (1S, 2R) -2-amino-1, 2-diphenyl ethanol are named SCDs. RCDs and SCDs have two-photon fluorescence property, and have excellent single-photon and two-photon cell imaging effects. Because RCDs have better hydroxyl radical generating capacity and photothermal conversion capacity, the RCDs are used for photodynamic and photothermal combined treatment, successfully inhibit the growth of tumors in a mouse tumor-bearing model, show good combined treatment effect and are potential photodynamic and photothermal combined treatment agents.
Description
Technical Field
The invention belongs to the field of fluorescent nano materials, and particularly relates to an orange fluorescent carbon dot based on citric acid and chiral 2-amino-1, 2-diphenylethanol, and a preparation method and application thereof.
Background
Cancer treatment has been a difficult problem to overcome in the medical community, patients often receive chemotherapy, radiotherapy and surgery, but these conventional therapies have serious side effects and impose a great burden on the patient's body. Photodynamic and photothermal treatments are bright swords polished by human beings in continuous fight against cancers, and have the advantages of accurate treatment and low toxic and side effects. In photodynamic therapy (PDT), photosensitizers generate high concentrations of ROS under light to oxidize damaged malignant cells; in Phototherapy (PTT), a photothermal agent rapidly accumulates heat under laser irradiation to raise the local temperature of a tumor site to kill cancer cells. However, because of the hypoxic microenvironment or heat resistance of tumor cells, the effect of PDT or PTT alone is limited, making tumor cells incapable of eradication, and combining PDT and PTT is a necessary option, but this may involve cumbersome design steps and high cost investment, so it is urgent to develop a simple therapeutic agent capable of achieving both PDT and PTT.
Carbon Dots (CDs) are a new type of Carbon nanomaterial. In 2004, the luminescent carbon nanomaterial first appears in the fields of scientific researchers, in 2006, the luminescent carbon nanomaterial is reported by the name of a carbon dot for the first time, the excellent Photoluminescence (PL) property of CDs makes the luminescent carbon nanomaterial acquire importance of a plurality of students, and with further knowledge and research on CDs, the more excellent property of CDs is mined, so that the luminescent carbon nanomaterial has great application advantages in the fields of sensing, biology, photoelectric devices, anti-counterfeiting and the like, and CDs is already a big research hotspot in the field of nanomaterials. Recent researches show that the carbon dot can realize PDT and PTT cooperative treatment, has the advantages of low cost, simple preparation, photobleaching resistance, low toxicity and the like, can realize in vivo tumor imaging guided PDT/PTT combined treatment, and in addition, the multi-photon fluorescence excitation has deeper penetration depth and smaller toxic and side effects, thereby being more beneficial to biological application of the carbon dot. The carbon dots have great application potential in clinic, so that the development of more carbon dots with excellent photodynamic and photothermal properties proves that the carbon dots can be supported to be used as phototherapy agents for tumor treatment is of great significance.
Disclosure of Invention
In view of the above problems, the present invention aims to provide a carbon dot based on citric acid and chiral 2-amino-1, 2-diphenylethanol, and preparation and application thereof, wherein the carbon dot has single or two-photon fluorescence properties, and has excellent in-vitro and in-vivo PDT/PTT combined treatment effects, and can be used as a safe and low-toxicity phototherapy agent for cancer treatment.
In order to achieve the above object, the present invention provides the following technical solutions:
an orange fluorescent carbon dot based on citric acid and chiral 2-amino-1, 2-diphenyl ethanol, wherein the raw material consists of citric acid and (1R, 2S) -2-amino-1, 2-diphenyl ethanol or (1S, 2R) -2-amino-1, 2-diphenyl ethanol, and the molar ratio of the citric acid to the chiral 2-amino-1, 2-diphenyl ethanol is 1:1-5.
In the invention, the particle size range of fluorescent carbon points (RCDs) of the citric acid and (1R, 2S) -2-amino-1, 2-diphenylethanol is 0.8-6.3nm; further, the average particle diameter was 2.7nm.
In the invention, the particle size range of fluorescent carbon points (SCDs) of the citric acid and the (1S, 2R) -2-amino-1, 2-diphenylethanol is 1.3-5.6nm; further, the average particle diameter was 3.0nm.
The invention also provides a preparation method of the fluorescent carbon dots (RCDs or SCDs), which comprises the following steps:
(1) Mixing citric acid and (1R, 2S) -2-amino-1, 2-diphenyl ethanol or (1S, 2R) -2-amino-1, 2-diphenyl ethanol for high temperature solid phase reaction;
(2) And (3) cooling, dissolving and purifying the reactant obtained in the step (1) by column chromatography to obtain the carbon dots.
In the invention, the temperature of the high-temperature solid phase preparation in the step (1) is 180-220 ℃, and the preparation time is 6-10h.
In the invention, in the step (2), a solvent is added to fully dissolve the reactant obtained in the step (1), and then the separation and purification are carried out in a column chromatography mode;
further, the solvent in step (2) is selected from organic solvents such as ethyl acetate, methylene chloride, and the like.
The research results of the inventor show that the orange fluorescent carbon dots, RCDs and SCDs in the invention all show single-photon or two-photon fluorescence characteristics. For the dual-light fluorescence characteristic, RCDs and SCDs are logarithmic relations between laser power and emitted light intensity under different powers and long-wavelength excitation light (infrared light region excitation light), respectively, which shows that the RCDs and the SCDs have the dual-photon fluorescence characteristic.
The invention also uses the orange fluorescent carbon dots for fluorescent imaging.
Further, the orange fluorescent carbon dots are used as single-photon and/or two-photon cell imaging probes or dyes.
In some embodiments of the invention, the orange fluorescent carbon dots are used for fluorescent imaging, specifically, after the fluorescent carbon dots are added into a culture solution and incubated with cells, the carbon dots which do not enter the cells are washed out by PBS, and then observed under a confocal fluorescent microscope, and the inside of the cells presents orange fluorescence;
in the invention, for citric acid and (1R, 2S) -2-amino-1, 2-diphenyl ethanol fluorescent carbon points, the excitation light wavelength in single photon fluorescent imaging is 380 nm-540 nm, preferably 488nm; the excitation wavelength in two-photon fluorescence imaging is 800nm to 1000nm, preferably 900nm.
In the invention, for citric acid and (1S, 2R) -2-amino-1, 2-diphenyl ethanol fluorescent carbon dots, the excitation light wavelength in single photon imaging is 380 nm-540 nm, preferably 490nm; the excitation wavelength in two-photon fluorescence imaging is 800nm to 1000nm, preferably 850nm.
The present invention also provides a fluorescent imaging probe or dye comprising RCDs and/or SCDs.
The inventor researches and discovers that the photodynamic and photothermal properties of RCDs and SCDs are good, ROS can be generated under the irradiation of light, and the light energy can be converted into heat energy.
Based on the above, the orange fluorescent carbon dots are also used for preparing anticancer drugs;
further, orange fluorescent carbon dots are used for preparing an anti-adenocarcinoma drug;
further, the orange fluorescent carbon dots are used for preparing the breast cancer resisting medicine.
The adenocarcinoma in the present invention is a cancer formed by glandular epithelial cells, such as breast cancer, colon cancer, prostate cancer, etc.
In some embodiments of the invention, the orange fluorescent carbon dots described above are used to prepare photodynamic and/or photothermal therapeutic agents for cancer treatment.
The invention also provides a photodynamic and/or photothermal therapeutic agent comprising RCDs and/or SCDs.
The invention has the beneficial effects that:
(1) According to the invention, citric acid is used as a carbon source, chiral 2-amino-1, 2-diphenylethanol is used as a nitrogen source, the nitrogen source is not reported, and the raw material is novel;
(2) The preparation process of the carbon dots is simple and the cost is low;
(3) The RCDs and SCDs provided by the invention have two-photon fluorescence properties, can be used as a two-photon fluorescence imaging probe or dye, and have the advantages of small tissue autofluorescence background, large penetration depth and slight damage to biological tissues;
(4) The RCDs provided by the invention also have better capability of generating hydroxyl radicals and photothermal conversion capability, and the RCDs can generate the hydroxyl radicals at 808nm (1 w/cm 2 ) Under irradiation, the temperature of the RCDs solution may rise to about 46 ℃, which indicates that RCDs are potentially useful in photodynamic, photothermal combination therapy. Experimental results prove that the RCDs have excellent in-vitro and in-vivo photodynamic and photothermal combined treatment effects, successfully inhibit tumor growth in a mouse tumor-bearing model, and detect blood biochemistry and tissue H&The E staining results demonstrate that RCDs have no significant toxicity to mice, and have potential as candidate drugs for tumor phototherapy.
Drawings
FIG. 1 is a transmission electron microscope/high resolution transmission electron microscope (TEM/HRTEM) image of RCDs prepared according to the present invention.
FIG. 2 is a graph showing the fluorescence of (a) RCDs solid at 490nm, 900nm excitation; (b) Two-photon fluorescence spectra of RCDs under 900nm excitation at different powers and (c) a graph of the relationship between laser power and RCDs fluorescence intensity.
FIG. 3 is a fluorescence spectrum of RCDs solution (containing DCFH) at various illumination times.
FIG. 4 is an Electron Paramagnetic Resonance (EPR) spectrum of an RCDs solution after light treatment.
FIG. 5 is a graph showing the temperature change of RCDs solution and blank solution under 808nm laser irradiation.
FIG. 6 is a single photon, two photon fluorescence imaging of 4T1 cells after co-incubation with RCDs.
FIG. 7 is a fluorescence image of Calcein-AM/PI stained 4T1 cells.
FIG. 8 shows the tumor growth of mice during (a) treatment; (b) tumor tissue size after 14 days; (c) graph of body weight change trend of mice.
FIG. 9 is a transmission electron microscope/high resolution transmission electron microscope (TEM/HRTEM) image of SCDs prepared according to the present invention.
FIG. 10 is a graph of fluorescence of (a) SCDs solid at 490nm, 850nm excitation; (b) Two-photon fluorescence spectra of SCDs under excitation of different powers of 850nm, and (c) a relationship graph between laser power and SCDs fluorescence intensity.
FIG. 11 is a single photon, two photon fluorescence imaging of 4T1 cells after co-incubation with SCDs.
Detailed Description
The technical solutions provided in the present invention are described in detail below by way of specific examples, but the scope of the claims is not limited to the descriptions.
Example 1
The preparation method of the RCDs comprises the following steps:
(1) Mixing 0.384g of ground citric acid and 0.640g of (1R, 2S) -2-amino-1, 2-diphenyl ethanol (molar ratio 1:1.5), adding into a high-pressure reaction kettle, placing into a blast drying oven, and keeping for 6 hours after the temperature rises to 180 ℃;
(2) After the reaction is finished, opening the reaction kettle after the reaction kettle is naturally cooled to room temperature, and adding ethyl acetate into the reaction kettle to stir and dissolve; the orange fluorescent carbon dots RCDs are separated and purified by column chromatography.
FIG. 1 is a Transmission Electron Microscope (TEM) image of RCDs prepared in this example, and it can be seen from the figure that the prepared RCDs are approximately round and have good dispersibility; the particle size is in the range of 0.8-6.3nm, and the average particle size is 2.7nm. High Resolution Transmission Electron Microscopy (HRTEM) images of RCDs showed significant lattice fringes at the carbon sites with a interplanar spacing of 0.23nm.
FIG. 2 (a) is a fluorescence spectrum of RCDs solid at 490nm and 900nm excitation with emission peak positions at about 590 nm; FIG. 2 (b) is a two-photon fluorescence spectrum of RCDs solid under excitation of 900nm at different powers, with the RCDs fluorescence being stronger as the output power is greater; FIG. 2 (c) shows the relationship between the laser power and the logarithmic of the fluorescence intensity emitted from RCDs, with a slope of 1.83, indicating that RCDs have two-photon fluorescence properties.
FIG. 3 is a graph showing the fluorescence of RCDs solution (containing DCFH) at various illumination times, showing that the peak at about 525nm increases gradually with increasing illumination time, because RCDs solution generates Reactive Oxygen Species (ROS) under illumination conditions, and DCFH is oxidized to form strong green fluorescent DCF after reacting with ROS.
FIG. 4 is an Electron Paramagnetic Resonance (EPR) spectrum of an RCDs solution after light treatment. And the DMPO is used as a free radical capturing agent, and an Electron Paramagnetic Resonance (EPR) test is carried out on the RCDs solution subjected to the light irradiation treatment, so that the test result shows that the RCDs solution has a stronger hydroxyl free radical signal. With reference to fig. 3 and 4, the photodynamic performance test results show that RCDs have potential for type I photodynamic therapy.
FIG. 5 shows the trend of temperature change of RCDs solution under 808nm laser irradiation, the initial temperature of RCDs solution is 21.7deg.C, the temperature can be raised to 42.4deg.C at 10min, the temperature approaches 46 deg.C at 20min, the temperature is only 29.3deg.C at 20min, the temperature is about 32deg.C, the temperature rising rate of RCDs solution is significantly higher than that of blank control, and the temperature can be up to 46 deg.C, which indicates that RCDs have better photothermal conversion capability and potential for photothermal treatment.
Example 2:
a method of preparing SCDs comprising the steps of:
(1) Mixing 0.384g of ground citric acid and 0.640g of (1S, 2R) -2-amino-1, 2-diphenyl ethanol (molar ratio 1:1.5), adding into a high-pressure reaction kettle, placing into a blast drying oven, and keeping for 6 hours after the temperature rises to 180 ℃;
(2) After the reaction is finished, opening the reaction kettle after the reaction kettle is naturally cooled to room temperature, and adding ethyl acetate into the reaction kettle to stir and dissolve; the orange fluorescent carbon dots SCDs are separated and purified by column chromatography.
FIG. 9 is a Transmission Electron Microscope (TEM) image of SCDs prepared in this example, and it can be seen from the figure that the prepared SCDs are approximately round and have good dispersibility; the particle size is 1.3-5.6nm, and the average particle size is 3.0nm. High Resolution Transmission Electron Microscopy (HRTEM) images of SCDs showed significant lattice fringes at the carbon sites with a interplanar spacing of 0.21nm.
FIG. 10 (a) is a graph of fluorescence of SCDs solid at 490nm and 850nm excitation with emission peak positions at about 590 nm; FIG. 10 (b) is a two-photon fluorescence spectrum of SCDs solid under excitation of 850nm at different powers, with the SCDs fluorescence being stronger as the output power is larger; FIG. 10 (c) shows the relationship between the laser power and the logarithm of the fluorescence intensity emitted from SCDs, with a slope of 1.77, indicating that SCDs have two-photon fluorescence properties.
Application example 1
The RCDs obtained in example 1 of the present invention were used for fluorescence imaging of mouse breast cancer cells (4T 1), and the specific procedures were as follows:
(1) Inoculating 4T1 cells into 20mm diameter confocal culture dish, placing into 37 deg.C 5% CO 2 Incubating in a cell incubator;
(2) Taking out the confocal dish in the step (1), sucking out the old culture medium, rinsing the cells with PBS, adding the culture medium containing RCDs again (RCDs concentration is 20. Mu.g/mL), placing in 37 ℃ C., 5% CO 2 Incubating in a cell incubator for 4 hours;
(3) After the incubation, the old medium was aspirated, and the cells were rinsed 3 times with PBS solution to remove excess RCDs that did not enter the cells, and then observed under a confocal fluorescence microscope.
FIG. 6 is a fluorescent image of 4T1 cells incubated with RCDs, showing that RCDs are brightly fluorescent under excitation at 488nm and 900nm, and have excellent single-photon and two-photon imaging effects, and RCDs are mainly enriched in lysosome sites, showing lysosome targeting.
Application example 2
The RCDs obtained in example 1 of the present invention were used for phototherapy of mouse breast cancer cells (4T 1), and the specific procedures were as follows:
(1) Inoculating 4T1 cells in logarithmic phase into 4 confocal dishes, placing into 37 ℃ and 5% CO 2 Incubating for 24 hours in a cell incubator;
(2) Marking the 4 confocal cuvettes in the step (1) as a blank group, a light-only group (white light+808 nm laser), a dosing group (RCDs), a dosing+light-only group, and performing corresponding experimental treatment: after addition of fresh medium to the cells of the light-only group, the cells were irradiated with a xenon lamp (200 mw/cm 2 ) And 808nm laser (1 w/cm) 2 ) After 10min of irradiation of the cells, incubating for a further 12h; only the dosing group cells were replaced with medium containing RCDs (20. Mu.g/mL) with old medium and incubation continued; after replacement of old medium with medium containing RCDs (20. Mu.g/mL) in the administration + light group cells, the cells were irradiated with a xenon lamp (200 mw/cm 2 ) And 808nm laser (1 w/cm) 2 ) Irradiating the cells for 10min, and placing the cells into an incubator for continuous incubation; after addition of the new medium, the blank group was incubated without any treatment.
(3) After the incubation, the old medium was removed, and the mixture was incubated with Calcein-AM/PI buffer for 30min, and finally rinsed with PBS, and then observed under a confocal fluorescence microscope.
FIG. 7 shows that cells in both the light-only and dosing groups were labeled with Calcein-AM, with strong green fluorescence at 488nm excitation, and red fluorescence of PI-stained dead cells was not observed at 552nm excitation, indicating little toxicity of either light or RCDs to the cells; whereas cells of the dosing + light group showed a large area red fluorescent signal under 552nm excitation, almost all nuclei of cells were stained with PI, indicating that ROS produced by RCDs under white light irradiation and heat produced under 808nm laser irradiation had a better killing effect on 4T 1. RCDs successfully achieve photodynamic/photothermal co-therapy at the cellular level. Based on this, we further constructed a mouse subcutaneous tumor model to study its in vivo phototherapy effect.
Application example 3
The RCDs obtained in example 1 of the present invention were used for phototherapy of subcutaneous tumors in mice, and the specific procedures were as follows:
(1) Constructing a mouse tumor model: BALB/C mice (female, 4 weeks old) were used as subjects, 100. Mu.L of 4T1 finePBS suspension of cells (about 2X 10 6 ) The mice can eat freely by injecting into the tail side of the mice subcutaneously and then placing the mice in a mouse feeding room for normal feeding;
(2) Five days after cancer cell inoculation, mice were equally divided into four groups, namely, a blank group, a dosing group, an illumination group, a dosing+illumination group, and were subjected to different treatments, respectively. The experimental steps are as follows: the blank group was not subjected to any treatment; tumors of the light-only mice were injected in situ with 100. Mu.L of PBS solution, using a xenon lamp (200 mw/cm 2 2 min), 808nm laser (1 w/cm) 2 10 min) irradiating the tumor site of the mouse; tumor in-situ injection of 100. Mu.L of RCDs solution (100. Mu.g/mL) was performed on mice in the dosing group alone without light irradiation; tumors of mice in the +light group of administration were injected in situ with 100. Mu.L of RCDs solution (100. Mu.g/mL) using a xenon lamp (200 mw/cm 2 2 min), 808nm laser (1 w/cm) 2 10 min) irradiating tumor sites of the mice.
(3) The body weight and tumor size of the mice were recorded every two days and observed for 14 days. Tumor volume calculation formula: 1/2 tumor length x tumor width 2 。
Fig. 8 (a) shows the change in tumor volume of mice during treatment, and it can be seen from the graph that tumors of mice in the blank group and the administration group only grow rapidly and continuously, tumors of mice in the light group only are affected by light irradiation, growth is slightly slow, and tumor growth of mice in the administration+light group is significantly inhibited; fig. 8 (b) is the tumor tissue volume size after 14 days, and it can be seen that the tumor volume of the mice in the administration + light group is significantly smaller than that of the other three groups, even completely ablated, which indicates that RCDs have a significant phototherapy effect. Fig. 8 (c) reflects the weight change of mice, and it can be seen from the figure that the weights of the four groups of mice were not significantly reduced during the treatment period and were gradually gaining weight, which indicates that the treatment used in the experiment did not have great toxic or side effects on the body of the mice.
The foregoing is a further detailed description of the invention in connection with specific embodiments, and it is not intended that the invention be limited to those specific embodiments. It will be apparent to those skilled in the art that several deductions or substitutions may be made without departing from the spirit of the invention, and these shall be considered to be within the scope of the invention.
Claims (15)
1. An orange fluorescent carbon dot based on citric acid and chiral 2-amino-1, 2-diphenyl ethanol, which is characterized in that raw materials consist of citric acid and (1R, 2S) -2-amino-1, 2-diphenyl ethanol or (1S, 2R) -2-amino-1, 2-diphenyl ethanol, and the molar ratio of the citric acid to the chiral 2-amino-1, 2-diphenyl ethanol is 1:1-5;
a method of making a carbon dot comprising the steps of:
(1) Mixing citric acid and (1R, 2S) -2-amino-1, 2-diphenyl ethanol or (1S, 2R) -2-amino-1, 2-diphenyl ethanol for high temperature solid phase reaction;
(2) Cooling, dissolving and purifying the reactant obtained in the step (1) by column chromatography to obtain the carbon dots;
the temperature of the high-temperature solid phase preparation in the step (1) is 180-220 ℃, and the preparation time is 6-10h.
2. The carbon dot of claim 1, wherein the carbon dot particle size based on citric acid and (1 r,2 s) -2-amino-1, 2-diphenylethanol is in the range of 0.8-6.3nm; the carbon point particle size based on citric acid and (1S, 2R) -2-amino-1, 2-diphenylethanol is in the range of 1.3-5.6nm.
3. The carbon dot of claim 1, wherein the citric acid and (1 r,2 s) -2-amino-1, 2-diphenylethanol based carbon dot has an average particle size of 2.7nm; the average particle diameter of the carbon dots based on citric acid and (1S, 2R) -2-amino-1, 2-diphenylethanol is 3.0nm.
4. A method of preparing a carbon dot as claimed in any one of claims 1 to 3, comprising the steps of:
(1) Mixing citric acid and (1R, 2S) -2-amino-1, 2-diphenyl ethanol or (1S, 2R) -2-amino-1, 2-diphenyl ethanol for high temperature solid phase reaction;
(2) And (3) cooling, dissolving and purifying the reactant obtained in the step (1) by column chromatography to obtain the carbon dots.
5. The method according to claim 4, wherein the high temperature solid phase preparation in the step (1) is carried out at a temperature of 180-220 ℃ for a preparation time of 6-10 hours.
6. The method according to claim 4, wherein in the step (2), a solvent is added to sufficiently dissolve the reactant obtained in the step (1), and then the separation and purification are performed by column chromatography.
7. The method of claim 6, wherein the solvent comprises one or both of ethyl acetate and methylene chloride.
8. Use of a carbon dot according to any one of claims 1-3 in fluorescence imaging.
9. The use according to claim 8, characterized in that carbon dots are used as single-photon and/or two-photon cell imaging probes or dyes.
10. The use according to claim 8, wherein carbon dots are added to the culture medium, incubated with cells, washed off with PBS without entering the cells, and then observed under confocal fluorescence microscopy, and the inside of the cells exhibits orange fluorescence.
11. The use according to claim 10, characterized in that for carbon dots based on citric acid and (1 r,2 s) -2-amino-1, 2-diphenylethanol, the excitation light wavelength at single photon fluorescence imaging is 380nm to 540nm; the excitation wavelength in the two-photon fluorescence imaging is 800 nm-1000 nm; for carbon points based on citric acid and (1S, 2R) -2-amino-1, 2-diphenylethanol, the excitation light wavelength at the time of single photon imaging is 380 nm-540 nm; the excitation wavelength in the two-photon fluorescence imaging is 800 nm-1000 nm.
12. The use according to claim 10, characterized in that for carbon dots based on citric acid and (1 r,2 s) -2-amino-1, 2-diphenylethanol, the excitation light wavelength at single photon fluorescence imaging is 488nm; the excitation wavelength in the two-photon fluorescence imaging is 900nm; for carbon dots based on citric acid and (1 s,2 r) -2-amino-1, 2-diphenylethanol, the excitation light wavelength at single photon imaging was 490nm; the excitation wavelength at the time of two-photon fluorescence imaging was 850nm.
13. A fluorescent imaging probe or dye comprising a carbon dot according to any one of claims 1 to 3.
14. Use of a carbon dot according to any one of claims 1-3 for the preparation of an anti-breast cancer medicament.
15. A photodynamic and/or photothermal therapeutic agent comprising a carbon dot according to any one of claims 1-3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211099781.5A CN115465853B (en) | 2022-09-07 | 2022-09-07 | Orange light carbon dot based on citric acid and chiral 2-amino-1, 2-diphenyl ethanol and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211099781.5A CN115465853B (en) | 2022-09-07 | 2022-09-07 | Orange light carbon dot based on citric acid and chiral 2-amino-1, 2-diphenyl ethanol and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115465853A CN115465853A (en) | 2022-12-13 |
| CN115465853B true CN115465853B (en) | 2023-06-20 |
Family
ID=84370359
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211099781.5A Active CN115465853B (en) | 2022-09-07 | 2022-09-07 | Orange light carbon dot based on citric acid and chiral 2-amino-1, 2-diphenyl ethanol and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115465853B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107841307A (en) * | 2016-08-04 | 2018-03-27 | 南京工业大学 | Large-scale preparation method of fluorescent carbon quantum dots |
| CN114015438A (en) * | 2021-11-11 | 2022-02-08 | 杭州电子科技大学 | Preparation method of nitrogen-boron co-doped ultraviolet blue dual-wavelength fluorescent carbon dots |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL297595A (en) * | 1964-09-14 | |||
| DE29810218U1 (en) * | 1998-06-08 | 1998-08-13 | Wella Ag, 64295 Darmstadt | Multi-component kit for dyeing and decoloring fibers |
| JP2001131101A (en) * | 1999-11-02 | 2001-05-15 | Kissei Pharmaceut Co Ltd | Method for producing optically active alcohol compound |
| CN104707638B (en) * | 2013-12-13 | 2017-06-30 | 中国科学院大连化学物理研究所 | A kind of nitrogenous amorphous carbon layer parcel CNT one-dimensional material with core shell structure and its preparation method and application |
| CN104528692A (en) * | 2015-01-28 | 2015-04-22 | 中国药科大学 | Synthesis method of nitrogen-doped fluorescent carbon dots |
| CN105255487B (en) * | 2015-10-19 | 2017-04-19 | 南京医科大学 | Amino alcohol functional CDs (carbon dots), preparation method and application of amino alcohol functional CDs in copper ion measurement |
| CN108587613A (en) * | 2018-01-09 | 2018-09-28 | 河南工学院 | A kind of preparation method of butyl thiosemicarbazide modified carbon quantum dot fluorescence probe and its application in Selective recognition copper ion |
| CN108424546B (en) * | 2018-02-14 | 2019-11-08 | 东华大学 | A kind of salt, preparation method and its application of hybrid modification phosphoric acid |
| CN108862241B (en) * | 2018-08-06 | 2020-10-09 | 厦门大学 | Preparation method of nitrogen-boron-fluorine ternary-element-codoped hollow carbon nano-microspheres |
| US12108759B2 (en) * | 2018-11-04 | 2024-10-08 | B.G. Negev Technologies & Applications, Ltd., At Ben-Gurion University | Synthesis of antimicrobial carbon dots and uses thereof |
| CN110615428B (en) * | 2019-09-04 | 2020-08-18 | 西安交通大学 | Preparation method of amphiphilic graphene quantum dot material |
| CN110982513B (en) * | 2019-11-29 | 2022-10-04 | 郑州大学 | Preparation method of fluorescent carbon dots and application of fluorescent carbon dots in cell imaging |
| CN112251223B (en) * | 2020-09-14 | 2023-02-24 | 西华大学 | Nitrogen-doped fluorescent carbon dot based on citric acid and benzoylurea as well as preparation method and application thereof |
-
2022
- 2022-09-07 CN CN202211099781.5A patent/CN115465853B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107841307A (en) * | 2016-08-04 | 2018-03-27 | 南京工业大学 | Large-scale preparation method of fluorescent carbon quantum dots |
| CN114015438A (en) * | 2021-11-11 | 2022-02-08 | 杭州电子科技大学 | Preparation method of nitrogen-boron co-doped ultraviolet blue dual-wavelength fluorescent carbon dots |
Non-Patent Citations (1)
| Title |
|---|
| 王颖 ; 李洪仁.一步法合成荧光碳纳米粒子及其表征.《沈阳大学学报(自然科学版)》.2015,(第3期),第185-188页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115465853A (en) | 2022-12-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106039326B (en) | A kind of preparation method of the nano anti-cancer probe of zirconium-porphyrin metal organic framework materials | |
| CN110003461B (en) | Polyiodide-modified BODIPY derivative and preparation method and application thereof | |
| AU2013357030B2 (en) | Chlorin derivative useful in photodynamic therapy and diagnosis | |
| CN103316340A (en) | Gold nanocomposite particle having plasma photothermal/photodynamic therapy performance, and preparation method thereof | |
| CN109796972A (en) | A kind of carbon quantum dot and its preparation method and application of singlet oxygen control release type | |
| CN103539799B (en) | A kind of water soluble amino poly carboxylic acid modifies preparation method and the purposes of phthalocyanine compound | |
| WO2021143829A1 (en) | Non-peripheral quaternary ammonium group modified zinc phthalocyanine and method for preparation thereof and application thereof | |
| EP3682899A1 (en) | Compound amphiphilic peptide nanomicelle, preparation and use thereof | |
| CN113456836B (en) | Manganese-heme coordination polymer nanoparticle and preparation method and application thereof | |
| CN107715110B (en) | Biodegradable black phosphorus-based X-ray photodynamic therapy photosensitizer and preparation method and application thereof | |
| CN115465853B (en) | Orange light carbon dot based on citric acid and chiral 2-amino-1, 2-diphenyl ethanol and preparation method and application thereof | |
| CN113384697A (en) | Multifunctional nano particle for tumor diagnosis and treatment integration, preparation and application | |
| CN110339356B (en) | Carbon nanodot reagent, preparation method and application thereof | |
| CN110724517A (en) | Rare earth/chlorophyll composite probe and preparation method and application thereof | |
| CN110743013A (en) | Up-conversion nano composite material for dual-power cooperative treatment, preparation method and application | |
| CN114601925A (en) | Photosensitive nano material jointly modified by hyaluronic acid and RSL3, preparation method and application thereof | |
| CN108175857A (en) | For near infrared light excitation lower bismuth sulfide-zinc protoporphyrin composite material and preparation method and application with photodynamic therapy for cancer property | |
| Lan et al. | Chemo-photodynamic antitumour therapy based on Er-doped upconversion nanoparticles coated with hypocrellin B and MnO2 | |
| CN113527349A (en) | Photosensitizer with tumor targeting property and preparation method and application thereof | |
| CN111635403A (en) | Second near-infrared window nano photosensitizer based on NDI (Newcastle disease Virus) molecules and preparation method | |
| CN104306973A (en) | Preparation method and application of titanium dioxide carbon nanometer composite material-polymer composite hydrogel | |
| CN110038126A (en) | Application of the oxide of cobalt in preparation tumour light treatment agent | |
| CN110947000B (en) | CuS-NiS2Nanometer flower and preparation method and application thereof | |
| CN117224673B (en) | Titanium-based nano material for enhancing acoustic power treatment of bladder cancer | |
| CN114540011B (en) | Near infrared two-region fluorescent probe molecule and nanoparticle for multi-mode diagnosis and treatment integration |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |