Composite nanomaterial based on semiconductor polymer-fullerene derivative as well as preparation method and application of composite nanomaterial

Abstract

The invention discloses a composite nanomaterial based on a semiconductor polymer-fullerene derivative and a preparation method and application of the composite nanomaterial, and relates to the field of nano biomedical materials and technologies.The preparation method comprises the steps that a conjugated polymer PCPDTBT and a fullerene C60 derivative PCBM are dissolved in chloroform and mixed, the mixed solution and a CTAB aqueous solution are mixed and subjected to ultrasonic emulsification, and the composite nanomaterial is obtained; removing the chloroform to obtain a nanometer core dispersion liquid; coating the surface of the nano core with a mesoporous silicon dioxide layer; and modifying polyethylene glycol on the surface of the mesoporous silica layer to obtain the composite nanoparticles based on the semiconductor polymer-fullerene derivative. The composite nanoparticle can efficiently generate < 1 > O2 and. OH under the irradiation of 660 nm laser, realizes I-type and II-type photodynamic therapy, has photothermal therapy performance and fluorescence imaging capability, can meet the requirement of near-infrared two-region imaging, and can be used as an optical therapy reagent guided by near-infrared fluorescence imaging.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of nanobiomedical materials and technology, and particularly relates to a semiconductor polymer-fullerene derivative-based composite nanomaterial and a preparation method and application thereof. BACKGROUND

[0002] Semiconductor polymers have unique electron delocalization characteristics and excellent optical and electrical properties due to the alternating single and double bond structure in the main chain. In recent years, they have attracted widespread attention in the fields of optoelectronic devices, optical diagnosis and treatment, etc. Among them, the semiconductor polymer poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']dithiophene)-alt-4,7(2,1,3-benzothiadiazole)] (PCPDTBT) has strong near-infrared fluorescence emission, and can generate O2 and ·OH under light irradiation, which has certain application potential in photodiagnosis and treatment. However, its photosensitization efficiency is still significantly poorer than that of small molecule photosensitizers. 1 O2 and ·OH, has certain application potential in photodiagnosis and treatment. However, its photosensitization efficiency is still significantly poorer than that of small molecule photosensitizers.

[0003] In the field of organic electronic devices, it is found that fullerene derivative PCBM can form a charge transfer state with PCPDTBT, thereby improving the photoelectric properties of the polymer. It has been found that in the mixed film of fullerene C60 derivative PCBM and PCPDTBT, there is a charge transfer state of PCPDTBT-PCBM, which promotes the triplet state sensitization of the polymer, and ultimately improves the active oxygen yield. However, similar effects of PCBM on other polymers have not been found. However, this finding has not been applied to the field of photodynamic therapy. In addition, PCPDTBT coated with amphiphilic block copolymer Pluronic F127 and fullerene C70 derivative (PC70BM) can greatly improve the photothermal properties of semiconductor polymers, but the fluorescence is almost completely quenched, and has no promoting effect on the generation of active oxygen. SUMMARY

[0004] In order to provide a semiconductor polymer nanomaterial with high singlet oxygen, high hydroxyl radical yield, high photothermal conversion efficiency, and fluorescence emission covering the near-infrared region, a semiconductor polymer-fullerene derivative-based composite nanomaterial and a preparation method and application thereof are provided. The composite nanomaterial takes PCPDTBT doped with PCBM as an optically active core, and is constructed by mesoporous silica coating and polyethylene glycol surface modification.

[0005] A preparation method of a semiconductor polymer-fullerene derivative-based composite nanomaterial, comprising the following steps:

[0006] Step one, the conjugated polymer PCPDTBT and fullerene C60 derivative PCBM are dissolved in chloroform respectively and mixed, the mixed solution is mixed with the aqueous solution of cetyltrimethylammonium bromide (CTAB) and ultrasonic emulsified, and the chloroform is removed by heating evaporation to obtain a nanometer core dispersion liquid;

[0007] Step two, the nanometer core dispersion liquid is added to the CTAB aqueous solution and mixed and ultrasonic, and the nanometer core surface is coated with a mesoporous silica layer by adding tetraethyl orthosilicate, ethyl acetate and sodium hydroxide aqueous solution under heating condition and reacting;

[0008] Step three, the surface of the mesoporous silica layer is modified with polyethylene glycol to obtain a semiconductor polymer-fullerene derivative-based composite nanomaterial.

[0009] Further, in step one:

[0010] The concentration of the chloroform solution of the semiconductor polymer PCPDTBT and the fullerene C60 derivative PCBM is 1 mg / mL, and the concentration of the CTAB aqueous solution is 1-20 mg / mL;

[0011] The volume ratio of the chloroform solution of the semiconductor polymer PCPDTBT, the chloroform solution of the fullerene C60 derivative PCBM and the CTAB aqueous solution is 2:1:25.

[0012] Further, in step one, the temperature for heating evaporation to remove chloroform is 60-70℃.

[0013] Further, in step two, the mixed solution of the nanometer core dispersion liquid and the CTAB aqueous solution is heated to 70℃, and then tetraethyl orthosilicate, ethyl acetate and sodium hydroxide aqueous solution are added and mixed for 40 min.

[0014] Further, in step two, the concentration of the CTAB aqueous solution is 0-2 mg / mL, and the concentration of the sodium hydroxide aqueous solution is 2M;

[0015] The volume ratio of the nanometer core dispersion liquid to the CTAB aqueous solution is 9:1; the volume ratio of the mixed solution of the nanometer core dispersion liquid and the CTAB aqueous solution, tetraethyl orthosilicate, ethyl acetate and sodium hydroxide aqueous solution is 25:0.1:0.5:0.15.

[0016] Furthermore, in step three, the method for modifying the surface of the mesoporous silica layer with polyethylene glycol is as follows: under heating conditions of 70°C, methoxy-polyethylene glycol-silane-5000 (mPEG-silane, Mw 5000) and methoxy-polyethylene glycol-silane-500 (mPEG-silane, Mw 500) are added sequentially and reacted for a period of time. After cooling, the mixture is washed by ultrafiltration and dispersed in ammonium nitrate ethanol solution. After heating and stirring at 50°C for a period of time, the composite nanoparticle aqueous solution is obtained by ultrafiltration.

[0017] Furthermore, the specific steps for step three are as follows:

[0018] 1) Add methoxy-polyethylene glycol-silane-5000 to the reaction solution obtained in step 2 under heating conditions of 70℃ and react for 1 h. The concentration of methoxy-polyethylene glycol-silane-5000 in the reaction solution is 4~8 mg / mL.

[0019] 2) Continue adding methoxy-polyethylene glycol-silane-500 and react for 2 h. The concentration of methoxy-polyethylene glycol-silane-500 in the reaction solution is 1~3 mg / mL.

[0020] 3) The reaction solution was washed with an ultrafiltration tube and dispersed in a 5-10 mg / mL ammonium nitrate ethanol solution. The solution was heated at 50°C for 2 h to remove CTAB. After cooling, water was added and purified by ultrafiltration to obtain an aqueous solution of composite nanoparticles SP / PCBM@mSiO2-PEG.

[0021] The composite nanomaterials prepared by the above method can be used to prepare combined photothermal and photodynamic therapeutic drugs, and to prepare infrared fluorescence imaging-guided optical therapeutic agents.

[0022] Beneficial Effects: This invention prepares SP / PCBM@mSiO2-PEG composite nanoparticles by incorporating the fullerene derivative PCBM into the semiconductor polymer PCPDTBT. The reactive oxygen species generation and photothermal conversion capabilities of these composite nanoparticles are significantly improved compared to materials without PCBM doping, and they can efficiently generate reactive oxygen species under 660 nm laser irradiation. 1 O2 and ·OH enable type I and type II photodynamic therapy, while also exhibiting better photothermal therapy performance. The coating of a polyethylene glycol-modified mesoporous silica layer allows the composite nanomaterial to retain a certain fluorescence emission intensity, while also possessing good aqueous dispersibility and tumor targeting. The fluorescence performance of the composite material significantly decreases after PCBM doping, but it still retains fluorescence imaging capabilities, meeting the requirements for near-infrared II imaging, and can be used as a near-infrared fluorescence imaging-guided optical therapy agent. Attached Figure Description

[0023] Figure 1 This is a transmission electron microscope image of the product obtained in Example 1;

[0024] Figure 2 The UV-Vis absorption spectra of the product obtained in Example 1 and PCPDTBT and PCBM in CATB aqueous solution are shown.

[0025] Figure 3 The photothermal-cooling cycle curve of the product obtained in Example 1;

[0026] Figure 4 The products obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were added 1 The decrease in absorbance at 417 nm after different laser illumination times following the use of O2 detection indicator DPBF;

[0027] Figure 5 The increase in absorbance at 660 nm after illumination for different durations is shown for the products obtained in Examples 1 and 2 and Comparative Examples 1 and 2 after the addition of the ·OH detection indicator TMB.

[0028] Figure 6 The phototoxicity of the products obtained in Examples 1 and 2 and Comparative Example 2 at different concentrations;

[0029] Figure 7 The fluorescence emission intensity is the product obtained in Examples 1 and 2 and Comparative Examples 1 and 2. Detailed Implementation

[0030] The technical solution of the present invention will be described in detail below through embodiments, but the scope of protection of the present invention is not limited to the embodiments described.

[0031] (a) In the following examples, the photodynamic effect of the material is evaluated by detecting whether the prepared material can generate singlet oxygen. The detection method is: using... 1 O2 detection indicator 1,3-diphenylisobenzofuran (DPBF) was mixed with the products obtained in various examples or comparative examples in different proportions. The resulting aqueous solution of nanoparticles was then irradiated with laser light, and the change in absorbance before and after irradiation was used to analyze the O2 detection process. 1 Tests were conducted on O2 generation.

[0032] (ii) In the following examples, the photodynamic effect of the material was evaluated by detecting whether the prepared material could generate hydroxyl radicals. The detection method was as follows: In a NaAc / HAc buffer solution at pH=4, the products obtained in each example or comparative example were mixed in different proportions using the ·OH detection indicator 3,3',5,5'-tetramethylbenzidine (TMB). The mixed nanoparticle aqueous solution was then irradiated with laser light, and the change in absorbance before and after irradiation was used to test the generation of ·OH radicals.

[0033] (III) The preparation method of PCPDTBT semiconductor polymer used in the following examples, see the synthesis steps of the semiconductor polymer disclosed in the publication

Albrecht S, Janietz S, Schindler W, Frisch J, Kurpiers J, Kniepert J, et al. Fluorinated Copolymer PCPDTBT with Enhanced Open-Circuit Voltage and Reduced Recombination for Highly Efficient Polymer Solar Cells. Journal of the American Chemical Society. 2012; 134(36): 14932-44.

[0034] Fullerene derivative PCBM ([6,6]-phenyl-C61-butyric acid methyl ester) was purchased from Anhui Zesheng Science and Technology Co., Ltd.; CTAB (cetyltrimethylammonium bromide) was purchased from Merck Group, Damstadt, Germany; methoxy-polyethylene glycol-silane-5000 (mPEG-silane, Mw 5000) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; methoxy-polyethylene glycol-silane-500 (mPEG-silane, Mw 500) was purchased from Gelest Company, USA; F127 was purchased from Merck Group, Damstadt, Germany.

[0035] Example 1

[0036] The present embodiment provides a preparation method of SP / PCBM@mSiO2-PEG nanoparticles, comprising the following steps:

[0037] 1) The conjugated polymer PCPDTBT and the fullerene derivative PCBM were dissolved in chloroform at a concentration of 1 mg / mL, and mixed at a volume ratio of 2:1.

[0038] 2) The above mixture was mixed with an aqueous solution of cetyltrimethylammonium bromide (CTAB) at a concentration of 8 mg / mL at a volume ratio of 3:25, and ultrasonic emulsification was performed, followed by heating and evaporation at 60-70°C to remove chloroform to obtain a nanocore dispersion liquid;

[0039] 3) The above nanocore dispersion liquid was mixed with an aqueous solution of CTAB at a concentration of 1 mg / mL at a volume ratio of 1:9 and ultrasonic, and the mixture was heated to 70°C and added with tetraethyl orthosilicate, ethyl acetate and aqueous sodium hydroxide solution (2 M), the volume ratio of each solution was 25:0.1:0.5:0.15, respectively, and after fully mixed, the reaction was carried out for 40 min, and a mesoporous silica layer was coated on the surface of the nanocore.

[0040] 4) 70°C heating conditions to the above reaction solution was added methoxy-polyethylene glycol-silane-5000 (mPEG-silane, Mw 5000) at a concentration of 8 mg / mL in the reaction solution; after 1 h of reaction, methoxy-polyethylene glycol-silane-500 (mPEG-silane, Mw 500) was continuously added at a concentration of 2 mg / mL in the reaction solution. After 2 h of reaction, the reaction solution was ultrafiltration washed and dispersed in a 7.5 mg / mL ammonium nitrate ethanol solution, heated at 50°C for 2 h to remove CTAB, and after cooling, water was added for ultrafiltration purification to obtain a composite nanoparticle SP / PCBM@mSiO2-PEG aqueous solution.

[0041] As shown in Figure 1 , the particle size of the SP / PCBM@mSiO2-PEG nanoparticles prepared in Example 1 was about 49.3 nm, which indicated that the material had a relatively optimal size range. Figure 2 In the UV-Vis absorption spectrum, PCBM had no obvious characteristic absorption peak, but had a certain absorption at the short wavelength part, and the composite material prepared in Example 1 had both the absorption characteristics of PCBM and PCPDTBT, indicating that the two were successfully compounded. Figure 3 It was shown that after laser irradiation of SP / PCBM@mSiO2-PEG, the solution was obviously heated, and had a relatively high light-heat conversion ability and light-heat stability. Figure 4 In the UV-Vis absorption spectrum, the absorbance of the product obtained in Example 1 at 417 nm decreased the most, which indicated that the method of incorporating PCBM and using mesoporous silica to coat could obtain the best 1 O2 generation ability. Figure 5 The absorbance of the product obtained in Example 1 at 660 nm increased the most, which indicated that the method of incorporating PCBM and using mesoporous silica to coat could obtain the best ·OH generation ability. Figure 6 In the cell survival rate after near-infrared light irradiation, the tumor cells treated in Example 1 had the lowest survival rate, which indicated that the material had the highest phototoxicity. Figure 7 It was shown that incorporating PCBM would cause a certain degree of fluorescence emission to weaken, but was significantly higher than that of Comparative Example 1 modified by F127, and the fluorescence emission intensity of Example 1 could still meet the requirements of fluorescence imaging.

[0042] Example 2

[0043] Example 2 was different from Example 1 only in that the PCBM chloroform solution was replaced with an equal volume of chloroform and subsequent preparation to obtain SP@mSiO2-PEG nanoparticles.

[0044] As shown in Figures 4-7As shown, the product obtained in Example 2 did not contain PCBM, and although it had better fluorescence emission performance, its photothermal, photodynamic, and phototoxic properties were inferior to those of the product obtained in Example 1.

[0045] Example 3

[0046] The only difference between Example 3 and Example 1 is that the volume ratio of PCPDTBT chloroform solution and PCBM chloroform solution is 1:1, while the other conditions remain unchanged, to prepare SP / PCBM 1@mSiO2-PEG nanoparticles.

[0047] The product obtained in Example 3 contained too much PCBM compared to the product obtained in Example 1, and the photodynamic, fluorescence emission and phototoxicity properties of the product obtained in Example 3 were inferior to those of the product obtained in Example 1.

[0048] Comparative Example 1

[0049] This comparative example provides a method for preparing SP / PCBM@F127 nanoparticles, including the following steps:

[0050] 0.2 mg of the conjugated polymer PCPDTBT, 0.1 mg of the fullerene derivative PCBM, and 30 mg of F127 were dissolved in 1.5 mL of tetrahydrofuran. The mixture was then rapidly added to 9 mL of water using an ultrasonic cell disruptor. After sonication for 2 min, the tetrahydrofuran was removed by nitrogen gas under stirring. The nanoparticles were then obtained by ultrafiltration and washing.

[0051] like Figure 4 , Figure 5 , Figure 7 As shown, the product obtained in Comparative Example 1, compared to the product obtained in Example 1, had a polyethylene glycol-modified mesoporous silica layer coating replaced with surfactant F127. Although the product obtained in Comparative Example 1 had better photothermal properties, its fluorescence emission was almost completely quenched, and its photodynamic properties were significantly inferior to those of the product obtained in Example 1.

[0052] Comparative Example 2

[0053] The only difference between Comparative Example 2 and Comparative Example 1 is that PCBM was not added and subsequent preparation was carried out to obtain an aqueous solution of SP@F127.

[0054] like Figures 4-7 As shown, the fluorescence performance of Comparative Example 2 is slightly higher than that of Example 1, but its photodynamic therapy performance is significantly lower than that of Example 1.

[0055] The present application mixes and dopes semiconductor polymer PCPDTBT and fullerene C60 derivative PCBM in a reasonable ratio to prepare a composite nanomaterial (SP / PCBM@mSiO2-PEG) based on semiconductor polymer-fullerene derivative. The material takes [6,6]-phenyl C61 butyric acid methyl ester (PCBM) and semiconductor polymer PCPDTBT as the core, coats a mesoporous silica layer outside the core, and modifies polyethylene glycol on the surface. The incorporated PCBM and PCPDTBT can form a charge transfer state slightly higher than the triplet state of the semiconductor polymer, thereby promoting the triplet state sensitization of PCPDTBT, enhancing the active oxygen generation, and ultimately improving the photodynamic therapy effect; due to the energy level limitation, this mechanism has only been found between fullerene C60 derivative PCBM and semiconductor polymer PCPDTBT. At the same time, the charge transfer between PCBM and PCPDTBT can improve the photothermal effect of the semiconductor polymer. The polyethylene glycolized mesoporous silica layer (mSiO2-PEG) can stabilize the molecular conformation of the material and improve the optical properties and stability of the material, so that it can still maintain a high fluorescence emission intensity. At the same time, this surface modification method can improve the water solubility of the nanoparticles and endow the material with tumor targeting ability. The composite nanomaterial can efficiently generate singlet oxygen (O2) and hydroxyl radicals (·OH) and significantly heat under 660 nm near-infrared laser irradiation, and can be used for combined photothermal and photodynamic therapy. 1 O2) and hydroxyl radicals (·OH) and significantly heat under 660 nm near-infrared laser irradiation, and can be used for combined photothermal and photodynamic therapy.

[0056] As described above, although the present application has been shown and described with reference to certain preferred embodiments, it is to be understood that such is by way of illustration and not of limitation. Various changes and modifications can be made therein without departing from the spirit and scope of the present application.

Claims

1. A method for preparing composite nanomaterials based on semiconductor polymers-fullerene derivatives, characterized in that, Includes the following steps: Step 1: Dissolve the conjugated polymer PCPDTBT and the fullerene C60 derivative PCBM in chloroform and mix them. Mix the mixture with CTAB aqueous solution and ultrasonically emulsify. After heating and evaporating to remove the chloroform, a nano-core dispersion is obtained. Step 2: Add the nano-core dispersion to CTAB aqueous solution, mix and sonicate, add tetraethyl orthosilicate, ethyl acetate and sodium hydroxide aqueous solution under heating conditions to react, and coat the surface of the nano-core with a mesoporous silica layer. Step 3: Modify the surface of the mesoporous silica layer with polyethylene glycol to obtain composite nanoparticles based on semiconductor polymer-fullerene derivatives.

2. The preparation method according to claim 1, characterized in that, In step one: The concentration of chloroform solution of semiconductor polymer PCPDTBT and fullerene C60 derivative PCBM is 1 mg / mL, and the concentration of aqueous solution of CTAB is 1~20 mg / mL. The volume ratio of the semiconductor polymer PCPDTBT chloroform solution, the fullerene C60 derivative PCBM chloroform solution, and the CTAB aqueous solution is 2:1:

25.

3. The preparation method according to claim 1, characterized in that, In step one, the temperature for heating and evaporating to remove chloroform is 60~70℃.

4. The preparation method according to claim 1, characterized in that, In step two, the mixture of nanonucleus dispersion and CTAB aqueous solution is heated to 70°C, and then tetraethyl orthosilicate, ethyl acetate and sodium hydroxide aqueous solution are added and mixed thoroughly for 40 min.

5. The preparation method according to claim 1, characterized in that, In step two, the concentration of CTAB aqueous solution is 0~2 mg / mL, and the concentration of sodium hydroxide aqueous solution is 2 M; The volume ratio of nanonucleus dispersion to CTAB aqueous solution is 9:1; the volume ratio of the mixed solution of nanonucleus dispersion and CTAB aqueous solution, tetraethyl orthosilicate, ethyl acetate and sodium hydroxide aqueous solution is 25:0.1:0.5:0.

15.

6. The preparation method according to claim 1, characterized in that, In step three, the method for modifying the surface of the mesoporous silica layer with polyethylene glycol is as follows: Methoxy-polyethylene glycol-silane-5000 and methoxy-polyethylene glycol-silane-500 were added sequentially to the reaction solution obtained in step two under heating conditions of 70℃ and reacted for a period of time respectively. After cooling, the mixture was washed by ultrafiltration and dispersed in ammonium nitrate ethanol solution. After heating and stirring at 50℃ for a period of time, the composite nanoparticle aqueous solution was obtained by ultrafiltration.

7. The preparation method according to claim 1, characterized in that, The specific steps for step three are as follows: 1) Add methoxy-polyethylene glycol-silane-5000 to the reaction solution obtained in step 2 under heating conditions of 70℃ and react for 1 h. The concentration of methoxy-polyethylene glycol-silane-5000 in the reaction solution is 4~8 mg / mL. 2) Continue adding methoxy-polyethylene glycol-silane-500 and react for 2 h. The concentration of methoxy-polyethylene glycol-silane-500 in the reaction solution is 1~3 mg / mL. 3) The reaction solution was washed with an ultrafiltration tube and dispersed in a 5-10 mg / mL ammonium nitrate ethanol solution. The solution was heated at 50°C for 2 h to remove CTAB. After cooling, water was added and purified by ultrafiltration to obtain an aqueous solution of composite nanoparticles SP / PCBM@mSiO2-PEG.

8. The composite nanomaterials obtained by any of the preparation methods described in claims 1-7.

9. The use of the composite nanomaterial of claim 8 in the preparation of a combined photothermal and photodynamic therapeutic drug.

10. The application of the composite nanomaterial of claim 8 in the preparation of infrared fluorescence imaging-guided optical therapy reagents.

Images