CN108853497B - Construction of targeted photodynamic nanoprobe based on up-conversion nanoparticles and ultrathin silicon dioxide layer - Google Patents

Construction of targeted photodynamic nanoprobe based on up-conversion nanoparticles and ultrathin silicon dioxide layer Download PDF

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CN108853497B
CN108853497B CN201810724282.8A CN201810724282A CN108853497B CN 108853497 B CN108853497 B CN 108853497B CN 201810724282 A CN201810724282 A CN 201810724282A CN 108853497 B CN108853497 B CN 108853497B
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CN108853497A (en
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王宗花
岳姿宏
宋昕玥
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Qingdao University
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    • A61K41/008—Two-Photon or Multi-Photon PDT, e.g. with upconverting dyes or photosensitisers
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Abstract

The invention discloses a targeted photodynamic nanoprobe constructed based on up-conversion nanoparticles and an ultrathin silica layer. Constructed UCNPs @ SiO2the/MB/PEG-FA nanoprobe is distributed in the cytoplasm of the cancer cell through receptor-mediated endocytosis, generates active oxygen under the excitation of near infrared light, reduces the mitochondrial membrane potential in the cell and induces the irreversible apoptosis of the cancer cell. Constructed UCNPs @ SiO2the/MB/PEG-FA nano-probe also shows excellent tumor inhibition effect in animal experiments.

Description

Construction of targeted photodynamic nanoprobe based on up-conversion nanoparticles and ultrathin silicon dioxide layer
Technical Field
The invention relates to the field of materials and analytical chemistry, in particular to a novel method for realizing effective photodynamic therapy by using folic acid-polyethylene glycol modified ultrathin silica-coated upconversion nanoparticles as a photosensitizer carrier.
Background
As a clinically approved cancer treatment method, photodynamic therapy employs light-excited Photosensitizer (PS) to generate active oxygen, thereby irreversibly damaging tumor cells. Photodynamic therapy can control light to irradiate specific tumor parts, and reduce potential toxic and side effects on normal tissues. However, it still faces challenges such as limited penetration depth of uv-visible light, low reactive oxygen species generation efficiency, short half-life of reactive oxygen species and limited range of action. The absorption and scattering of near infrared light by cells and tissues are small, so that the near infrared light has more excellent biological tissue penetrating capability and small autofluorescence background. Therefore, using near infrared light as a light source for photodynamic therapy will increase its penetration depth and sensitivity. Based on a two-photon or multi-photon mechanism, the upconversion nanoparticles (UCNPs) can convert continuous near-infrared excitation light into ultraviolet-visible region fluorescence with adjustable wavelength, and then based on luminescence resonance energyThe quantum transfer mechanism excites the PS to realize near infrared light-excited photodynamic therapy. UCNPs have gained widespread attention as emerging photosensitizer carriers. Currently, three methods are generally adopted to load PS on UCNPs, namely silica loading, non-covalent bond physical adsorption and covalent bond coupling. Silicon dioxide (SiO)2) The silicon layer has the advantages of low toxicity, easy functionalization, high loading capacity and the like, and SiO grows on the surface of UCNPs2The silicon layer can meet the requirements of different PS molecular loads. However, UCNPs-based PDT has problems such as relatively low quantum yield of UCNPs, limited efficiency of luminescence resonance energy transfer, and easy aggregation of photosensitizers. The luminescence resonance energy transfer efficiency depends on the distance between the energy donor and acceptor, and the effective energy transfer usually occurs within 10nm of both. Usually, SiO2The silicon layer is controlled to be in the range of 20-100nm, so that only PS molecules near the surface of UCNPs are in an effective energy transfer range, and are in an excitable state. Whereas the fluorescence of UCNPs with a diameter of less than 10nm is susceptible to quenching by environmental influences.
Disclosure of Invention
In view of the prior art, the inventors believe that the SiO on the surface of UCNPs is controlled2The thickness of the silicon layer is an effective measure for improving the transfer of the luminescence resonance energy between the UCNPs and the PS. The inventors propose to use thin SiO2Silicon layer wrapped UCNPs, i.e. UCNPs @ SiO2As an effective PS carrier to achieve effective PDT.
Methylene Blue (MB) can generate a large amount of Reactive Oxygen Species (ROS), has high photodynamic efficiency, and MB easily passes through cell membranes to target mitochondria, so that photodynamic therapy involving MB can induce mitochondrial-dependent apoptosis in cancer cells. However, MB monomers are easily aggregated to form a dimer, an electron transfer reaction is easily generated instead of energy transfer with oxygen, and the Uv absorption peak thereof becomes 610nm, which is not spectrally matched with the emission wavelength (λ em ═ 650nm) of UCNPs, decreasing the photodynamic therapy effect. Thus, the synthesis of monodisperse UCNPs @ SiO2the/MB can improve the photodynamic therapy effect.
Polyethylene glycol (PEG) is a good hydrophilic modifier and can improve UCNPs @ SiO2The colloidal stability of (A), prevention of cell and serumThe nonspecific combination between the proteins prolongs the blood circulation time and improves the tumor targeted curative effect. Furthermore, targeting by selectively binding to the surface of cancer cells using specific ligands during drug delivery is of great interest for cancer therapy. Folate (FA), a 441Da vitamin, binds with high affinity to folate receptor alpha (FR-alpha) overexpressed on the surface of cancer cells. Thus, modification of the drug carrier with PEG and FA will enhance biocompatibility and improve receptor-mediated endocytosis.
Therefore, one of the objects of the present invention is to provide a UCNPs @ SiO2the/MB/PEG-FA nanoprobe is characterized in that UCNPs @ SiO is adopted through receptor-mediated endocytosis2the/MB @ PEG-FA nanoprobe is selectively introduced into the cytoplasm of cancer cells. When excited by Near Infrared (NIR) light, the energy transfer distance between UCNPs (energy donors) and MB (energy acceptors) is short and has good spectral matching, so that efficient luminescence resonance energy transfer occurs, active oxygen is generated, and mitochondrial-mediated cancer cell apoptosis is induced.
Another object of the present invention is to provide the UCNPs @ SiO2A preparation method of a/MB/PEG-FA nanoprobe.
The invention also aims to provide the UCNPs @ SiO2Application of the/MB/PEG-FA nanoprobe.
In order to achieve the purpose, the invention specifically adopts the following technical scheme:
firstly, the invention provides UCNPs @ SiO2the/MB/PEG-FA nanoprobe comprises an upconversion nanoparticle inner core, an ultrathin silicon dioxide shell layer wrapped on the surface of the inner core, methylene blue loaded on the shell layer and polyethylene glycol-folic acid.
Secondly, the invention provides the UCNPs @ SiO2The preparation method of the/MB/PEG-FA nano probe comprises the steps of
(1)UCNPs@SiO2Preparation of/MB:
mixing cyclohexane and a surfactant, stirring to form a reverse micelle, adding UCNPs, and mixing and stirring to form a first mixing system;
adding methylene blue and an ammonia water solution into the mixed system I, and mixing and stirring to form a mixed system II;
adding a silicon source into the second mixed system, carrying out mixed reaction, transferring the partially hydrolyzed negative silicon source into the hydrophilic interior of the reverse micelle to interact with the positive methylene blue, and hydrolyzing and condensing to obtain UCNPs @ SiO2/MB；
(2)UCNPs@SiO2Preparation of/MB/PEG-FA:
carboxyl activation of carboxylated PEG-FA, and then addition of the activated mixture to the UCNPs @ SiO2in/MB, the UCNPs @ SiO is prepared by mixing reaction2/MB@PEG-FA。
Finally, the invention provides said UCNPs @ SiO2Application of the/MB/PEG-FA nanoprobe in preparing photodynamic therapeutic agents.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
(1) in one embodiment of the present invention, two luminescent ion co-doped up-conversion nanoparticles (UCNPs) are prepared to enhance red fluorescence intensity, and then ultra-thin Silica (SiO) is used2) The layer carries the photosensitizer Methylene Blue (MB).
Up-converting nanoparticles (UCNPs) act as energy donors to excite energy acceptor Methylene Blue (MB) molecules to generate reactive oxygen species that induce apoptosis. Ultra-thin Silica (SiO)2) The layer is pulled close to the distance between the energy donor and the acceptor, and the efficiency of luminescence resonance energy transfer is improved.
Covalent attachment of polyethylene glycol-Folic acid (PEG-FA) to UCNPs @ SiO2The surface of the nano probe increases the biocompatibility and the targeting property of the nano probe to cancer cells.
(2) Constructed UCNPs @ SiO2the/MB/PEG-FA nanoprobe is distributed in the cytoplasm of the cancer cell through receptor-mediated endocytosis, generates active oxygen under the excitation of near infrared light, reduces the mitochondrial membrane potential in the cell and induces the irreversible apoptosis of the cancer cell. Constructed UCNPs @ SiO2the/MB/PEG-FA nano-probe also shows excellent tumor inhibition effect in animal experiments.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention.
FIG. 1: characterization of nanoprobes. (a) Er-doped UCNPs (NaYF)4@NaYF4:Yb,Er@NaYF4) And Ho, Tm doped UCNPs (NaYF)4@NaYF4:Yb,Ho/Tm@NaYF4) The relative fluorescence intensity of (a) is that the doping ratio of Y to Yb to Er is 80 to 18 to 2 (molar ratio), and the doping ratio of Ho to Tm is that the doping ratio of Y to Yb to Ho to Tm is 77.8 to 20 to 2 to 0.2 (molar ratio); (b) TEM images of Ho, Tm co-doped UCNP; (c) UCNP @ SiO2A TEM image of (a); (d) UCNPs and UCNPs @ SiO2XRD pattern of (a).
FIG. 2: nanoprobes generate an energy map of ROS. (a) UCNPs @ SiO2，UCNPs@SiO2(ii)/MB and UCNPs @ SiO2Relative luminous intensity of/MB @ PEG-FA, relative absorbance value of MB; (b) when the molecular weight is equal to 1.0mg/mLUCNPs @ SiO2When the/MB @ PEG-FA nanoprobe is mixed, a 980nm laser (1.5W/cm) is used2) Fluorescence spectra of ABDA irradiated for 65 minutes; (c) MB and UCNPs @ SiO2@ PEG-FA laser at 980nm (1.5W/cm)2) Effect of 65 minutes of irradiation on fluorescence intensity of ABDA; UCNPs @ SiO2Influence of/MB @ PEG-FA on ABDA fluorescence intensity under no laser irradiation; (d)1.0mg/mL UCNPs @ SiO2the/MB @ PEG-FA nano-probe is at 1.5W/cm2The laser was switched on and off alternately for 10min under irradiation of (1).
FIG. 3: the ability of the probe to enter a living cell. Incubating MCF-7 cells with nanoprobes prepared at 80.0 μ g/mL (a) for 0 hours; (b)4 hours; (c) for 6 hours. The fluorescent signals of the nanoprobe are recorded in a blue channel (450nm-510nm) and a green channel (515nm-575nm) by using two-photon laser confocal.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of the stated features, steps, operations, and/or combinations thereof, unless the context clearly indicates otherwise.
As introduced in the background art, the photo-excited photosensitizer in the prior art has certain defects, and in order to solve the technical problems, the invention provides a UCNPs @ SiO2the/MB/PEG-FA nano probe comprises an upconversion nano particle inner core (UCNPs) and an ultrathin silica shell layer (forming UCNPs @ SiO) wrapped on the surface of the inner core2) Methylene blue (forming UCNPs @ SiO) supported on the shell layer2/MB) and polyethylene glycol-folic acid.
The upconversion nanoparticles are composed of a host material, including but not limited to a halide, an oxide, a sulfide or a oxysulfide, a sensitizer including but not limited to Yb, and an activator, and the upconversion nanoparticles of the present invention are not particularly limited3+、Gd3+Etc., and activators include, but are not limited to Er3+、Ho3+、Tm3+、Nd3+，Pr3+And the like. However, in order to enhance the intensity of red fluorescence, in one embodiment of the present invention, the host material is NaYF4The sensitizer is Yb3+The activator is Ho3+And Tm3+. I.e. the upconversion nanoparticles are NaYF4:Yb3+,Ho3+/Tm3+The up-conversion nanoparticles have the particle size of about 10-40 nm, uniform appearance and good dispersibility as shown in figure 1 (b); preferably, the upconverting nanoparticles are selective for oleic acid protected NaYF4:Yb3+,Ho3+/Tm3+(ii) a The mol ratio of rare earth ion doping is as follows: 18 to 20 percent of Yb; 2-5% of Ho and 0.2-0.8% of Tm.
There are many methods for synthesizing UCNPs, including precipitation, sol-gel, microemulsion, combustion, hydrothermal (solvothermal) and thermal cracking, etc., and the upconversion nanoparticles can be prepared by conventional preparation methods in the art, and are not particularly limited thereto.
In one embodiment of the present invention, the ultra-thin silica shell layer has a thickness of less than 10.0 nm; preferably, the thickness of the ultrathin silica shell layer is 5.0-7.5 nm. The ultrathin silicon dioxide shell layer draws the distance between an energy donor and an energy acceptor, and improves the luminous resonance energy transfer efficiency.
In one embodiment of the present invention, the polyethylene glycol-folic acid coats UCNPs @ SiO with polyethylene glycol-folic acid through amidation reaction2On the surface of the/MB.
In one embodiment of the present invention, the polymerization degree of the polyethylene glycol is 1500 to 2500.
In an exemplary embodiment of the invention, the UCNPs @ SiO is provided2The preparation method of the/MB/PEG-FA nanoprobe comprises the following steps:
(1)UCNPs@SiO2preparation of/MB:
mixing cyclohexane and a surfactant, stirring to form a reverse micelle, adding UCNPs, and mixing and stirring to form a first mixing system;
adding methylene blue and an ammonia water solution into the mixed system I, and mixing and stirring to form a mixed system II;
adding a silicon source into the second mixed system, carrying out mixed reaction, transferring the partially hydrolyzed negative silicon source into the hydrophilic interior of the reverse micelle to interact with the positive methylene blue, and hydrolyzing and condensing to obtain UCNPs @ SiO2/MB；
(2)UCNPs@SiO2Preparation of/MB/PEG-FA:
carboxyl activation of carboxylated PEG-FA, and then addition of the activated mixture to the UCNPs @ SiO2in/MB, the UCNPs @ SiO is prepared by mixing reaction2/MB@PEG-FA。
In one embodiment of the present invention, in step (1), the surfactant is Igepal CO-520(NP-5), and the silicon source is tetraethyl orthosilicate (TEOS) and a silicon amide source (3-aminopropyl) triethoxysilane (APTES).
In one embodiment of the invention, in the step (1), the feeding ratio of the cyclohexane, the surfactant and the UCNPs is (8-12) mL: (0.3-0.8) mL: (0.3-0.5) mmol; mixing and stirring cyclohexane and a surfactant for 1-2 hours to form a reverse micelle; adding UCNPs, mixing and stirring for 1-2 h.
In one embodiment of the invention, in the step (1), the feeding ratio of the methylene blue, the ammonia water solution and the UCNPs is (2-6) mg: (40-80) μ L: (0.3-0.5) mmol; mixing and stirring for 2-3 h.
In one embodiment of the invention, in the step (1), the feeding ratio of TEOS, APTES and UCNPs is (60-100) μ L: (10-40) μ L: (0.3-0.5) mmol; mixing and reacting for 24-36 h.
In one embodiment of the present invention, in the step (2), the specific steps of activation are: mixing COOH-PEG-FA, NHS and EDC in a molar ratio of (1-2): 2-4): 1-2 in dimethyl sulfoxide (DMSO), and activating for 1-2 h.
In one embodiment of the present invention, in step (2), the activated mixture is mixed with UCNPs @ SiO2The feeding proportion of/MB is (200-300) mu L: (1-3) mL, and mixing and reacting for 10-14 h.
In yet another exemplary embodiment of the present invention, there is provided the UCNPs @ SiO2Application of the/MB/PEG-FA nanoprobe in preparing photodynamic therapeutic agents.
In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.
Experimental reagents and materials in this example:
rare earth oxides (including Y) having a purity of greater than 99.99 (w/w)%2O3，Yb2O3、Er2O3、Ho2O3And Tm2O3) Purchased from Sigma-Aldrich. Octadecene, oleic acid and methylene blue were supplied by Aladdin reagent, Inc. (Shanghai, China), and theyThe analytical reagent is available from chemical reagents of the national pharmaceutical group, chemical reagents ltd (shanghai, china). The ultra pure water was supplied using OKP purification system (lake instruments, shanghai, china). Mice were purchased from vitally biotechnology limited (wuhan, china). In addition, the animal care and utilization committee at the near-yieldable university has reviewed and approved animal feeding and processing procedures.
Example 1 oleic acid protected NaYF4:Yb3+,Ho3+/Tm3+Preparation of UCNPs:
(1) preparation of rare earth oleate
Weighing 1.129gY2O3(5mmol) and 20mL concentrated HCl in a round bottom flask, covered with plastic wrap, punctured and allowed to stir at 60 ℃. After overnight reaction, the temperature was raised to 140 ℃ and concentrated hydrochloric acid was evaporated to dryness to obtain YCl3. The synthesized YCl310mL of ultrapure water was added and dissolved by sonication. Then 5mL of ultrapure water was added, filtered with a syringe and a 0.22um green filter tip, injected into the flask, and then 20mL of ethanol, 35mL of cyclohexane and 30mmol of sodium oleate were added, and the mixture was refluxed at 78 ℃ for 4 hours. Then, the temperature is reduced to 30-40 ℃, and the mixture is transferred into a separating funnel to obtain the upper solution. Then, 20mL of ultrapure water and 20mL of ethanol were added (shaking to uniformity). The upper layer was separated by layers and the liquid was separated three times. Then transferring the mixture into a round-bottom flask, adding an explosion-proof ball, and performing rotary evaporation. Then, 12mL of octadecene and 12mL of oleic acid were added thereto by syringe and mixed well to obtain Y (oleate)3。
Oleate (Y: Yb: Ho: Tm: 77.8:20:2:0.2, molar ratio, total number of moles 5mmol) of the light-emitting layer was also synthesized by the above method, and was written as ln (oleate)3. The method comprises the following specific steps:
weighing Y2O3、Yb2O3、Ho2O3、Tm2O3(Y: Yb: Ho: Tm: 77.8:20:2:0.2, molar ratio, total molar number 5mmol) and 20mL of concentrated hydrochloric acid were placed in a round-bottomed flask, covered with a wrap film, perforated, and stirred at 60 ℃. After the reaction is carried out overnight, the temperature is adjusted to 140 ℃, and concentrated hydrochloric acid is volatilized to obtain the mixed rare earth chloride. And adding the synthesized mixed rare earth chloride into 10mL of ultrapure water, and dissolving by ultrasonic. 5mL of ultrapure water was addedWater, using syringe and 0.22um green filter, injected into the flask, then add 20mL ethanol, 35mL ethane, 30mmol sodium oleate, at 78 degrees C, reflux for 4 h. Then, the temperature is reduced to 30-40 ℃, and the mixture is transferred into a separating funnel to obtain the upper solution. Then, 20mL of ultrapure water and 20mL of ethanol were added (shaking to uniformity). The upper layer was separated by layers and the liquid was separated three times. Then transferring the mixture into a round-bottom flask, adding an explosion-proof ball, and performing rotary evaporation. Then, 12mL of octadecene and 12mL of oleic acid were added thereto by syringe and mixed well to obtain Ln (oleate)3。
(2) Synthesis of UCNPs
1.0mmol Y(oleate)3And 10.0mmol NaF are added into the solution mixed by octadecene and oleic acid in equal proportion, and the mixture is pumped and inflated for three cycles. The reaction was carried out at 115 ℃ for 1h and the temperature was raised to 340 ℃. After 90min of reaction, a small amount of the sample was taken out, and 0.4mmol of Ln (oleate) was added3After reaction for 20min, a small amount of the sample solution was taken out, and 0.6mmol of Y (oleate) was added thereto3After 20min of reaction, the reaction mixture was quickly cooled to room temperature. Adding ethanol with the same volume into the product, shaking, centrifuging at 8000rpm for 10min, pouring the supernatant, recovering, retaining the lower solid precipitate, dispersing in cyclohexane, ultrasonically dispersing uniformly, centrifuging at 2000rpm for 5min, taking the supernatant, adding ethanol with the same volume, shaking, centrifuging at 8000rpm for 10min, pouring the supernatant, recovering and retaining the lower solid, repeating the above operation once, and taking the supernatant as the final product, namely the oleic acid-protected NaYF4:Yb3+,Ho3+/Tm3+UCNPs。
Example 2 oleic acid protected NaYF4:Yb3+,Er3+Preparation of UCNPs:
the same as in example 1, except that: in the oleate of the light-emitting layer, Y: Yb: Er ═ 80:18:2, the molar ratio, and the total number of moles was 5 mmol.
Example 3UCNPs @ SiO2Preparation of/MB
10.0mL of cyclohexane was mixed with 0.660mL of Igepal CO-520(NP-5) and stirred for 1 hour to form reverse micelles. Thereafter, 0.450mmol of the oleic acid-protected UCNPs of example 1 was added and vigorously stirred for 1h to facilitate the conversion of oleate and NP-5And ligand exchange between the cells, resulting in the entrapment of UCNPs in the pool. Then, 225. mu.L of an aqueous LMB solution (4mg/mL) and 60. mu.L of aqueous ammonia (30%, m) were added dropwiseSolute:mSolvent(s)) And then stirred for 2 hours. Finally, 90. mu.L of tetraethyl orthosilicate (TEOS) and 20. mu.L of (3-aminopropyl) triethoxysilane (APTES) were slowly added to the solution and reacted for 24 h. The partially hydrolyzed negatively charged TEOS transferred to the hydrophilic interior of the reverse micelle to interact with the positively charged MB. By hydrolysis and condensation, UCNPs @ SiO is obtained2/MB。
Example 4UCNP @ SiO2Preparation of/MB @ PEG-FA
COOH-PEG-FA, NHS and EDC were mixed in dimethyl sulfoxide (DMSO) in a molar ratio of 1:2.5:1(7.2,18 and 7.2. mu. mol) and activated for 1 hour. Then, 250. mu.L of the activated mixture was added to 2mL of UCNPs @ SiO in example 32Per MB, then reacted for 12 hours under slow shaking. Centrifugal collection of UCNPs @ SiO2/. MB @ PEG-FA, washed several times with ultrapure water, and finally dispersed in PBS buffer solution (pH-7.5).
The experimental results are shown in FIGS. 1 to 3:
FIG. 1 is a schematic representation of the preparation of UCNPs @ SiO2And synthesizing and characterizing the/MB @ PEG-FA nanoprobe. Two light emitting ions Ho3+And Tm3+The doped up-converting nanoparticles have strong red fluorescence. The red emission is due to5F5And1G4excited state to5I8And3F4transition of the ground state (fig. 1 (a)). Synthetic UCNPs and UCNPs @ SiO, as shown in FIGS. 1(b-d)2Showing high homogeneity and pure hexagonal phase. Measured by TEM, SiO2The thickness is about 5-7.5 nm. Uv-Vis analysis and Zeta potential analysis prove that MB is loaded on SiO in the silicification process2In the silicon layer. Uv-Vis analysis demonstrated that PEG-FA was coated on UCNPs @ SiO by amidation reaction2the/MB nanometer probe is arranged on the surface of the probe so as to improve the dispersibility and the targeting property of the probe. The introduction of PEG-FA changed the zeta potential value from negative (-30.6) to positive (23.4) and allowed UCNPs @ SiO2the/MB @ PEG-FA nanoprobe is monodisperse, so that the capability of entering cells is enhanced.
FIG. 2 is a graph showing the UCNPs @ SiO prepared by evaluation2The ability of the/MB @ PEG-FA nanoprobe to generate ROS. Good spectral matching and shortened energy transfer distance ensure effective LRET efficiency. UCNPs @ SiO2The luminescence intensity at 650nm was reduced by 90% for excitation of MB to generate ROS (fig. 2 (a)). Detection of UCNPs @ SiO by ABDA fluorescence method2The efficiency of the/MB @ PEG-FA nanoprobe in generating ROSs. As shown in FIG. 2(b), when ABDA was mixed with the nanoprobes under 980nm laser irradiation, the fluorescence intensity gradually decreased. After 65 minutes of irradiation, 70% of the fluorescence of the ABDA was quenched. In contrast, UCNPs @ SiO2The @ PEG-FA and MB molecules had no effect on the fluorescence intensity of ABDA after NIR irradiation. And UCNPs @ SiO2the/MB @ PEG-FA also had no effect on the fluorescence intensity of ABDA in the absence of NIR irradiation. Indicating UCNPs @ SiO2the/MB @ PEG-FA and NIR are two indispensable conditions for the production of ROSs. Shows that after UCNPs are excited by NIR, luminescence resonance energy transfer to SiO occurs2MB molecules in the silicon layer are excited to generate ROSs.
FIG. 3 is a UCNPs @ SiO fabricated by investigation using a two-photon laser confocal microscope2the/MB @ PEG-FA nanoprobe enters the intracellular process. As shown in FIG. 3, intracellular UCNPs @ SiO as incubation time was extended2The fluorescence intensity of the/MB @ PEG-FA nanoprobe gradually increases, indicating that more nanoprobes successfully engulf MCF-7 cells. Superposition display of bright field and luminous image UCNPs @ SiO2the/MB @ PEG-FA nanoprobe is mainly located in the cytoplasmic region.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (10)

1. UCNPs @ SiO2the/MB/PEG-FA nanoprobe is characterized in that: the nanoprobe comprises an upconversion nanoparticle inner core UCNPs, an ultrathin silicon dioxide shell layer wrapped on the surface of the inner core, methylene blue MB and polyethylene glycol-folic acid PEG (polyethylene glycol-folate) loaded on the shell layer-FA; the matrix material selected by the up-conversion nano particles is NaYF4The sensitizer is Yb3+The luminescent ion is Ho3+And Tm3+；
The synthesis method of UCNPs comprises the following steps:
weighing 1.129gY2O3And 20mL of concentrated hydrochloric acid in a round-bottom flask, covering with a preservative film, and pricking to obtain a solution with a concentration of 60mLoC, stirring; after overnight reaction, the temperature was raised to 140 deg.CoC, volatilizing concentrated hydrochloric acid to obtain YCl3(ii) a The synthesized YCl3Adding 10mL of ultrapure water, and ultrasonically dissolving; adding 5mL ultrapure water, filtering with syringe and 0.22um green filter tip, injecting into flask, adding 20mL ethanol, 35mL cyclohexane, 30mmol sodium oleate, adding into the flask, stirring at 78 deg.CoC, refluxing for 4 hours; then reducing the temperature to 30-40 DEG CoC, transferring the supernatant into a separating funnel, and taking the supernatant; then adding 20mL of ultrapure water and 20mL of ethanol, and uniformly oscillating; taking the upper layer by layering, and separating liquid for three times; then transferring the mixture into a round-bottom flask, adding an explosion-proof ball, and performing rotary evaporation; then, 12mL of octadecene and 12mL of oleic acid were added thereto by syringe and mixed well to obtain Y (oleate)3；
Oleate of the light-emitting layer was also synthesized by the above method and noted Ln (oleate)3(ii) a Wherein the molar ratio of Y, Yb, Ho and Tm is 77.8:20:2:0.2, and the total mole number of Y, Yb, Ho and Tm is 5mmol, which is as follows:
weighing Y in a molar ratio of Y to Yb to Ho to Tm =77.8 to 20 to 2 to 0.22O3、Yb2O3、Ho2O3、Tm2O3Making the total mole number be 5mmol, placing the obtained product and 20mL of concentrated hydrochloric acid into a round bottom flask, covering with preservative film, pricking, and making the obtained product be 60 mmoloC, stirring; after overnight reaction, the temperature was raised to 140 deg.CoC, volatilizing concentrated hydrochloric acid to obtain mixed rare earth chloride; adding the synthesized mixed rare earth chloride into 10mL of ultrapure water, and dissolving by ultrasonic; adding 5mL ultrapure water, filtering with syringe and 0.22um green filter tip, injecting into flask, adding 20mL ethanol, 35mL cyclohexane, 30mmol sodium oleate, adding into the flask, stirring at 78 deg.CoC, refluxing for 4 hours; then reducing the temperature to 30-40 DEG CoC, transferring the supernatant into a separating funnel, and taking the supernatant; then adding 20mL of ultrapure water and 20mL of ethanol, and uniformly oscillating; taking the upper layer by layering, and separating liquid for three times; then transferring the mixture into a round-bottom flask, adding an explosion-proof ball, and performing rotary evaporation; then, 12mL of octadecene and 12mL of oleic acid were added thereto by syringe and mixed well to obtain Ln (oleate)3；
1.0 mmol Y(oleate)3Adding 10.0mmol NaF into solution mixed with octadecene and oleic acid in equal proportion, and performing three cycles of air suction and air inflation; reacting at 115 ℃ for 1h, and heating to 340 DEG CoC; after 90min of reaction, a small amount of the sample was taken out, and 0.4mmol of Ln (oleate) was added3After reaction for 20min, a small amount of the sample solution was taken out, and 0.6mmol of Y (oleate) was added thereto3After reacting for 20min, quickly cooling to room temperature; adding ethanol with the same volume into the product, shaking, centrifuging at 8000rpm for 10min, pouring the supernatant, recovering, retaining the lower solid precipitate, dispersing in cyclohexane, ultrasonically dispersing uniformly, centrifuging at 2000rpm for 5min, taking the supernatant, adding ethanol with the same volume, shaking, centrifuging at 8000rpm for 10min, pouring the supernatant, recovering and retaining the lower solid, repeating the above operation once, and taking the supernatant as the final product, namely the oleic acid-protected NaYF4:Yb3+, Ho3+/Tm3+ UCNPs；
UCNPs@SiO2The preparation method of the/MB comprises the following steps:
mixing cyclohexane and a surfactant, stirring to form a reverse micelle, adding UCNPs, and mixing and stirring to form a first mixing system;
adding methylene blue and an ammonia water solution into the mixed system I, and mixing and stirring to form a mixed system II;
adding a silicon source into the second mixed system, carrying out mixed reaction, transferring the partially hydrolyzed negative silicon source into the hydrophilic interior of the reverse micelle to interact with the positive methylene blue, and hydrolyzing and condensing to obtain UCNPs @ SiO2/MB；
UCNPs@SiO2The preparation method of the/MB/PEG-FA comprises the following steps:
activating carboxyl group of carboxylated PEG-FA, and adding the activated mixtureInto the UCNPs @ SiO2in/MB, the UCNPs @ SiO is prepared by mixing reaction2/MB@PEG-FA。
2. The nanoprobe of claim 1, which is characterized in that: the thickness of the ultrathin silicon dioxide shell layer is less than 10 nm.
3. The nanoprobe of claim 2, which is characterized in that: the thickness of the ultrathin silicon dioxide shell layer is 5.0-7.5 nm.
4. The nanoprobe of claim 1, which is characterized in that: in the step (1), the surfactant is Igepal CO-520, and the silicon source is tetraethyl orthosilicate and (3-aminopropyl) triethoxysilane.
5. The nanoprobe of claim 1, which is characterized in that: in the step (1), the feeding proportion of the cyclohexane, the surfactant and the UCNPs is (8-12) mL: (0.3-0.8) mL: (0.3-0.5) mmol; mixing and stirring cyclohexane and a surfactant for 1-2 hours to form a reverse micelle; adding UCNPs, mixing and stirring for 1-2 h.
6. The nanoprobe of claim 1, which is characterized in that: in the step (1), the feeding proportion of the methylene blue, the ammonia water solution and the UCNPs is (2-6) mg: (40-80) μ L: (0.3-0.5) mmol; mixing and stirring for 2-3 h.
7. The nanoprobe of claim 4, which is characterized in that: in the step (1), the feeding proportion of tetraethyl orthosilicate, 3-aminopropyl triethoxysilane and UCNPs is (60-100) mu L: (10-40) μ L: (0.3-0.5) mmol; mixing and reacting for 24-36 h.
8. The nanoprobe of claim 1, which is characterized in that: in the step (2), the specific steps of activation are as follows: mixing COOH-PEG-FA, NHS and EDC in a molar ratio of (1-2): 2-4): 1-2 in dimethyl sulfoxide, and activating for 1-2 h.
9. The nanoprobe of claim 8, which is characterized in that: in the step (2), the activated mixture is mixed with UCNPs @ SiO2The feeding proportion of/MB is (200-300) mu L: (1-3) mL, and mixing and reacting for 10-14 h.
10. The UCNPs @ SiO of any of claims 1-92Application of the/MB/PEG-FA nanoprobe in preparing photodynamic therapeutic agents.
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