CN110947007B - Rare earth up-conversion diagnosis and treatment integrated nano composite material, preparation method and application thereof - Google Patents
Rare earth up-conversion diagnosis and treatment integrated nano composite material, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a rare earth up-conversion diagnosis and treatment integrated nano composite material, which takes oil-soluble up-conversion luminescent nano particles (UCNPs) as cores to lead cuprous oxide (Cu)2O) the surface of the up-conversion nanoparticle grows into a shell in an epitaxial manner, and the formed interface nucleates and grows to form the cuprous oxide modified rare earth up-conversion nano composite material; wherein Cu2O can generate fluorescence resonance energy transfer with the up-conversion emission generated by the excitation of UCNPs in near infrared light, and then generate enough active oxygen to meet the requirement of photodynamic therapy; meanwhile, the fluorescent nanoparticle is matched with the oil-soluble up-conversion luminescent nanoparticle to realize diagnosis and treatment integration. The invention also provides a preparation method of the material, which takes the oil-soluble up-conversion luminescent nano-particles as nuclei to lead cuprous oxide to nucleate and grow on the surfaces of the up-conversion nano-particles. The nano composite material has the advantages of uniform size, good stability and good biocompatibility, can be used for imaging diagnosis guided photodynamic therapy, and meets the requirement of clinical diagnosis and treatment integration.
Description
Technical Field
The invention relates to the technical field of nano biological materials, in particular to a rare earth up-conversion diagnosis and treatment integrated nano composite material, a preparation method and application thereof.
Background
Cancer has become one of the major diseases that endanger human health, and the traditional anticancer methods have some limitations relatively, such as drug resistance in chemotherapy, serious side effects in radiotherapy, high recurrence rate in surgery, and the like.
Photodynamic therapy (PDT) is a new treatment means in recent years, and has the advantages of good controllability, small side effect and the like. The principle is that the photosensitizer activates surrounding oxygen molecules to generate active oxygen under the excitation of a light source, so that the important structure and function of cells are damaged, and finally the purpose of destroying pathological tissues is achieved.
Photodynamic therapy (PDT) has attracted a great deal of attention in the area of cancer therapy due to the precise and predictable response to phototherapy for a particular lesion. PDT is a non-invasive treatment applied in the biomedical field. Under the excitation of laser with specific wavelength, a proper photosensitizer is selected to generate Reactive Oxygen Species (ROS) with cytotoxicity, and tumor cells are killed, so that the purpose of treating tumors is achieved. PDT requires photosensitizers that generate ROS efficiently, however most organic photosensitizers are susceptible to light-induced and enzymatic degradation, limiting the PDT therapeutic efficacy. Inorganic photosensitizers are reported to be of increasing interest due to their good stability in biological environments.
In recent years, fluorescence imaging has become one of the research hotspots in optical imaging technology, because fluorescence imaging has the advantages of high sensitivity, no damage to cells and biological tissues, and the like. Among them, rare earth doped up-conversion luminescent nano materials (UCNPs) have attracted much attention as a new fluorescent material because it usually uses low energy light excitation (usually near infrared 980nm, 808nm) to emit high energy light (red light, green light, near infrared 800nm), and these advantages can eliminate biological background fluorescence interference. UCNPs can convert NIR light of a long wavelength into ultraviolet, visible, or near infrared light of a short wavelength by anti-stokes shift, and can activate a photosensitizer nearby by Fluorescence Resonance Energy Transfer (FRET) to generate a large amount of ROS. In addition, because of its unique optical properties, UCNPs have been reported in large numbers as imaging agents in medical treatment processes, and simultaneously, combined with photosensitizers, impart a wide variety of functions thereto. In order to obtain an efficient energy transfer from UCNPs to the photosensitizer, the photosensitizer should be as close as possible to the UCNPs, and the absorption of the photosensitizer should overlap as much as possible with the emission of the UCNPs.
However, in the prior art, due to the limitations of preparation processes and material component properties, few photosensitizers can be directly excited by NIR light to generate enough Reactive Oxygen Species (ROS), so that the use of photosensitizers with unique structures and low degradation tendency in PDT to generate enough Reactive Oxygen Species (ROS) with cytotoxicity cannot be satisfied to achieve the expected therapeutic effect. Meanwhile, at present, a nanocomposite material which meets the PDT requirement and has a fluorescence imaging function for diagnosing cancer diseases, combines treatment and has a diagnosis and treatment integrated function is not available.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a rare earth upconversion diagnosis and treatment integrated nano composite material with diagnosis and treatment integrated functions aiming at PDT requirements, which adopts a core-shell structure and a Cu structure which is unique in structure and not easy to degrade2O is used as a photosensitizer to generate enough reactive oxygen species ROS with cytotoxicity to meet PDT requirements and simultaneously has a fluorescence imaging function for diagnosing cancer diseases;
the invention also provides a preparation method of the rare earth up-conversion diagnosis and treatment integrated nano composite material, the method has simple steps, the preparation process is efficient and stable, easy to control and high in repeatability, industrialization is easy, and the prepared product has stable performance and good consistency.
The invention also aims to provide the application of the material.
In order to achieve the purpose, the invention adopts the technical scheme that:
a rare earth up-conversion diagnosis and treatment integrated nano composite material is prepared by taking oil-soluble up-conversion luminescent nano particles as cores and enabling Cu to be in a Cu-rich state2O epitaxially grows on the surface of the upconversion nanoparticle to form a shell, and Cu with interface nucleation growth is formed2O-modified rare earth up-conversion nanocomposites; upon NIR light excitation, the upconversion emission FRET of UCNPs is transferred to Cu2O, generating enough ROS in an aerobic environment to meet the requirements of PDT; meanwhile, the fluorescent nanoparticle is matched with the oil-soluble up-conversion luminescent nanoparticle to realize diagnosis and treatment integration.
The oil-soluble rare earth up-conversion luminescent nanoparticle comprises: NaYF4:Yb,Er、NaYF4:Yb,Tm、NaYF4:Yb,Er,Tm、NaYF4:Yb,Er@NaGdF4、NaYF4:Yb,Tm@NaGdF4、NaYF4:Yb,Er,Tm@NaGdF4、NaYF4:Yb,Er@NaYF4:Nd,Yb、NaYF4:Yb,Tm@NaYF4Nd and Yb.
The preparation method of the rare earth up-conversion diagnosis and treatment integrated nano composite material is characterized by comprising the following steps of:
(1) preparing a dispersion of oil-soluble rare earth up-conversion luminescent nanoparticles in cyclohexane, adding a predetermined amount of Cu (NO)3)2Dropwise adding the solution into the upconversion nanoparticle dispersion liquid, and violently stirring to obtain a first dispersion liquid;
(2) preparing a hydrazine hydrate solution, adding the hydrazine hydrate solution into the first dispersion liquid under stirring for dispersing and mixing, violently stirring to obtain a second dispersion liquid, transferring the second dispersion liquid into a high-pressure reaction kettle for hydrothermal reaction, centrifuging, washing and dispersing the obtained product to obtain the rare earth up-conversion diagnosis and treatment integrated nano composite material.
The steps (1) to (2) specifically include the following steps:
(1) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of Cu (NO)3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(2) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 h, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 h, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth upconversion nanoparticle epitaxially-grown cuprous oxide nanocomposite.
The application of the rare earth upconversion diagnosis and treatment integrated nano composite material is characterized in that the rare earth upconversion diagnosis and treatment integrated nano composite material is used as an imaging agent in fluorescence imaging.
The application of the rare earth upconversion diagnosis and treatment integrated nanocomposite is characterized in that the rare earth upconversion diagnosis and treatment integrated nanocomposite is used for photodynamic therapy, and sufficient ROS are generated under the excitation of NIR laser so as to achieve the treatment effect on cancer.
The invention has the advantages that:
1. the rare earth up-conversion nano particle nano composite material for epitaxial growth of cuprous oxide can realize that fluorescence imaging is used for diagnosis of cancer diseases and is combined with treatment, so that the diagnosis and treatment integrated nano composite material is developed. The modified material (photosensitizer) adopted by the invention adopts cuprous oxide crystals, has a unique structure and is not easy to degrade, and under the coordination of other components and a preparation process, the modified material has good biocompatibility and a good photodynamic treatment effect, and becomes a high-efficiency photosensitizer.
Cu used in the invention2O is a p-type metal oxide semiconductor with a band gap of 2.17eV, which can be well matched with visible light spectrum, and Cu is used in the photocatalysis process of water2O exhibits excellent ability to absorb oxygen and consume photo-generated electrons. Cu2O nanoparticles have been attracting attention in the fields of solar energy conversion, photocatalysis, biosensors, and the like. Currently, most photosensitizers generally absorb strongly in the visible or Ultraviolet (UV) light, however, shallow penetration of visible or UV light in biological tissue results in limited treatment depth. Near Infrared (NIR) light is located in the optical window of biological tissue and thus has a good penetration depth, but few photosensitizers can be excited by NIR light to generate sufficient ROS. Therefore, UCNPs adopted by the invention can convert the non-visible light into visible light under the excitation of NIR laser, and then transfer energy to Cu through FRET2O，Cu2O is a reliable and long-acting PDT photosensitizer, and can generate enough ROS under the aerobic condition to meet the PDT requirement and ensure the curative effect.
The nano composite material provided by the invention has the advantages of uniform size, good stability and good biocompatibility, has the function of photodynamic therapy, can be applied to the fields of up-conversion fluorescence imaging, photodynamic therapy and the like, and meets the requirement of clinical diagnosis and treatment integration.
2. According to the preparation method provided by the invention, cuprous oxide uniformly grows on the surface of the rare earth upconversion nano particles by an epitaxial growth method at room temperature to obtain the rare earth upconversion nanocomposite with cuprous oxide epitaxially grown on the rare earth upconversion nano particles, and the rare earth upconversion nanocomposite with upconversion luminescence imaging and photodynamic therapy is obtained; the preparation method of the nano composite material for diagnosis and treatment integration provided by the invention adopts the method of epitaxial growth of cuprous oxide to prepare the nano composite material, the steps are few, the preparation process is efficient, stable and high in repeatability, the industrialization is easy, and the prepared product has uniform size, stable performance and good consistency.
3. The application of the rare earth up-conversion nano particle epitaxial growth cuprous oxide nano composite material provided by the invention is realized through a unique core-shell structure, UCNPs and Cu2Due to the synergistic effect of the O nano particles, the O nano particles can be applied to fluorescence imaging and photodynamic therapy, and diagnosis and treatment are integrated. The up-conversion emission of UCNPs is transferred to Cu through FRET under the irradiation of 980 or 808 nanometer laser of the composite material2O, ROS that oxidize DPBF, thereby providing a therapeutic effect in killing cancer cells.
To more clearly explain the structural features and effects of the present invention, the following detailed description is given with reference to the accompanying drawings and specific embodiments.
Drawings
FIG. 1 is a graph of upconversion fluorescence spectra and UV absorption spectra of cuprous oxide nanocomposites epitaxially grown with rare earth erbium-doped upconversion nanoparticles according to example 1 of the present invention;
FIG. 2 is a Transmission Electron Microscope (TEM) photograph of the cuprous oxide nanocomposite epitaxially grown by rare earth erbium-doped up-conversion nanoparticles of example 1 of the present invention;
FIG. 3 is a graph of the time-dependent degradation of 1, 3-Diphenylisobenzofuran (DPBF) caused by the ROS generation of a rare earth erbium-doped up-conversion nanoparticle epitaxially grown cuprous oxide nanocomposite material under 980nm laser irradiation in example 1 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The rare earth up-conversion diagnosis and treatment integrated nano composite material provided by the invention takes oil-soluble up-conversion luminescent nano particles as cores, so that cuprous oxide (Cu) is generated2O) the surface of the up-conversion nanoparticle grows into a shell in an epitaxial manner, and the formed interface nucleates and grows to form the cuprous oxide modified rare earth up-conversion nano composite material; wherein cuprous oxide (Cu)2O) can generate enough active oxygen (ROS) under the direct excitation of near infrared light (NIR), thereby having a therapeutic effect on killing cancer cells and meeting the requirement of photodynamic therapy (PDT); meanwhile, the fluorescent nanoparticle is matched with the oil-soluble up-conversion luminescent nanoparticle to realize diagnosis and treatment integration.
The oil-soluble rare earth up-conversion luminescent nanoparticle comprises: NaYF4:Yb,Er、NaYF4:Yb,Tm、NaYF4:Yb,Er,Tm、NaYF4:Yb,Er@NaGdF4、NaYF4:Yb,Tm@NaGdF4、NaYF4:Yb,Er,Tm@NaGdF4、NaYF4:Yb,Er@NaYF4:Nd,Yb、NaYF4:Yb,Tm@NaYF4Nd and Yb. In other embodiments, other oil-soluble rare earth upconversion luminescent nanoparticles having similar structures and properties may also be used.
The composite material and the preparation method thereof provided by the embodiment specifically are rare earth erbium-doped up-conversion diagnosis and treatment integrated nano composite materials, and the preparation method comprises the following steps:
(1) preparing oil-soluble rare earth erbium-doped up-conversion luminescent nanoparticles with the particle size of 25-30 nm;
(2) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of the solutionCu(NO3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(3) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 h, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 h, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth erbium-doped upconversion nanoparticle epitaxially-grown cuprous oxide nanocomposite.
FIG. 1 is an up-conversion fluorescence spectrum and an ultraviolet absorption spectrum of cuprous oxide of a rare earth erbium-doped up-conversion nanoparticle epitaxially grown cuprous oxide nanocomposite material in example 1, wherein emission peaks at 540nm and 654nm corresponding to Er can be observed from the fluorescence spectrum under excitation of 980nm laser3+Is/are as follows4S3/2/2H11/2→4H15/2And4F9/2→4I15/2and transition is carried out, and 980nm is just positioned at an optical window of the biological tissue, so that Fluorescence Resonance Energy Transfer (FRET) is generated in the rare earth up-conversion nano particle epitaxially-grown cuprous oxide nano composite material, the subsequent photodynamic therapy effect is supported, and the weakened luminescence of the nano composite material can still be used for up-conversion fluorescence imaging.
The NIR laser can be selected to be 808 +/-3 nanometers or 980 +/-3 nanometers in wavelength, and is determined by the excitation requirement of the selected converted luminescent nanoparticles.
Example 2:
the composite material and the preparation method thereof provided by the embodiment are particularly a cuprous oxide nanocomposite material epitaxially grown by rare earth thulium-doped up-conversion nanoparticles, which are basically the same as those in embodiment 1, and the difference is that the method comprises the following steps:
(1) preparing oil-soluble rare earth thulium-doped up-conversion luminescent nanoparticles with the particle size of 25-30 nm;
(2) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of Cu (NO)3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(3) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 hours, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 hours, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth thulium doped up-conversion nano particle epitaxially grown cuprous oxide nano composite material.
Fig. 2 is a TEM photograph of the cuprous oxide nanocomposite epitaxially grown by the rare earth thulium-doped upconversion nanoparticles in example 2 of the present invention, and it can be seen from the drawing that cuprous oxide crystals are uniformly wrapped around the upconversion nanoparticles, which indicates that the method can effectively obtain the cuprous oxide nanocomposite epitaxially grown by the rare earth thulium-doped upconversion nanoparticles with good morphology and uniform growth, and the average particle size of the nanocomposite is about 30-50 nm, because the small-sized nanoparticles are more easily endocytosed by cells, which is beneficial to circulation in vivo, and thus, the method has important significance for the application of the small-sized nanoparticles in biological imaging and therapy.
Example 3:
the composite material and the preparation method thereof provided by the embodiment are particularly a rare earth erbium/thulium co-doped up-conversion nanoparticle epitaxially grown cuprous oxide nanocomposite material which is basically the same as the composite material and the preparation method thereof provided by the embodiments 1 and 2, and the difference is that the composite material comprises the following steps:
(1) preparing oil-soluble rare earth erbium/thulium co-doped up-conversion luminescent nanoparticles with the particle size of 25-30 nm;
(2) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of C in the solutionu(NO3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(3) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 hours, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 hours, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the nano composite material of the erbium/thulium co-doped rare earth upconversion nano particles for epitaxial growth of cuprous oxide.
FIG. 3 is a graph of UCNPs @ Cu under 980nm laser excitation (0.5W/cm, 10 min)2The time-dependent degradation pattern of DPBF (1, 3-diphenyl isobenzofuran) caused by the generation of Reactive Oxygen Species (ROS) by O can be seen, and the ultraviolet visible absorption band of DPBF at the wavelength of 410 nm is continuously reduced along with the prolonging of the irradiation time. The results show that the generated ROS are continuously consumed as the irradiation time is prolonged, confirming the efficient generation of ROS. Under the irradiation of 980nm near-infrared laser, the up-conversion energy of UCNPs is transferred to Cu through energy resonance2O, thereby generating ROS that oxidize DPBF.
Example 4:
the composite material and the preparation method thereof provided by the embodiment are particularly a rare earth erbium-doped core-shell upconversion nanoparticle epitaxially grown cuprous oxide nanocomposite, which are basically the same as those in the embodiments 1, 2 and 3, and have the difference that the preparation method comprises the following steps:
(1) the oil-soluble surface with the prepared grain diameter of 30 to 35nm is coated with NaGdF4The rare earth erbium-doped up-conversion luminescent nanoparticles of the inert layer;
(2) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of Cu (NO)3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2The solution is added dropwise into the prepared oil-soluble rare earth to be turnedVigorously stirring the luminescent nanoparticles at room temperature for 15-60 min to obtain a first dispersion liquid;
(3) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 h, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 h, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth erbium-doped core-shell upconversion nanoparticle epitaxially-grown cuprous oxide nanocomposite.
Example 5:
the composite material and the preparation method thereof provided by the embodiment are particularly a cuprous oxide nanocomposite material epitaxially grown by rare earth thulium-doped core-shell upconversion nanoparticles, which are basically the same as those in the embodiments 1, 2, 3 and 4, and have the difference that the preparation method comprises the following steps:
(1) the surface of the prepared grain diameter of 30 to 35nm is coated with NaGdF4Oil-soluble rare earth thulium-doped up-conversion luminescent nanoparticles of the inert layer;
(2) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of Cu (NO)3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(3) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 hours, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 hours, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth thulium doped core-shell upconversion nanoparticle epitaxially grown cuprous oxide nanocomposite.
Example 6:
the composite material and the preparation method thereof provided by the embodiment are specifically rare earth erbium/thulium co-doped core-shell up-conversion nano particle epitaxial growth cuprous oxide nano composite materials, which are basically the same as the examples 1, 2, 3, 4 and 5, and have the difference that the preparation method comprises the following steps:
(1) the surface of the prepared grain diameter of 30 to 35nm is coated with NaGdF4Oil-soluble rare earth erbium/thulium co-doped up-conversion luminescent nanoparticles of the inert layer;
(2) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of Cu (NO)3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(3) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 hours, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 hours, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth erbium/thulium co-doped core-shell upconversion nano particle epitaxial growth cuprous oxide nano composite material.
Example 7:
the composite material and the preparation method thereof provided by the embodiment are specifically a rare earth erbium-doped core-shell upconversion nanoparticle epitaxially grown cuprous oxide nanocomposite, which are basically the same as those in the embodiments 1, 2, 3, 4, 5 and 6, and have the difference that the preparation method comprises the following steps:
(1) the oil-soluble surface with the prepared grain diameter of 30 to 35nm is coated with NaYF4Rare earth erbium-doped up-conversion luminescent nanoparticles of Nd and Yb layers;
(2) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of Cu (NO)3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(3) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 h, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 h, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth erbium-doped core-shell upconversion nanoparticle epitaxially-grown cuprous oxide nanocomposite.
Example 8:
the composite material and the preparation method thereof provided by the embodiment are specifically a rare earth thulium-doped core-shell upconversion nanoparticle epitaxially grown cuprous oxide nanocomposite, which are basically the same as those in the embodiments 1, 2, 3, 4, 5, 6 and 7, and have the difference that the preparation method comprises the following steps:
(1) the oil-soluble surface with the prepared grain diameter of 30 to 35nm is coated with NaYF4Rare earth thulium doped up-conversion luminescent nanoparticles of Nd and Yb layers;
(2) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of Cu (NO)3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(3) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 hours, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 hours, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth thulium doped core-shell upconversion nanoparticle epitaxially grown cuprous oxide nanocomposite.
Example 9:
the composite material and the preparation method thereof provided in this embodiment are, specifically, a rare earth erbium/thulium co-doped core-shell up-conversion nanoparticle epitaxially grown cuprous oxide nanocomposite, which are substantially the same as those in embodiments 1, 2, 3, 4, 5, 6, 7, and 8, and are different in that the method includes the following steps:
(1) the oil-soluble surface with the prepared grain diameter of 30 to 35nm is coated with NaYF4Rare earth erbium/thulium co-doped up-conversion luminescent nano-particles of Nd and Yb layers;
(2) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of Cu (NO)3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(3) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 hours, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 hours, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth erbium/thulium co-doped core-shell upconversion nano particle epitaxial growth cuprous oxide nano composite material.
Examples 7, 8, 9 can also use 808nm lasers to excite the nanocomposites.
The application of the rare earth upconversion diagnosis and treatment integrated nano composite material prepared in each embodiment is used as an imaging agent in fluorescence imaging. The rare earth up-conversion nano particle nano composite material for epitaxial growth of cuprous oxide has the functions of diagnosis and treatment integration, and has the functions of up-conversion luminescence imaging and photodynamic treatment.
The rare earth upconversion diagnosis and treatment integrated nano composite material prepared in each embodiment is applied to photodynamic therapy, under the irradiation of NIR laser, UCNPs convert NIR into visible light through an upconversion process, and the visible light energy is transferred to a photosensitizer Cu through a FRET process2O, ROS that oxidize DPBF are produced in aerobic environments, thereby providing a therapeutic effect for killing cancer cells.
The key point of the invention is that cuprous oxide is epitaxially grown on the surface of the oil-soluble up-conversion luminescent nano particles by an epitaxial growth method to obtain the rare earth up-conversion nano particle epitaxially-grown cuprous oxide nanocomposite material, and the rare earth up-conversion nanocomposite material simultaneously having photodynamic therapy and up-conversion fluorescence imaging is obtained.
The preparation method provided by the invention has the advantages of compact and efficient process, convenience in operation, easiness in structure control, good repeatability and the like; the nano material and the application thereof provided by the invention have multiple purposes, can obviously improve the diagnosis and treatment effect, and can realize the diagnosis and treatment effect on cancers.
The present invention is not limited to the above embodiments, but rather, a method of epitaxially growing a cuprous oxide nanocomposite using other rare earth upconversion nanoparticles obtained by the same or similar method as the above, such as different rare earth ion doped upconversion nanocrystals (NaYF)4:Yb,Er；NaGdF4:Yb,Er；NaGdF4Yb, Tm, etc.), etc., as well as variations in the specific values within the ranges of the ratios of the components recited herein, are within the scope of the invention.
Claims (7)
1. The rare earth up-conversion diagnosis and treatment integrated nano composite material is characterized in that oil-soluble up-conversion luminescent nano particles (UCNPs) are used as cores, and cuprous oxide (Cu) is used as a core2O) the surface of the up-conversion nanoparticle grows into a shell in an epitaxial manner, and the formed interface nucleates and grows to form the cuprous oxide modified rare earth up-conversion nano composite material; up-conversion emission of UCNPs under near infrared light (NIR) excitation is transferred to Cu via Fluorescence Resonance Energy Transfer (FRET)2O, Reactive Oxygen Species (ROS) that generate oxidized 1, 3-Diphenylisobenzofuran (DPBF) in an aerobic environment to meet the demand of photodynamic therapy (PDT); the oil soluble UCNPs and Cu2And the O is mutually cooperated to realize diagnosis and treatment integration.
2. The rare earth up-conversion diagnosis and treatment integrated nanocomposite material according to claim 1, wherein the oil-soluble rare earth up-conversion luminescent nanoparticles comprise: NaYF4:Yb,Er、NaYF4:Yb,Tm、NaYF4:Yb,Er,Tm、NaYF4:Yb,Er@NaGdF4、NaYF4:Yb,Tm@NaGdF4、NaYF4:Yb,Er,Tm@NaGdF4、NaYF4:Yb, Er@NaYF4:Nd,Yb、NaYF4:Yb, Tm@NaYF4Nd and Yb.
3. The preparation method of the rare earth up-conversion diagnosis and treatment integrated nano composite material according to claim 1 or 2, characterized by comprising the following steps:
(1) preparing a dispersion of oil-soluble rare earth up-conversion luminescent nanoparticles in cyclohexane, adding a predetermined amount of Cu (NO)3)2Dropwise adding the solution into the upconversion nanoparticle dispersion liquid, and violently stirring to obtain a first dispersion liquid;
(2) preparing a hydrazine hydrate solution, adding the hydrazine hydrate solution into the first dispersion liquid under stirring for dispersing and mixing, violently stirring to obtain a second dispersion liquid, transferring the second dispersion liquid into a high-pressure reaction kettle for hydrothermal reaction, centrifuging, washing and dispersing the obtained product to obtain the rare earth up-conversion diagnosis and treatment integrated nano composite material.
4. The preparation method of the rare earth up-conversion diagnosis and treatment integrated nanocomposite material according to claim 3, wherein the steps (1) to (2) specifically comprise the following steps:
(1) preparation of Cu (NO)3)2Weighing 0.2-0.3 g of Cu (NO)3)2Dissolving the Cu (NO) in 35-50 mL of deionized water, and dissolving the dissolved Cu (NO)3)2Dropwise adding the solution into the prepared oil-soluble rare earth up-conversion luminescent nanoparticles, and violently stirring at room temperature for 15-60 min to obtain a first dispersion liquid;
(2) preparing 0.5-2 mol/L hydrazine hydrate solution, quickly adding 8-10 mL hydrazine hydrate solution into the first dispersion liquid, mixing and stirring, observing that the color of the solution is changed from blue to yellow, violently stirring for 1-2 h, transferring the obtained solution into an autoclave, keeping the temperature at 150-200 ℃ for 3-5 h, centrifugally washing with ethanol and deionized water, and finally dispersing in deionized water to obtain the rare earth upconversion nanoparticle epitaxially-grown cuprous oxide nanocomposite.
5. The rare earth upconversion diagnosis and treatment integrated nanocomposite material according to claim 1, wherein the wavelength of the NIR laser is 808 ± 3 nm or 980 ± 3 nm.
6. Use of the rare earth upconversion theranostic nanocomposite material according to claim 1 or 2 as an imaging agent in fluorescence imaging.
7. Use of a rare earth upconversion diagnosis and treatment integrated nanocomposite material according to claim 1 or 2 for the preparation of photodynamic therapy agents, wherein under NIR laser irradiation, UCNPs convert NIR into visible light emission by an upconversion process, and visible light energy is transferred to the photosensitizer Cu via FRET process2O, ROS that oxidize DPBF are produced in aerobic environments, thereby providing a therapeutic effect for killing cancer cells.
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