CN111234256B - Hydrogen peroxide responsive metal-polyphenol coordination polymer nanoparticle and preparation method and application thereof - Google Patents
Hydrogen peroxide responsive metal-polyphenol coordination polymer nanoparticle and preparation method and application thereof Download PDFInfo
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- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 239000013256 coordination polymer Substances 0.000 title claims abstract description 22
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
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Abstract
The invention provides a hydrogen peroxide-responsive metal-polyphenol coordination polymer nanoparticle and a preparation method and application thereof, belonging to the technical field of fine organic synthesis. The nano-particle is a coordination polymer nano-particle formed by a polyphenol substituted BODIPY derivative and metal. The preparation method of the nano-particles comprises the following steps: adding the polyphenol-substituted BODIPY derivative and metal chloride into a solvent, reacting for 0.5-2 hours, then dropwise adding the mixture into F127 or PEG water solution, dialyzing by using a dialysis bag with the molecular weight cutoff of 10KD, and taking the trapped fluid to obtain the nanoparticles. The nano-particle has excellent hydrogen peroxide response property, wider absorption spectrum and better photo-thermal effect, can be used as a nano-catalyst for Fenton reaction and a near-infrared two-region excited photo-acoustic contrast agent, and is expected to show good application prospect in synergistic photo-thermal and chemical power anti-tumor treatment.
Description
Technical Field
The invention belongs to the technical field of fine organic synthesis, and particularly relates to a hydrogen peroxide-responsive metal-polyphenol coordination polymer nanoparticle and a preparation method and application thereof.
Background
Photoacoustic imaging is an imaging method based on the photoacoustic conversion phenomenon. In the detection process, the sample absorbs the energy of the incident laser beam to generate thermal expansion, and the ultrasonic wave is generated, and the instrument converts the received ultrasonic wave into image information. The difference of the absorption of laser energy by the sample causes the difference of the ultrasonic wave intensity, thereby forming the difference of the brightness of the image. The photoacoustic imaging technology combines the advantages of optical imaging technology and ultrasonic imaging technology, and can realize high-resolution and high-contrast functional imaging of a tissue body with larger depth. However, tumor photoacoustic contrast agents with good photothermal effect are lacking in the prior art.
Disclosure of Invention
The invention aims to provide a metal-polyphenol coordination polymer nanoparticle which has excellent hydrogen peroxide response property, wider absorption spectrum and better photo-thermal effect, can be used as a nano catalyst of Fenton reaction and a near-infrared two-region excited photo-acoustic contrast agent, and is expected to show good application prospect in synergistic photo-thermal and chemical dynamic antitumor treatment.
The invention also aims to provide the preparation method of the metal-polyphenol coordination polymer nano-particles, which has the advantages of simple operation, low cost and better size uniformity of the obtained nano-particles.
Still another object of the present invention is to provide the use of the metal-polyphenol coordination polymer nanoparticles in the preparation of photoacoustic imaging contrast agents and tumor light therapy drugs.
The purpose of the invention is realized by adopting the following technical scheme:
a hydrogen peroxide response metal-polyphenol coordination polymer nanoparticle is a coordination polymer nanoparticle formed by a polyphenol substituted BODIPY derivative and a metal; the BODIPY derivative is selected from one of the following compounds:
wherein R is C1 to C8 alkyl straight chain or branched chain.
The preparation method of the hydrogen peroxide-responsive metal-polyphenol coordination polymer nanoparticles comprises the following steps: adding a polyphenol-substituted BODIPY derivative and a metal chloride into a solvent, reacting for 0.5-2 hours at room temperature, then dropwise adding the mixture into an F127 aqueous solution or a PEG aqueous solution, dialyzing by using a dialysis bag with the molecular weight cutoff of 10KD, and taking the trapped fluid to obtain the nanoparticles; the polyphenol substituted BODIPY derivative is selected from one of the following compounds:
wherein R is C1 to C8 alkyl straight chain or branched chain.
In a preferred technical scheme, the solvent is N, N-dimethyl amide or dimethyl sulfoxide.
In the invention, the molar ratio of the polyphenol substituted BODIPY derivative to the metal chloride is 0.5-6: 1.
In the invention, the metal chloride is one or more than two of copper chloride, ferric chloride, ferrous chloride and cobalt chloride.
In the invention, the particle size of the nano particles is 40-120 nm.
The invention also provides application of the hydrogen oxide-responsive metal-polyphenol coordination polymer nanoparticles in preparation of photoacoustic imaging contrast agents and tumor phototherapy drugs.
Has the advantages that: the metal-polyphenol coordination polymer nano particle has excellent hydrogen peroxide response property, wider absorption spectrum and better photothermal effect, the photothermal conversion efficiency reaches 30-50%, the metal-polyphenol coordination polymer nano particle can be used as a nano catalyst of Fenton reaction and a near-infrared two-region excited photoacoustic contrast agent, can improve the tissue penetration depth and the signal-to-noise ratio, realizes deep tumor imaging, and is expected to show good application prospect in synergistic photothermal and chemical power antitumor treatment. The preparation method of the metal-polyphenol coordination polymer nano particles is simple to operate and low in cost, and the obtained nano particles have uniform size and distribution.
Drawings
FIG. 1 is a drawing of BODIPY derivative BDP-4OH1H-NMR spectrum.
FIG. 2 is BDP-Fe nanoparticles and BDP-4OH absorption spectra, where the state of "BDP-4 OH NPs" is solid; the state of "BDP-4 OH" is liquid, i.e. a dichloromethane solution of BDP-4 OH; "BDP-Fe" is the BDP-Fe nanoparticles prepared in example 2.
FIG. 3 is a TEM image of BDP-Fe nanoparticles.
FIG. 4 is a temperature rise-fall curve of BDP-Fe nanoparticles and DI water, where BDP-Fe NPs are abbreviations for BDP-Fe nanoparticles and DI water is abbreviation for DI water.
FIG. 5 is a graph showing the temperature of BDP-Fe nanoparticle solution as a function of time, wherein-LN (theta) ═ LN [ (T-T) } is0)/ΔTmax]. Due to the fact thatThe slope of the curve is the time constant of the BDP-Fe nanoparticle solution system and is 238.96 s.
FIG. 6 is a temperature rise curve for different concentrations of BDP-Fe nanoparticles.
FIG. 7 is an absorption curve of hydrogen peroxide in response to time with o-phenylenediamine as an indicator.
Fig. 8 is a graph (a) of photoacoustic images of a 4T1 tumor-bearing mouse model at different times with BDP-Fe nanoparticles as contrast agents, and a graph (b) of relative intensity of photoacoustic signals at corresponding times.
FIG. 9 is the reaction equation in example 2.
Fig. 10 is an enlarged view of the middle portion of the two arrows in fig. 9.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope or spirit of the invention.
EXAMPLE 1 preparation of BODIPY derivative BDP-4OH
0.324g of BODIPY (abbreviated as BODIPY, from Annai Gi chemical, 1mmol) and 0.552g of 3, 4-dihydroxybenzaldehyde (4mmol) were weighed into a two-necked flask under nitrogen protection, and 0.5mL of glacial acetic acid (acetic acid), 0.5mL of piperidine (piperidine) and 10mL of N, N-Dimethylformamide (DMF) were added and reacted at 120 ℃ for 1 hour.
After the reaction, the reaction solution was poured into 100mL of water, and the residue was filtered, washed several times with water, and then separated by a silica gel column to obtain 0.35g of a black solid product with a reaction yield of 63%. The black solid product is identified by nuclear magnetism, and the result is as follows:1H NMR(400MHz,DMSO-d6)δ9.53(s,2H),9.34(s,2H),7.59-7.56(m,2H),7.44-7.34(m,4H),7.28(d,J＝16.8Hz,2H),7.10(s,2H),6.95-6.90(m,5H),6.83(d,J＝8.0Hz,2H),1.40(s,6H).13c NMR (100MHz, DMSO-d6) NMR (101MHz,) delta 152.75,148.19,148.18,146.36,146.35,141.65,137.92,137.90,134.92,132.87,129.66,128.95,128.47,128.45,121.26,118.50,116.59,115.48,113.57, 14.69. FIG. 1 is a black solid product1H-NMR spectrum. Thus, the black solid product was confirmed to have the following structural formula:
the black solid product (BODIPY derivative) prepared in this example was abbreviated BDP-4 OH.
Thus, the equation for the above reaction is as follows:
example 2 preparation of nanoparticle BDP-Fe nanoparticles.
11mg of BDP-4OH (0.02mmol) prepared in example 1 and 5.4mg of FeCl were weighed out3·6H2O (0.02mmol) was dissolved in N, N-dimethylformamide, and then 50. mu.L of triethylamine was added thereto, followed by stirring at room temperature for 30 minutes. The reaction was added dropwise to 4.4mg/mL of a polyethylene glycol-polypropylene glycol-polyethylene glycol block copolymer (F127, EO) with vigorous stirring106PO70EO106And c) then dialyzing with a dialysis bag with the molecular weight cut-off of 10KD, taking the cut-off liquid to obtain a BDP-Fe nano particle (abbreviated as BDP-Fe NPs) solution, and storing at room temperature for later use. The reaction principle is as follows: the phenolic hydroxyl group in BDP-4OH is coordinated and polymerized with ferric ions to form the nano particles with a three-dimensional network structure, and the reaction equations are shown in figure 9 and figure 10.
The ultraviolet-visible-near infrared absorption spectrum shows that the absorption spectrum of solid BDP-4OH, the absorption spectrum of BDP-4OH in dichloromethane solvent and the absorption spectrum of BDP-Fe nanoparticles are respectively tested, and the results are shown in FIG. 2. The BDP-Fe nano-particles show a wider near infrared absorption peak from 633nm to 1300nm and are originated from electronic transition from a ligand to a metal center. The BDP-Fe nano particles have stronger near infrared two-region (NIR-II) absorption peaks, so the BDP-Fe nano particles can be used as NIR-II photothermal reagents.
The shape and size of the BDP-Fe nanoparticles are observed through a transmission electron microscope, and as a result, as shown in FIG. 3, the particles are spherical, the size is uniform, the particle size is 20-40 nm, and the particle size is less than 200nm, which indicates that the BDP-Fe nanoparticles can enter tumor tissues through strong penetration and long retention (EPR) effects.
EXAMPLE 3 photothermal Effect study of BDP-Fe nanoparticles
In two cuvettes, 1.0mL and 1.0mL of deionized water were added to 100. mu.g/mL of BDP-Fe nanoparticle solution (prepared in example 2), respectively. Respectively using 730nm laser (power: 1W/cm)2) The nanoparticle solution and deionized water were irradiated for 10 minutes and then allowed to cool naturally for 15 minutes, during which time the temperature change of the nanoparticle solution and deionized water was recorded with a thermal imager, with one temperature being recorded every 10 seconds. The photothermal conversion efficiency (η) of the nanoparticle BDP-Fe was calculated according to the following formula:
wherein tau issIs the time constant of the sample system; m isDAnd cDRespectively the mass and specific heat capacity (4.2kJ/Kg) of deionized water; delta TmaxThe highest temperature (23.1 ℃) which rises after BDP-Fe nano particles are irradiated by laser; i is the power of the laser (1W/cm)2) (ii) a A is the absorbance of the BDP-Fe nanoparticles at 730 nm; qsIs the change of heat quantity of deionized water from the beginning to the highest temperature when the deionized water is irradiated by a 730nm laser.
In FIG. 4, it is observed that the laser (power: 1W/cm) has a wavelength of 730nm2) Maximum temperature change (Δ T) of nanoparticle solution and deionized water under irradiationmax) 23.1 ℃ and 4.3 ℃ respectively. From fig. 5, it was found that the slope (time constant) of the straight line was 238.96s, and the photothermal conversion efficiency of the BDP-Fe nanoparticles was 49% as calculated, and thus, the BDP-Fe nanoparticles were excellent photothermal agents.
BDP-Fe nanoparticle solutions with different concentrations are processed by a 730nm laser (power: 1W/cm)2) The irradiation was carried out for 10 minutes, during which the temperature change was recorded with a thermal imager, with a temperature being recorded every 10 seconds. As a result, as shown in FIG. 6, it can be seen that, as the concentration of BDP-Fe nanoparticles increases, the solution isThe temperature difference is also gradually increased, which shows that the photothermal effect of the BDP-Fe nanoparticles has better concentration dependence.
EXAMPLE 4 Hydrogen peroxide response Properties of BDP-Fe nanoparticles
An aqueous solution of o-phenylenediamine was prepared in a concentration of 1mM using water as a solvent. 1.0mL of 1mM o-phenylenediamine aqueous solution, 0.2mL of 1mM hydrogen peroxide aqueous solution, 0.2mL of 200 mu g/mL BDP-Fe nanoparticle solution and 0.6mL deionized water are added into a cuvette and uniformly mixed, the o-phenylenediamine is gradually oxidized to generate 2, 3-diaminophenol oxazine with the progress of time, and the change of the absorption spectrum of the reaction solution with the time is tested. As a result, as shown in FIG. 7, it can be seen that the absorption curves of the reaction solution at different reaction times by the action of hydrogen peroxide using o-phenylenediamine as an indicator. Under acidic (pH 5) conditions, after the BDP-Fe nanoparticles are added, the absorption peak of the oxidation product of the o-phenylenediamine, namely 2, 3-diaminophenol oxazine, at 420nm is gradually enhanced, which shows that the 2, 3-diaminophenol oxazine is more and more, and the BDP-Fe nanoparticles keep higher reactivity with the time.
Example 5 application of BDP-Fe nanoparticles as contrast Agents
Constructing a breast cancer model of a mouse, and when the tumor volume reaches 120mm3150 μ L of BDP-Fe nanoparticle solution at 200 μ g/mL was injected via the tail vein of mice with an insulin needle. Thereafter, mice were anesthetized with isoflurane as anesthetic, and photoacoustic signals and images were collected at different time points (0, 1, 2, 4, 8 and 24 hours, where 0 is the photoacoustic signal at the tumor without nanoparticle injection, and this is taken as background) under NIR-II laser irradiation at 1100nm, and the results are shown in fig. 8. From fig. 8, it can be observed that the photoacoustic signal at the tumor gradually increased with time after the administration, peaked at around 4 hours, and then gradually became weaker. After 24 hours, the tumor has stronger photoacoustic signals. This example illustrates that BDP-Fe nanoparticles can be used as contrast agents for near-infrared two-region photoacoustic imaging.
Claims (7)
1. A hydrogen peroxide-responsive metal-polyphenol coordination polymer nanoparticle is characterized in that the nanoparticle is a coordination polymer nanoparticle formed by a polyphenol-substituted BODIPY derivative and a metal; the polyphenol substituted BODIPY derivative is selected from one of the following compounds:
wherein R is C1 to C8 alkyl straight chain or branched chain; the metal is selected from one or more of copper chloride, ferric chloride, ferrous chloride and cobalt chloride.
2. A method for preparing hydrogen peroxide-responsive metal-polyphenol coordination polymer nanoparticles as claimed in claim 1, comprising the steps of: adding a polyphenol-substituted BODIPY derivative and a metal chloride into a solvent, adding triethylamine, reacting for 0.5-2 hours at room temperature, then dropwise adding the mixture into an F127 aqueous solution or a PEG aqueous solution, dialyzing by using a dialysis bag with the molecular weight cutoff of 10KD, and taking the trapped fluid to obtain the nanoparticles; the polyphenol substituted BODIPY derivative is selected from one of the following compounds:
wherein R is C1 to C8 alkyl straight chain or branched chain.
3. The method of preparing hydrogen peroxide-responsive metal-polyphenol coordination polymer nanoparticles of claim 2, characterized in that the solvent is N, N-dimethylamide or dimethylsulfoxide.
4. The method for preparing hydrogen peroxide-responsive metal-polyphenol coordination polymer nanoparticles according to claim 3, wherein the molar ratio of the polyphenol-substituted BODIPY derivative to the metal chloride is 0.5-6: 1.
5. The method of claim 4, wherein the metal chloride is one or more of copper chloride, ferric chloride, ferrous chloride, and cobalt chloride.
6. The method for preparing hydrogen peroxide-responsive metal-polyphenol coordination polymer nanoparticles according to claim 5, wherein the particle size of the nanoparticles is 20-120 nm.
7. Use of the hydrogen oxide-responsive metal-polyphenol coordination polymer nanoparticles of claim 1 in the preparation of photoacoustic imaging contrast agents and tumor phototherapy drugs.
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