CN115252824A - Multifunctional up-conversion nanocrystalline for guiding photothermal therapy through fluorescence and magnetic resonance imaging and preparation method thereof - Google Patents
Multifunctional up-conversion nanocrystalline for guiding photothermal therapy through fluorescence and magnetic resonance imaging and preparation method thereof Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 50
- 238000007626 photothermal therapy Methods 0.000 title claims abstract description 28
- 238000000799 fluorescence microscopy Methods 0.000 title claims abstract description 20
- 238000002595 magnetic resonance imaging Methods 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229910052761 rare earth metal Inorganic materials 0.000 claims abstract description 55
- -1 rare earth nitrate Chemical class 0.000 claims abstract description 42
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- MWFSXYMZCVAQCC-UHFFFAOYSA-N gadolinium(iii) nitrate Chemical compound [Gd+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O MWFSXYMZCVAQCC-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
The invention provides a multifunctional up-conversion nanocrystal for fluorescence and magnetic resonance imaging guided photothermal therapy and a preparation method thereof, wherein the nanocrystal has a chemical formula of NaYbF4:Y3+/Gd3+/RE3+. The preparation method comprises the following steps: adding an ammonium fluoride solution and a rare earth nitrate solution into an oleic acid solution, an alcohol solution and a sodium hydroxide solution, fully stirring, transferring into a reaction kettle, obtaining a product under high pressure and low temperature in a short time, and washing and drying to obtain the rare earth ion doped up-conversion nanocrystal. The invention provides a preparation methodHas the advantages of simple process, short time consumption and high yield. The nanocrystal provided by the invention can perform up-conversion luminescence under the excitation of near infrared light, and Gd in a nano system3+The compound can be used as a magnetic resonance imaging contrast agent, and has high photothermal conversion efficiency due to the hexagonal thin sheet or short rod-shaped structure. The single nanocrystal provided by the invention has dual-mode fluorescence and magnetic resonance imaging, and has wide application prospect in guiding photothermal therapy.
Description
Technical Field
The invention belongs to the crossed field of inorganic nano materials and biomedicine, and particularly relates to a rare earth ion doped magnetic up-conversion nanocrystal with dual-mode fluorescence imaging and magnetic resonance imaging guided photothermal therapy and a preparation method thereof.
Background
Photothermal therapy (PTT) has become a new research hotspot as a non-invasive way to trigger tumor ablation to treat neoplastic diseases. Due to the complex and unique microenvironment and metabolic activity of tumor tissues, the single photothermal treatment mode may have the limitation that the inaccurate acquisition of tumor position information causes damage to surrounding healthy tissues, so that the photothermal treatment effect is not as ideal as expected. The multi-mode imaging is matched with the photothermal therapy, so that the tumor position information can be accurately acquired, the tumor ablation is effectively promoted, and the healthy tissue is hardly damaged, so that the wide attention is paid. The nano material can be used for constructing a composite probe for tumor diagnosis and treatment due to the properties of multifunction, easy preparation, high stability and the like, and shows great application potential in the biomedical field, such as early diagnosis, high-efficiency treatment and the like of tumors. Therefore, the construction of a single nanostructure material with multimode imaging capability and high photothermal conversion efficiency has great research value in the field of biomedical therapy.
In the thesis, 2016, Z.Gao et al synthesized Fe3O4@ CS-ICG/DOX nanocomposite, wherein Fe3O4@ CS and ICG exhibit magnetic resonance imaging and fluorescence imaging at tumors, enabling photothermal therapy of tumors under near infrared excitation (Dalton trains., 45,19519-19528, 2016). In 2017, H.Zhang et al passed through in Fe3O4In situ growth of porphyrin-metal on the @ C nucleusOrganic Framework (PMOF), in which Fe3O4@ C was used as a T2-weighted Magnetic Resonance (MR) imaging and photothermal therapy agent, PMOF was fluorescence imaged, enabling fluorescence and MR bimodal imaging guided PTT therapy in tumor-bearing mouse models (sci. Rep.7,44153, 2017). In 2019, the Gd chelating conjugated polymer based therapeutic nano material is designed and prepared by X.Hu et al, fluorescence imaging can be provided in vivo by utilizing a low band gap donor-acceptor of the polymer, and Gd in the nano material is utilized3+Can be used for MRI imaging examination. After administration of the material to mice, the tumor sites of the mice showed fluorescence intensity and strong MR signal that inhibited tumor growth (Theranostics, 9 (14): 4168-4181, 2019). Recently, x.chen et al prepared a carrier-free multi-component self-assembled nanosystem (MnAs-ICG nanoscals) based on electrostatic and coordination interactions, fulfilling the capability of magnetic resonance imaging and fluorescence imaging guided photothermal therapy in a single nanosystem. However, photothermal therapy guided by fluorescence and magnetic resonance imaging has been mostly focused on organic small molecule nano-material composite materials so far, and research on unloaded rare earth ion doped lamellar magnetic upconversion nanocrystals and preparation methods thereof with dual-mode fluorescence imaging and magnetic resonance imaging guided photothermal therapy has not been reported yet.
In the patent aspect, in 2016, yanzhen university Yanghapeng invented a core-shell type multifunctional nano material, wherein an inner core is an up-conversion nano luminescent material, a shell is an alkaline manganese compound, and nano gold particles are deposited between the inner core and the shell. The up-conversion nano material can realize fluorescent marking; alkaline manganese compound, which is decomposed into Mn as MRI contrast agent after entering tumor cells2+For magnetic resonance imaging; the nanocrystals have a photothermal effect (201610149181.3). In 2019, sunlinin and other people of Shanghai university invented manganese-zinc ferrite-coated magnetic up-conversion luminescent nano material, and the up-conversion nanocrystalline part is NaGdF4Or NaNdF4The material has magnetism due to the existence of Gd ions and Mn ions, is used as a magnetic resonance imaging contrast agent, has a photothermal effect, and is expected to be used in the medical field of cancer treatment and the like (201911115285.2). Mongolian liver of Fujian medical university in 2021 yearsA NaErF loaded by viroid hollow manganese oxide is invented by people such as Lioulong in gallbladder hospitals4:2％Ho@NaYF4Rare earth nano material, manganese ion used for chemokinetic treatment of a transfer focus and nuclear magnetic resonance imaging contrast agent, and 650nm and 1180nm fluorescence of rare earth nanocrystalline radiation can be used for fluorescence imaging (202111096606.6). In the above patent documents related to the rare earth doped nano material in fluorescence and magnetic resonance dual-mode imaging guided photothermal therapy, there is no report on rare earth ion doped up-conversion nanocrystals and preparation methods thereof, in which a single and simple-prepared nano system is improved by controlling the body surface ratio of the nano material to improve the photothermal conversion rate on the premise of ensuring the luminous intensity.
As described above, in recent years, although the synthesis method of the rare earth doped fluoride fluorescent composite material has been rapidly developed, the application range is expanding, and the method is spread in a series of fields such as biological imaging (fluorescence imaging, magnetic resonance imaging, photoacoustic imaging, and the like), tumor therapy (photodynamic therapy, photothermal therapy), information storage and decryption, and temperature sensor manufacturing. However, in the application of biomedical therapy field, the research on single and unloaded rare earth doped thin-sheet magnetic nano material with multimode imaging capability and high photothermal conversion efficiency has not been reported, and no patent related to the research is published.
Disclosure of Invention
The invention aims to provide a multifunctional rare earth ion-doped up-conversion nanocrystal for fluorescence and magnetic resonance imaging-guided photothermal therapy and a preparation method thereof, in order to simplify a nano system for multi-modal imaging-guided tumor therapy and a preparation process thereof.
Technical scheme of the invention
A rare earth ion doping magnetism multi-functional upconversion nanocrystalline for fluorescence and magnetic resonance imaging guide light and heat treatment, the chemical formula is: naYbF4:Y3+/Gd3+/RE3+Wherein RE3+Is Er3+、Tm3+Or Ho3+One or any combination thereof.
The rare earth ion doped up-conversion nanocrystalline is in a hexagonal thin slice or a short rod shape (the crystal phase is a hexagonal crystal phase), the thickness of the thin slice is 35 nm-45 nm, and the radial length is 200 nm-300 nm; the axial length of the short rod is 80 nm-230 nm, and the radial length is 50 nm-110 nm.
The rare earth doped up-conversion nano crystal can perform up-conversion luminescence, can realize up-conversion visible light radiation under the excitation of 950-1000 nm low-power near infrared light, and can clearly see the characteristic emission peak of an activator ion in the luminescence spectrum.
The preparation method of the rare earth ion doped magnetic multifunctional up-conversion nanocrystalline provided by the invention comprises the following steps:
step 1, preparing a sodium hydroxide (NaOH) solution with the concentration of 0.2g/mL, then adding oleic acid and absolute ethyl alcohol into the NaOH solution, and uniformly stirring to obtain a light yellow solution;
the volume ratio of the NaOH solution to the oleic acid to the absolute ethyl alcohol is 3;
step 2, slowly dripping NH with the molar concentration of 2mol/L into the mixed solution obtained in the step 14Stirring the solution F vigorously for 5-10min to obtain a uniformly mixed solution; the NH4The volume ratio of the solution F to the absolute ethyl alcohol in the step 1 is 1;
step 3, co-doping the up-conversion nanocrystalline chemical formula NaYbF according to rare earth ions4:Y3+/Gd3+/RE3+(RE3+Is Er3+、Tm3+、Ho3+One or any combination of the above) and dissolving the rare earth nitrate in deionized water, and stirring uniformly to form a transparent rare earth mixed solution;
the rare earth nitrate is a mixture of ytterbium nitrate, gadolinium nitrate, yttrium nitrate, thulium nitrate, erbium nitrate and holmium nitrate, and the molar percentage of the rare earth nitrate is (50-79): (20-40): (0-9): (0-1): (0-2): (0-1);
step 4, adding the mixed solution of the rare earth nitrate into the mixed solution of the step 2, and uniformly stirring to form a milky white suspension solution;
and 5, transferring the mixed suspension solution obtained in the step 4 into a stainless steel reaction kettle lined with polytetrafluoroethylene for hydrothermal reaction, after the reaction is finished, naturally cooling the reaction kettle to room temperature, washing and drying the product to obtain white solid powder, namely the rare earth ion doped lamellar or short rod-shaped magnetic up-conversion nanocrystalline.
Further, the sodium source is NaOH, the rare earth source is rare earth nitrate, and the fluorine source is NH4F, and NaOH crystal, NH used in the synthesis process4F. The purity of the ethanol is not lower than that of the analytical reagent, and the purity of the rare earth nitrate is not lower than 99.9%.
Further, the prepared multifunctional up-conversion nanocrystalline for fluorescence and magnetic resonance imaging guided photothermal therapy is doped with rare earth ions Y in fluoride matrix material3+、Gd3+、Yb3+、Er3+、Tm3+、Ho3+Respectively provided by rare earth yttrium nitrate, gadolinium nitrate, ytterbium nitrate, erbium nitrate, thulium nitrate and holmium nitrate, wherein Gd is3+Yb as a contrast agent3+As sensitizer, er3+、Tm3+、Ho3+Any one, two or three of the three ions act as an activator.
Further, in the hydrothermal reaction in the step 5, the temperature of the hydrothermal reaction is 160-200 ℃ and the reaction time is 2.5-3.5 h.
The invention has the following beneficial effects:
the rare earth ion doped magnetic upconversion nanocrystal provided by the invention can perform upconversion luminescence, and converts near-infrared pump light into visible light emission with shorter wavelength. Meanwhile, the magnetic property of the up-conversion nanocrystal is combined to realize multifunctional multi-modal imaging of fluorescence imaging and magnetic resonance imaging (MRT) on a single material. By using multi-mode imaging to guide photo-thermal therapy (PTT), the tumor position information can be accurately acquired in real time, the tumor ablation is effectively promoted, and the curative effect of tumor treatment is improved. The rare earth ion doped slice or short rod-shaped magnetic up-conversion nano crystal is expected to provide a new idea for developing intelligent single nano materials for tumor diagnosis and treatment. The preparation method of the rare earth ion doped thin slice or short rod-shaped magnetic upconversion nanocrystal provided by the invention has the advantages of low experimental cost, low reaction energy consumption, simple and controllable preparation process, high product purity, short consumed time and the like.
Drawings
FIG. 1 is an X-ray diffraction pattern of a rare earth ion doped magnetic upconversion nanocrystal of example 1 of the present invention;
FIG. 2 is a scanning electron microscope image (a) and a particle radial dimension distribution (b) of the rare earth ion-doped magnetic upconversion nanocrystal of example 1 of the present invention;
FIG. 3 is an image of a scanning electron microscope of the rare earth ion doped magnetic upconversion nanocrystal of example 2 of the present invention;
FIG. 4 is a scanning electron microscope image of rare earth ion doped magnetic upconversion nanocrystals of example 3 of the present invention;
FIG. 5 is a luminescence spectrum of a rare earth ion-doped magnetic upconversion nanocrystal of example 1 of the present invention;
FIG. 6 is a luminescence spectrum of a rare earth ion-doped magnetic upconversion nanocrystal of example 2 of the present invention;
FIG. 7 is a photo-thermal conversion diagram of the rare earth ion doped magnetic upconversion nanocrystal of example 1 of the present invention.
Detailed Description
The invention will be further described with reference to the accompanying drawings and examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Various changes or modifications of the present invention based on the principle of the present invention after reading the contents of the present invention also fall within the scope of the present invention defined by the appended claims.
Example 1: this embodiment synthesizes a rare earth ion-doped lamellar magnetic NaYbF4:Y3+/Gd3+/Tm3+The method for up-converting the nanocrystalline is realized by the following steps:
step 1, respectively weighing 0.45g of NaOH solid powder, dissolving in 2.25mL of deionized water, and magnetically stirring to dissolve to obtain a transparent solution.
And 2, sequentially dripping 7.5mL of absolute ethyl alcohol and 7.5mL of oleic acid into the NaOH solution obtained in the step 1, and stirring the mixed solution at the rotating speed of 400rpm for 0.5h to obtain a light yellow mixed solution.
Step 3, obtaining from step 21.5mL of NH with a concentration of 2mol/L was added to the pale yellow mixture solution4And F, continuously stirring the formed mixed solution for 5min, wherein the whole dripping process ensures that the mixed solution is carried out at the rotating speed of 400 rpm.
Step 4, according to the chemical formula NaYbF of rare earth ion co-doped up-conversion nanocrystal4:Y3+/Gd3+/Tm3+Stoichiometric quantitative ratio of (Y: yb: gd: tm =93)3·6H2O, 0.45g Yb (NO)3)3·6H2O, 0.361g Gd (NO)3)3·6H2O and Tm (NO) of 0.009g3)3·6H2Dissolving O solid powder in 10mL of deionized water, and stirring vigorously for 0.5h to obtain a uniformly mixed rare earth nitrate mixed solution;
and step 5, slowly adding 3mL of the rare earth solution obtained in the step 4 into the solution formed in the step 3, and stirring the solution at the rotating speed of 400rpm for 0.5h to fully and uniformly mix the solution to obtain milky white suspension.
And 6, pouring the mixed solution prepared in the step 5 into a stainless steel high-pressure reaction kettle lined with polytetrafluoroethylene, carrying out hydrothermal reaction for 3 hours at 180 ℃, and naturally cooling the reaction kettle to room temperature after the hydrothermal reaction is finished.
And 7, transferring the solution with the precipitate after the hydrothermal reaction obtained in the step 6 is finished into a 50mL centrifuge tube, and centrifuging the solution for 10min at the rotation speed of 8000rpm by using a centrifuge to obtain the precipitate. The resulting precipitate was then washed three times with deionized water, ethanol, and the washed precipitate was redissolved in 1mL of deionized water to form a solution. Then placing the mixture in an air-blast drying oven to be dried at the temperature of 80 ℃ to obtain the rare earth ion doped lamellar magnetic NaYbF4:Y3+/Gd3+/Tm3+(Y: yb: gd: tm = 9.
NaYbF synthesized by the above synthesis method4:Y3+/Gd3+/Tm3+The upconverting microcrystalline is a hexagonal phase structure (fig. 1) and is in the form of a platelet (fig. 2). Under the excitation of 980nm near infrared light, the light emission spectrum thereofIn (1) can be clearly seen that Tm is3+Blue light emission peaks at 450nm, 475nm and red light emission peaks at 650nm and 695nm (FIG. 5). And under 980nm near-infrared excitation, the photothermal conversion efficiency is high (figure 7), and the method is expected to be applied to the field of photothermal therapy.
Example 2: the method synthesizes the rare earth ion doped short rod magnetic NaYbF4:Gd3+/Ho3+The procedure and method for up-converting nanocrystals were substantially the same as in example 1, except that:
the rare earth nitrate is a mixture of gadolinium nitrate, ytterbium nitrate and holmium nitrate, the mole percentage of which is 40 percent of Gd3+：59％Yb3+：1％Ho3+；
The temperature of the hydrothermal reaction is 200 ℃;
the rest of the process is basically the same as that of embodiment 1, and the description thereof is omitted.
NaYbF obtained by the above synthesis method4:Gd3+/Ho3+The up-conversion nanocrystals were hexagonal phase structures and were in the form of short rods (fig. 3). Under the excitation of 980nm near infrared light, ho can be clearly seen in the luminescence spectrum3+Blue light emission peaks at 541nm, 547nm and red light emission peak at 645nm (FIG. 6).
Example 3: the rare earth ion doped short rod magnetic NaYbF is synthesized by the embodiment4:Gd3+/Ho3+The procedure and method for up-converting nanocrystals were substantially the same as in example 1, except that:
said rare earth nitrate is a mixture of gadolinium nitrate, ytterbium nitrate and thulium nitrate, the molar percentage of which is 20%3+：79％Yb3+：1％Ho3+；
The temperature of the hydrothermal reaction is 200 ℃;
the rest of the process is basically the same as that of embodiment 1, and the description thereof is omitted.
NaYbF obtained by the above synthesis method4:Gd3+/Ho3+The up-conversion nanocrystals were hexagonal phase structures and were in the shape of short rods (fig. 4). Under the excitation of 980nm near infrared light, the fluorescent powder can be clearly seen in the luminous spectrumTo Ho3+Blue light emission peaks at 541nm, 547nm and red light emission peaks at 645 nm.
Claims (7)
1. A multifunctional up-conversion nanocrystal for fluorescence and magnetic resonance imaging guided photothermal therapy, characterized by: the up-conversion nano crystal is a magnetic crystal doped with rare earth ions and has a chemical formula of NaYbF4:Y3+/Gd3+/RE3+，RE3+Is Er3+、Tm3+Or Ho3+One or any combination thereof.
2. The multifunctional upconversion nanocrystal for fluorescence and magnetic resonance imaging guided photothermal therapy according to claim 1, wherein: the up-conversion nano crystal is in a thin sheet or short rod shape, the thickness of the thin sheet is between 35nm and 45nm, and the radial length of the thin sheet is between 200nm and 300nm; the axial length of the short rod is 80 nm-230 nm, and the radial length is 50 nm-110 nm.
3. The multifunctional upconversion nanocrystal for fluorescence and magnetic resonance imaging guided photothermal therapy according to claim 1, characterized in that: the crystalline phase of the upconverting nanocrystal is a hexagonal phase.
4. The multifunctional upconversion nanocrystal for fluorescence and magnetic resonance imaging guided photothermal therapy according to claim 1, wherein: the upconversion nanocrystal can realize upconversion visible light under the excitation of 950-1000 nm band light.
5. A preparation method of multifunctional up-conversion nanocrystals for fluorescence and magnetic resonance imaging-guided photothermal therapy comprises the following steps:
step 1, preparing a sodium hydroxide (NaOH) solution with the concentration of 0.2g/mL, then adding oleic acid and absolute ethyl alcohol into the NaOH solution, and uniformly stirring to obtain a light yellow solution;
the volume ratio of the NaOH solution to the oleic acid to the absolute ethyl alcohol is 3;
step (ii) of2. NH with the molar concentration of 2mol/L4Slowly dripping the solution F into the light yellow solution obtained in the step 1, and then stirring to obtain a uniform mixed solution;
the NH4The volume ratio of the solution F to the absolute ethyl alcohol in the step 1 is 1;
step 3, weighing rare earth nitrate powder according to the chemical formula of the up-conversion nanocrystalline in claim 1, dissolving the rare earth nitrate powder in deionized water, and uniformly stirring to form a transparent rare earth nitrate mixed solution;
the rare earth nitrate is a mixture of ytterbium nitrate, gadolinium nitrate, yttrium nitrate, thulium nitrate, erbium nitrate and holmium nitrate, and the molar percentage of the rare earth nitrate is (50-79): (20-40): (0-9): (0-1): (0-2): (0-1);
step 4, dripping the rare earth nitrate solution into the mixed solution in the step 2 and uniformly stirring to form a milky white suspension solution;
and 5, transferring the mixed suspension solution obtained in the step 4 into a stainless steel reaction kettle lined with polytetrafluoroethylene for hydrothermal reaction, after the reaction is finished, naturally cooling the reaction kettle to room temperature, washing and drying the product to obtain white solid powder, namely the rare earth ion doped magnetic up-conversion nanocrystalline.
6. The method for preparing multifunctional up-conversion nanocrystals for fluorescence and magnetic resonance imaging guided photothermal therapy as claimed in claim 5, wherein: gd in rare earth nitrate after chemical reaction3+、Yb3+And Er3+、Tm3+、Ho3+Any one, two or three of the three ions may be doped simultaneously into the fluoride host material, with Gd3+Yb as contrast agents3+Er as a sensitizer3+、Tm3+、Ho3+Any one, two or three ions in the three ions are used as an activator, so that the single material has the fluorescent visible light properties of magnetism and light drive.
7. The method for preparing multifunctional up-conversion nanocrystals for fluorescence and MRI-guided photothermal therapy according to claim 5, wherein the temperature of the hydrothermal reaction is 160-200 ℃ and the reaction time is 2.5-3.5 h, which has the advantages of simple process, short time consumption and high yield.
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