CN112852426A - Multifunctional nano template based on aggregation-induced emission and preparation method and application thereof - Google Patents
Multifunctional nano template based on aggregation-induced emission and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a multifunctional nano template based on aggregation-induced emission and a preparation method and application thereof, wherein the preparation method comprises the following steps: refluxing and stirring the mixed solution of dimethoxy triphenylamine thiophene and 1, 3-indandione to obtain MeOTTI; MeOTTI、DSPE‑PEG2000-SH and NaYF4:Yb3+,Er3+(Up-converting nanoparticles, UCNPs) and use KMnO4Performing surface oxidation to obtain MeOTTI, UCNPs @ DSPE-PEG @ MnO2Nanoparticles. The nano template prepared by the invention utilizes MnO on the basis of an I-type photodynamic photosensitizer with AIE property2The shell consumes endogenous glutathione to reserve active oxygen, and the up-conversion nanoparticles are introduced to increase the tissue penetrability of light, so that the large-depth light diagnosis and treatment effect is realized.
Description
Technical Field
The invention relates to the technical field of biological materials, in particular to a multifunctional nano template based on aggregation-induced emission and a preparation method and application thereof.
Background
Phototherology has proven to be an effective strategy to achieve personalized and precise treatment of cancer due to its non-invasive and light-controllable advantages. In recent years, development of a photo-therapeutic agent has been receiving wide attention, and a small organic fluorophore having a photosensitive characteristic has emerged due to good biocompatibility and biodegradability as well as easy-to-customize structure and optical properties. Conventional fluorophores with planar conformations suffer from intrinsic defects such as aggregate-quenching (ACQ), small stokes shift, poor photostability, which greatly limit their practical applications. In 2001, the Tang-loyal college team first proposed the concept of aggregation-induced emission (AIE), which solved the deficiency of ACQ.
The AIE molecules are classified into AIE molecules for type I Photodynamic Therapy (PDT) and AIE molecules for type II PDT according to the difference in the pathway of generating Reactive Oxygen Species (ROS), wherein the AIE molecules for type I PDT are considered to be a more efficient Photodynamic Therapy scheme by transferring energy to environmental substances to generate substances having a stronger killing effect, such as superoxide radicals or hydroxyl radicals, independent of the ambient oxygen content. However, the existing preparation of the AIE molecule with type I PDT is only reported, the PDT effect of the AIE molecule is easily influenced by the endogenous Glutathione (GSH) of tumor cells, the excitation wavelength and the emission wavelength of the AIE molecule are partially in the ultraviolet/visible range, and the tissue penetration depth is very limited.
Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
The invention aims to solve the technical problems that the existing preparation of an AIE molecule with type I PDT is only reported, the PDT effect of the AIE molecule is easily influenced by endogenous GSH of tumor cells, and the tissue penetration depth is limited.
The technical scheme adopted by the invention for solving the technical problem is as follows: a preparation method of a multifunctional nano template based on aggregation-induced emission comprises the following steps:
dissolving dimethoxy triphenylamine thiophene and 1, 3-indandione in a mixed solution of ethanol and chloroform, and carrying out reflux stirring under the protection of inert gas to obtain MeOTTI;
adding MeOTTI, DSPE-PEG2000-SH and NaYF4:Yb3+,Er3+Dissolving in tetrahydrofuran to prepare a mixed solution, performing dialysis treatment on the mixed solution, and performing centrifugal concentration to obtain MeOTTI, UCNPs @ DSPE-PEG nanoparticles (MU NPs);
mixing KMnO4Adding the solution into aqueous solution of MeOTTI, UCNPs @ DSPE-PEG nano particles, and stirring at room temperature to obtain multifunctional nano template MeOTTI, UCNPs @ MnO based on aggregation-induced emission2Nanoparticles (MUM NPs).
The preparation method of the multifunctional nano template based on aggregation-induced emission comprises the following steps of dissolving dimethoxy triphenylamine thiophene and 1, 3-indandione in a mixed solution of ethanol and chloroform, and carrying out reflux stirring under the protection of inert gas to obtain MeOTTI:
dissolving dimethoxy triphenylamine thiophene and 1, 3-indandione in a mixed solution of ethanol and chloroform, refluxing and stirring under the protection of inert gas, and then carrying out reduced pressure distillation to obtain a crude product;
the crude product was purified by silica gel column chromatography using ether/dichloromethane as eluent to give MeOTTI.
The preparation method of the multifunctional nano template based on aggregation-induced emission is characterized in that the temperature of reflux stirring is 40-50 ℃, and the time of reflux stirring is 11-13 h.
The multifunctional nano template preparation method based on aggregation-induced emission is characterized in that the molar ratio of dimethoxy triphenylamine thiophene to 1, 3-indandione is (1-1.2): 1.
the preparation method of the multifunctional nano template based on aggregation-induced emission comprises the steps of mixing MeOTTI and DSPE-PEG2000-SH and NaYF4:Yb3+,Er3+Dissolving in tetrahydrofuran to prepare a mixed solution, performing dialysis treatment on the mixed solution, and performing centrifugal concentration to obtain the MeOTTI, UCNPs @ DSPE-PEG nanoparticles, wherein the steps comprise:
adding MeOTTI, DSPE-PEG2000-SH and NaYF4:Yb3+,Er3+Dissolving in tetrahydrofuran, carrying out ultrasonic treatment for 4-6 min, and standing for 20-40 min to obtain a mixed solution;
injecting the mixed solution into water, performing ultrasonic treatment on the mixed solution injected into the water, and then filling the mixed solution into a dialysis bag for dialysis treatment;
and (3) carrying out centrifugal concentration on the mixed solution after dialysis treatment to obtain MeOTTI, UCNPs @ DSPE-PEG nanoparticles.
The preparation method of the multifunctional nano template based on aggregation-induced emission is characterized in that the dialysis treatment time is 23-25 hours, and water is changed every 3-5 hours in the dialysis treatment process.
The preparation method of the multifunctional nano template based on aggregation-induced emission comprises the following steps of adding MeOTTI, UCNPs @ DSPE-PEG nano particles into an aqueous solution of the MeOTTI, the UCNPs @ DSPE-PEG nano particles, wherein the concentration of the MeOTTI, the UCNPs @ DSPE-PEG nano particles is 0.15-0.25 mg/mL, and KMnO4The concentration is 150-250 mu g/mL, KMnO4The mass ratio of the particles to the MeOTTI, UCNPs @ DSPE-PEG nanoparticles is 1-4: 200.
The preparation method of the multifunctional nano template based on aggregation-induced emission comprises the following steps of stirring at room temperature for 25-35 min, and centrifuging at a rotating speed of 9000-11000 rpm for 8-12 min after stirring at room temperature.
The multifunctional nano template based on aggregation-induced emission is prepared by the preparation method of the multifunctional nano template based on aggregation-induced emission.
The multifunctional nano template based on aggregation-induced emission is applied to efficient multi-modal light diagnosis and treatment.
Has the advantages that: the nano template prepared by the invention utilizes MnO on the basis of an I-type photodynamic photosensitizer with AIE property2Depletion of endogenous GSH by the outer shell preserves ROS, producing Mn2+Not only can be reacted with H2O2Generating Fenton-like reaction to further generate hydroxyl free radicals, and can be used for nuclear magnetic resonance imaging to realize fluorescence and nuclear magnetic resonance combined bimodal imaging navigation; the introduced up-conversion nanoparticles increase the tissue penetrability of light, further enhance the generation of ROS under the combined irradiation of 980nm laser and white light, and realize the deep light diagnosis and treatment effect.
Drawings
FIG. 1 is a synthetic roadmap for the type I PDT photosensitizer MeOTTI with AIE properties provided in an example of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of MeOTTI prepared in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance carbon spectrum of MeOTTI prepared in example 1 of the present invention;
FIG. 4 is a high resolution mass spectrum of MeOTTI prepared in example 1 of the present invention;
FIG. 5 is a graph of the UV-VIS absorption spectrum of MeOTTI in methylene chloride and the fluorescence spectrum in n-hexane prepared in example 1 of the present invention;
FIG. 6 is a graph showing fluorescence spectra of MeOTTI prepared in example 1 of the present invention in dichloromethane/n-hexane mixed solutions of different ratios;
FIG. 7 is a transmission electron microscopy image and an elemental distribution plot of MUM NPs prepared in example 4 of the present invention;
FIG. 8 is an active oxygen generation energy diagram of MeOTTI NPs and MUM NPs prepared in examples 2 and 4 of the present invention under white light/980 nm laser irradiation;
FIG. 9 is a graph comparing the hydroxyl radical generating capacity of MU NPs prepared in example 3 of the present invention in PBS solutions of different GSH concentrations;
FIG. 10 is a graph comparing the hydroxyl radical generating capacity of MUM NPs prepared in example 4 of the present invention in PBS solutions of different GSH concentrations;
FIG. 11 is a graph of the viability of 4T1 cells in application example 1 of the present invention in different samples and conditions;
FIG. 12 is a graph of fluorescence imaging and MRI imaging of tumor sites in mice in application example 2 of the present invention;
FIG. 13 is a graph showing the tumor growth inhibition ratio of each group of mice in application example 3 of the present invention.
Detailed Description
The invention provides a multifunctional nano template based on aggregation-induced emission and a preparation method and application thereof, and the invention is further described in detail below in order to make the purposes, technical schemes and advantages of the invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Aggregation-induced emission (AIE) molecules have the advantages of high aggregation state brightness, large Stokes shift, strong photobleaching resistance and the like, so that the AIE molecules have important significance in fluorescence imaging. Currently, AIE molecules are considered to be suitable for the fields of Photoacoustic Imaging (PAI), Photothermal Imaging (PTI), and Photothermal therapy (PTT), and the AIE molecules, particularly when aggregated, have been proven to be an excellent Reactive Oxygen Species (ROS) provider, and thus can be applied to fluorescence Imaging guided photodynamic therapy (PDT).
The AIE molecules are classified into AIE molecules for type I PDT and AIE molecules for type II PDT according to the pathway of generating Reactive Oxygen Species (ROS). Wherein, the AIE molecule of II type PDT transfers the energy of the triplet state to the ambient oxygen to generate singlet oxygen, and the AIE molecule of the form has extremely high dependence on the ambient oxygen content, thus being greatly inhibited in the tumor hypoxia state; the AIE molecule of type II PDT transfers energy to environmental substances to generate substances with stronger killing effect such as superoxide radical or hydroxyl radical, and the AIE molecule of type I PDT is considered to be a more efficient photodynamic treatment scheme because the AIE molecule does not depend on the content of environmental oxygen.
Few reports exist on the existing preparation of AIE molecules with type I PDT, the PDT effect of the AIE molecules is not only related to the ROS generation capacity of photosensitizer molecules, but also closely related to a tumor microenvironment, for example, endogenous high-expression Glutathione (GSH) of tumor cells is a strong antioxidant substance, the ROS fast digestion capacity of the GSH plays an important role in maintaining the functions of the tumor cells and ensuring the survival of the cells, and the GSH endows the cancer cells with anti-apoptosis property and is a great obstacle in the anti-cancer treatment process. In addition, the excitation and emission wavelengths of AIE molecules are in the uv/visible range in large part, tissue penetration depth is very limited, and this problem is difficult to ameliorate by molecular structure modulation.
In order to solve the above problems, the present invention provides a method for preparing a multifunctional nano template based on aggregation-induced emission, comprising the steps of:
s1, dissolving dimethoxy triphenylamine thiophene and 1, 3-indandione in a mixed solution of ethanol and chloroform, and carrying out reflux stirring under the protection of inert gas to obtain the MeOTTI.
In order to prepare the AIE molecule for PDT type I, dimethoxy triphenylamine thiophene and 1, 3-indandione are used as raw materials in this embodiment, the synthetic route is shown in fig. 1, a mixed solution of ethanol and chloroform is used as a solvent, dimethoxy triphenylamine thiophene (MeOTT) and 1, 3-indandione are dissolved in the solvent, and reflux stirring is performed under the protection of inert gas, so as to obtain PDT photosensitizer type I with AIE property MeOTTI.
In one embodiment, step S100 specifically includes:
s11, dissolving dimethoxy triphenylamine thiophene and 1, 3-indandione in a mixed solution of ethanol and chloroform, refluxing and stirring under the protection of inert gas, and then carrying out reduced pressure distillation to obtain a crude product;
s12, the crude product was purified by silica gel column chromatography with ether/dichloromethane as eluent to give MeOTTI.
Specifically, dimethoxy triphenylamine thiophene and 1, 3-indandione are dissolved in a mixed solution of ethanol and chloroform in an inert gas such as N2Under protection, carrying out reflux stirring on the reaction solution at 40-50 ℃ for 11-13 h, and then carrying out reduced pressure distillation on the reaction product to obtain a crude product; since the crude product contains impurities, after the crude product is obtained in this example, the crude product is separated and purified by silica gel column chromatography using a mixed solution of diethyl ether and dichloromethane as an eluent, to obtain MeOTTI. Wherein the volume ratio of the diethyl ether to the dichloromethane in the eluent is 1: 1, the molar ratio of dimethoxy triphenylamine thiophene to 1, 3-indandione is 1-1.2: 1.
s2, adding MeOTTI and DSPE-PEG2000-SH and NaYF4:Yb3+,Er3+Dissolving the mixture in tetrahydrofuran to prepare a mixed solution, and performing dialysis treatment and centrifugal concentration on the mixed solution to obtain the MeOTTI, UCNPs @ DSPE-PEG nanoparticles.
Considering that the excitation and emission wavelengths of the AIE molecules are partly in the uv/vis range, the tissue penetration depth is very limited, while the up-conversion material NaYF4:Yb3+,Er3+The fluorescent material is a luminescent material capable of absorbing low-energy light and exciting high-energy light, and has the advantages of small background interference, small matrix damage, long fluorescence service life, difficult photobleaching, good biocompatibility and the like compared with the traditional organic dye and quantum dot fluorescent labeling materials. After preparing type I PDT photosensitizer MeOTTI with AIE property in this example, MeOTTI, distearoyl phosphatidyl acetamide-polyethylene glycol 2000-sulfhydryl (DSPE-PEG) were added2000-SH) and NaYF4:Yb3+,Er3+Dissolving the mixture in tetrahydrofuran to prepare a mixed solution, then carrying out dialysis treatment on the mixed solution, and then carrying out centrifugal concentration to obtain the MeOTTI, UCNPs @ DSPE-PEG nanoparticles. By NaYF4:Yb3+,Er3+The formed rare earth doped up-conversion fluorescent Nanoparticles (UCNPs) enable the prepared nano ions to be excited by infrared lightThe tissue penetrability of light is increased, and the light diagnosis and treatment effect of large depth can be realized.
In a specific embodiment, the step S2 specifically includes:
s21, adding MeOTTI and DSPE-PEG2000-SH and NaYF4:Yb3+,Er3+Dissolving in tetrahydrofuran, carrying out ultrasonic treatment for 4-6 min, and standing for 20-40 min to obtain a mixed solution;
s22, injecting the mixed solution into water, performing ultrasonic treatment on the mixed solution injected into the water, and then putting the mixed solution into a dialysis bag for dialysis treatment;
s23, carrying out centrifugal concentration on the mixed solution after dialysis treatment to obtain the MeOTTI, UCNPs @ DSPE-PEG nano particles.
Specifically, when preparing the MeOTTI, UCNPs @ DSPE-PEG nano-particles, the MeOTTI and the DSPE-PEG are firstly prepared2000-SH and NaYF4:Yb3+,Er3+Dissolving in tetrahydrofuran, and performing ultrasonic treatment for 4-6 min to obtain MeOTTI and DSPE-PEG2000-SH and NaYF4:Yb3+,Er3+Uniformly dispersing in tetrahydrofuran, and standing for 20-40 min to obtain a mixed solution; then quickly injecting the obtained mixed solution into water, carrying out ultrasonic treatment on the mixed solution injected into the water for 2-4 min by using an ultrasonic probe, then filling the mixed solution into a dialysis bag for dialysis treatment for 23-25 h, and changing water every 3-5 h in the dialysis treatment process; and after the dialysis treatment is finished, carrying out centrifugal concentration on the mixed solution after the dialysis treatment to obtain the MeOTTI, UCNPs @ DSPE-PEG nano particles.
S3, mixing KMnO4Adding into aqueous solution of MeOTTI, UCNPs @ DSPE-PEG nano particles, stirring at room temperature to obtain MeOTTI, UCNPs @ DSPE-PEG @ MnO2Nanoparticles.
Considering that the PDT effect of the existing AIE molecules is easily influenced by the endogenous Glutathione (GSH) of tumor cells, after obtaining the nanoparticles of MeOTTI, UCNPs @ DSPE-PEG in the embodiment, KMnO is added4Adding the mixture into aqueous solution of MeOTTI, UCNPs @ DSPE-PEG nano particles, stirring for 25-35 min at room temperature, and stirring in the process of strong oxidizing KMnO4Carrying out surface oxidation on the MeOTTI, UCNPs @ DSPE-PEG nano particles,in situ formation of MnO on the surface of MeOTTI, UCNPs @ DSPE-PEG nanoparticles2(ii) a Centrifuging at 9000 rpm-11000 rpm for 8-12 min after stirring to obtain MeOTTI, UCNPs @ DSPE-PEG @ MnO2The nano-particles are multifunctional nano-templates based on aggregation-induced emission. Wherein the concentration of the MeOTTI, UCNPs @ DSPE-PEG nanoparticles in the aqueous solution of the MeOTTI, UCNPs @ DSPE-PEG nanoparticles is 0.15-0.25 mg/mL, and KMnO4The concentration is 150-250 mu g/mL, KMnO4The mass ratio of the particles to the MeOTTI, UCNPs @ DSPE-PEG nanoparticles is 1-4: 200. The multifunctional nano template prepared in the embodiment utilizes MnO on the basis of an I-type photodynamic photosensitizer with AIE property2Depletion of endogenous GSH by the outer shell preserves ROS, producing Mn2+Not only can be reacted with H2O2Generating Fenton-like reaction to further generate hydroxyl free radicals, and can be used for nuclear magnetic resonance imaging to realize fluorescence and nuclear magnetic resonance combined bimodal imaging navigation; the introduced up-conversion nanoparticles increase the tissue penetrability of light, further enhance the generation of ROS under the combined irradiation of 980nm laser and white light, and realize the deep light diagnosis and treatment effect.
The invention also provides a multifunctional nano template based on aggregation-induced emission, which is prepared by adopting the preparation method. In the embodiment, the multifunctional nano template based on aggregation-induced emission utilizes MnO on the basis of an I-type photodynamic photosensitizer with AIE property2Depletion of endogenous GSH by the outer shell preserves ROS, producing Mn2+Not only can be reacted with H2O2Generating Fenton-like reaction to further generate hydroxyl free radicals, and can be used for nuclear magnetic resonance imaging to realize fluorescence and nuclear magnetic resonance combined bimodal imaging navigation; the introduced up-conversion nanoparticles increase the tissue penetrability of light, further enhance the generation of ROS under the combined irradiation of 980nm laser and white light, and realize the deep light diagnosis and treatment effect.
The invention also provides application of the multifunctional nano template based on aggregation-induced emission in efficient multi-mode light diagnosis and treatment. The multifunctional nano template based on aggregation-induced emission prepared by the invention not only has the characteristics of an I-type photodynamic photosensitizer with AIE property, namely MnO2Endogenous source of consumption of the outer shellGSH retains ROS, produces Mn2+Not only can be reacted with H2O2Generating Fenton-like reaction to further generate hydroxyl free radicals, and can be used for nuclear magnetic resonance imaging to realize fluorescence and nuclear magnetic resonance combined bimodal imaging navigation; the upconversion nanoparticles in the template can increase the tissue penetrability of light, further enhance the generation of ROS under the combined irradiation of 980nm laser and white light, and realize a large-depth light diagnosis and treatment effect.
The invention is further illustrated by the following specific examples.
Example 1
In N2Under protection, 0.415g of MeOT and 0.175g of 1, 3-indandione were added to a mixed solution of 10mL of dry ethanol and 10mL of chloroform, and the mixture was heated to 45 ℃ in a 50mL round-bottom flask and stirred under reflux for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain a crude product, which was subjected to separation and purification by silica gel column chromatography using ether/dichloromethane (1: 1) as an eluent to obtain 0.33g of red solid product MeOTTI in a yield of 60%.
Example 2
1mg of MeOTTI molecule solid powder and 15mg of DSPE-PEG2000-SH (commercial) was added to 1mL THF and allowed to stand for 30 minutes with sonication for 5 minutes. The above mixed solution was quickly poured into 9mL of water, followed by sonication with an ultrasonic probe for 2 minutes. The mixed solution was put into a dialysis bag (MWCO 8000-. And centrifugally concentrating to finally obtain the MeOTTI @ DSPE-PEG nano particles (MeOTTI NPs).
Example 3
1mg of MeOTTI molecule solid powder, 15mg of DSPE-PEG2000-SH (commercial) and 6. mu.L NaYF4:Yb3+,Er3+(5mg/mL in THF, commercially available) was added to 1mL THF and allowed to stand for 30 minutes with sonication for 5 minutes. The above mixed solution was quickly poured into 9mL of water, followed by sonication with an ultrasonic probe for 2 minutes. The mixed solution is put into a dialysis bag (MWCO8000-14000Da) for dialysis for 24 hours, and water is changed every 4 hours. And (4) centrifugally concentrating to finally obtain MeOTTI, UCNPs @ DSPE-PEG nanoparticles (MU NPs).
Example 4
KMnO with a volume of 150. mu.L4(200. mu.g/mL) was added to 10mL of an aqueous solution of MU NPs (0.2mg/mL), stirred at room temperature for 30 minutes, and centrifuged at 10000rpm for 10 minutes to obtain MeOTTI, UCNPs @ DSPE-PEG @ MnO2 NPs(MUM NPs)。
Application example 1
After trypsinizing the cells in logarithmic growth phase, the complete medium was resuspended in a cell suspension, which was subsequently seeded at a density of 5X 103 cells/well in 96-well plates at 37 ℃ in 5% CO2Culturing in incubator, adding MeOTTI NPs or MUM NPs with different concentrations after 24 hr to make the final concentration of sample 0.5,1,2,3,4 and 5 μ M respectively, culturing for 12 hr, and illuminating (power 0.3W/cm)2980nm laser for 5 minutes or white light for 15 minutes), while the groups not illuminated under the same experimental conditions also performed dark toxicity studies. After 12h of incubation, 3 washes with PBS followed by 2h of incubation in the dark with fresh 10% CCK-8 FBS-free medium followed by measurement of absorbance (OD) at 450nm with a microplate reader, the corresponding cell viability calculation is by the following equation: cell viability (%) - (OD sample-OD background)/(OD control-OD background) × 100%.
Application example 2
Transplanted tumor 4T1 mice were anesthetized with an oxygen flux of 2% isoflurane 2L/min, followed by intratumoral injection of MeOTTI nanoparticles (20. mu.L, 1 mM). In vivo near-infrared one-zone fluorescence imaging was obtained at predetermined time intervals (1, 6 and 12 hours) post-injection using an IVIS spectroscopic imaging system (PerkinElmer) and a commercial series II 900/1700 imaging system. mu.L of MUM NPs (1mg/mL) was injected into the tumor and in situ MRI was performed at 0,0.5,3,6,9 and 12 hours to obtain fluorescence and MRI images of the tumor site in mice as shown in FIG. 12.
Application example 3
Dividing transplanted tumor 4T1 tumor mice into 6 groups (5 mice in each group, including physiological saline group, MUM NPs group, laser + white light group, MeOTTI NPs + white light group, MUM NPs + white light group and MUM NPs + laser + white light group), when the tumor volume reaches 100mm3Thereafter, 20. mu.L of MUM NPs physiological saline solution was injected by intratumoral injection. 12h after intratumoral injectionTumors of each group of mice were continuously irradiated with white light for 15 minutes or 980nm laser (0.3W/cm)2) Irradiating for 5min for treatment. Tumor size and body weight of each mouse were recorded every three days after each treatment. The tumor volume is measured with a vernier caliper according to the general formula V ═ tumor length x tumor width2) And/2 calculation. Tumor growth inhibition ratio using relative volume V/V0(V0As initial tumor volume before treatment).
Fig. 2 is a nuclear magnetic resonance hydrogen spectrum of the MeOTTI prepared in example 1 of the present invention, fig. 3 is a nuclear magnetic resonance carbon spectrum of the MeOTTI prepared in example 1 of the present invention, fig. 4 is a high resolution mass spectrum of the MeOTTI prepared in example 1 of the present invention, and the molecular structure of the MeOTTI prepared in example 1 of the present invention can be seen from the hydrogen spectrum, the carbon spectrum and the mass spectrum of fig. 2 to 4.
FIG. 5 shows the UV-visible absorption spectrum of compound MeOTTI prepared in example 1 of the present invention in methylene chloride and the fluorescence spectrum of compound MeOTTI in n-hexane, and it can be seen from FIG. 5 that the maximum absorption peak of compound MeOTTI prepared in example 1 of the present invention is about 545nm and the luminescence peak of compound MeOTTI is about 704 nm.
FIG. 6 is a graph showing fluorescence spectra of MeOTTI prepared in example 1 of the present invention in dichloromethane/n-hexane mixed solutions of different ratios, and from FIG. 6, it can be seen that the fluorescence emission of MeOTTI increases with the increase of aggregation degree, indicating that MeOTTI prepared in example 1 of the present invention has AIE characteristics.
FIG. 7 is a transmission electron micrograph and an element distribution diagram of MUM NPs prepared in example 4 of the present invention, and it can be seen from FIG. 7 that MUM NPs prepared in example 4 of the present invention are regular nanospheres having a diameter of about 50nm and the coexistence of Mn, S and Y indicates MeOTTI, up-conversion nanoparticles (UCNPs) and MnO2The components are compounded into a whole and coexist.
FIG. 8 is a graph of the active oxygen generation energy of MeOTTI NPs and MUM NPs prepared in example 2 and example 4, respectively, under white light/980 nm laser irradiation. In the test, the active oxygen generating capacity of MeOTTI was evaluated using DCHF-DA as an indicator, 0.5mL of DCFH-DA (1X 10)-3M) ethanol solution was added to 2mL NaOH (1X 10)-2M) activation in solutionDCFH was obtained by digestion, and then 10mL of PBS (pH 7.4) was added to adjust the pH of the solution, and the solution was left in the dark. MeOTTI NPs and MUM NPs (0.2. mu.M) were evaluated for active oxygen generation capacity using DCFH (5. mu.M) in PBS (pH 7.4), irradiated with white light/980 nm laser, respectively, and fluorescence intensities at 525nm at different time points under 488nm excitation were recorded using a fluorescence spectrophotometer to obtain fluorescence enhancement multiples thereof. As can be seen from FIG. 8, the ROS-generating ability of MUM NPs can be further enhanced under the combined irradiation of 980nm laser and white light.
FIGS. 9 and 10 are graphs showing evaluation of hydroxyl radical generating ability of MU NPs and MUM NPs prepared in examples 3 and 4 of the present invention in PBS solutions of different GSH concentrations. In the test, hydroxyl radical generating capacity of the MeOTTI is evaluated by using HPF as an indicator, hydroxyl radical generating capacity of MU NPs and MUM NPs (0.2 MU M) are evaluated in PBS (PH 7.4) solution of HPF (5 MU M), and fluorescence intensity at 515nm under excitation of 490nm at different time points is recorded by using a fluorescence spectrophotometer after white light irradiation for a period of time to obtain fluorescence enhancement times of the MEOTTI. As can be seen from FIGS. 9 and 10, the hydroxyl radical generating ability of MU NPs and MUM NPs is significantly different in PBS solution containing a certain concentration of GSH, as can be seen from FIG. 9, 1mM GSH can reduce more than 60% of hydroxyl radicals, indicating that GSH has strong ability to consume hydroxyl radicals, while 5mM GSH only consumes 18% of hydroxyl radicals in MUM NPs sample, indicating that MnO is not present2GSH consumption is an important factor in preserving hydroxyl radicals.
Fig. 11 shows the survival rates of 4T1 cells in application example 1 under different samples and conditions, and as can be seen from fig. 11, when the drug concentration is 5 μ M, the cell survival rate of the control group not irradiated by laser exceeds 95%, which proves that the compound has small dark toxicity and good biocompatibility, and the cell survival rate of the experimental group of MUM NPs under the irradiation of laser and white light is only 17%, which proves that the MUM NPs have obvious phototherapeutic anti-proliferation effect on the breast cancer cells 4T 1.
Fig. 13 is a graph of the tumor growth inhibition rate of each group of mice in application example 3, and it can be seen from fig. 13 that the tumor growth inhibition rate of the group of the MUM NPs + laser + white light group is the maximum, which is more than 60%.
In summary, the invention discloses a multifunctional nano template based on aggregation-induced emission, a preparation method and an application thereof, comprising the following steps: dissolving dimethoxy triphenylamine thiophene and 1, 3-indandione in a mixed solution of ethanol and chloroform, and carrying out reflux stirring under the protection of inert gas to obtain MeOTTI; adding MeOTTI, DSPE-PEG2000-SH and NaYF4:Yb3+,Er3+Dissolving in tetrahydrofuran to prepare a mixed solution, performing dialysis treatment on the mixed solution, and performing centrifugal concentration to obtain MeOTTI, UCNPs @ DSPE-PEG nanoparticles; mixing KMnO4Adding the solution into aqueous solution of MeOTTI, UCNPs @ DSPE-PEG nano particles, and stirring at room temperature to obtain the multifunctional nano template based on aggregation-induced emission. The nano template prepared by the invention utilizes MnO on the basis of an I-type photodynamic photosensitizer with AIE property2Depletion of endogenous GSH by the outer shell preserves ROS, producing Mn2+Not only can be reacted with H2O2Generating Fenton-like reaction to further generate hydroxyl free radicals, and can be used for nuclear magnetic resonance imaging to realize fluorescence and nuclear magnetic resonance combined bimodal imaging navigation; the introduced up-conversion nanoparticles increase the tissue penetrability of light, further enhance the generation of ROS under the combined irradiation of 980nm laser and white light, and realize the deep light diagnosis and treatment effect.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (10)
1. A preparation method of a multifunctional nano template based on aggregation-induced emission is characterized by comprising the following steps:
dissolving dimethoxy triphenylamine thiophene and 1, 3-indandione in a mixed solution of ethanol and chloroform, and carrying out reflux stirring under the protection of inert gas to obtain MeOTTI;
adding MeOTTI, DSPE-PEG2000-SH and NaYF4:Yb3+,Er3+Dissolving in tetrahydrofuran to obtain mixed solutionPerforming dialysis treatment on the solution, and then performing centrifugal concentration to obtain MeOTTI, UCNPs @ DSPE-PEG nanoparticles;
mixing KMnO4Adding into aqueous solution of MeOTTI, UCNPs @ DSPE-PEG nano particles, stirring at room temperature to obtain MeOTTI, UCNPs @ DSPE-PEG @ MnO2Nanoparticles.
2. The method for preparing the multifunctional nano template based on aggregation-induced emission according to claim 1, wherein the step of dissolving dimethoxy triphenylamine thiophene and 1, 3-indandione in a mixed solution of ethanol and chloroform, and performing reflux stirring under the protection of inert gas to obtain MeOTTI comprises:
dissolving dimethoxy triphenylamine thiophene and 1, 3-indandione in a mixed solution of ethanol and chloroform, refluxing and stirring under the protection of inert gas, and then carrying out reduced pressure distillation to obtain a crude product;
the crude product was purified by silica gel column chromatography using ether/dichloromethane as eluent to give MeOTTI.
3. The preparation method of the multifunctional nano template based on aggregation-induced emission according to claim 2, wherein the temperature of the reflux stirring is 40-50 ℃, and the time of the reflux stirring is 11-13 h.
4. The method for preparing the multifunctional nano template based on aggregation-induced emission according to claim 2, wherein the molar ratio of dimethoxy triphenylamine thiophene to 1, 3-indandione is 1-1.2: 1.
5. the method for preparing multifunctional nano-template based on aggregation-induced emission according to claim 1, wherein the meOTTI and the DSPE-PEG are prepared2000-SH and NaYF4:Yb3+,Er3+Dissolving in tetrahydrofuran to prepare a mixed solution, performing dialysis treatment on the mixed solution, and performing centrifugal concentration to obtain the MeOTTI, UCNPs @ DSPE-PEG nanoparticles, wherein the steps comprise:
adding MeOTTI, DSPE-PEG2000-SH and NaYF4:Yb3+,Er3+Dissolving in tetrahydrofuran, carrying out ultrasonic treatment for 4-6 min, and standing for 20-40 min to obtain a mixed solution;
injecting the mixed solution into water, performing ultrasonic treatment on the mixed solution injected into the water, and then filling the mixed solution into a dialysis bag for dialysis treatment;
and (3) carrying out centrifugal concentration on the mixed solution after dialysis treatment to obtain MeOTTI, UCNPs @ DSPE-PEG nanoparticles.
6. The method for preparing the multifunctional nano template based on aggregation-induced emission as claimed in claim 5, wherein the dialysis treatment time is 23-25 h, and water is changed every 3-5 h during the dialysis treatment.
7. The method for preparing the multifunctional nano template based on aggregation-induced emission of claim 1, wherein the concentration of the MeOTTI, UCNPs @ DSPE-PEG nanoparticles in the aqueous solution of the MeOTTI, UCNPs @ DSPE-PEG nanoparticles is 0.15-0.25 mg/mL, and KMnO4The concentration is 150-250 mu g/mL, KMnO4The mass ratio of the particles to the MeOTTI, UCNPs @ DSPE-PEG nanoparticles is 1-4: 200.
8. The preparation method of the multifunctional nano template based on aggregation-induced emission according to claim 1, wherein the stirring time of room-temperature stirring is 25-35 min, and the multifunctional nano template is centrifuged at 9000-11000 rpm for 8-12 min after room-temperature stirring.
9. A multifunctional nano template based on aggregation-induced emission, which is prepared by the method for preparing the multifunctional nano template based on aggregation-induced emission according to any one of claims 1 to 8.
10. Use of the multifunctional nano-template based on aggregation-induced emission as claimed in claim 9 in efficient multi-modal photo-therapy.
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| CN113927027A (en) * | 2021-09-16 | 2022-01-14 | 福建医科大学孟超肝胆医院(福州市传染病医院) | Near-infrared region-excited rare earth nanocrystal loaded with viroid hollow manganese oxide and preparation method and application thereof |
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| CN114292639B (en) * | 2021-12-24 | 2023-07-21 | 深圳大学 | Multifunctional nano material based on aggregation-induced emission and MXenes, preparation method and application |
| CN114470202A (en) * | 2022-01-11 | 2022-05-13 | 浙江大学 | AIE-PET bimodal imaging agent and preparation method and application thereof |
| CN114470202B (en) * | 2022-01-11 | 2023-09-15 | 浙江大学 | AIE-PET bimodal imaging agent and preparation method and application thereof |
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