CN114539232A - pH reversible activation near-infrared two-region aggregation-induced emission I type photosensitizer and application thereof - Google Patents

pH reversible activation near-infrared two-region aggregation-induced emission I type photosensitizer and application thereof Download PDF

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CN114539232A
CN114539232A CN202210096480.0A CN202210096480A CN114539232A CN 114539232 A CN114539232 A CN 114539232A CN 202210096480 A CN202210096480 A CN 202210096480A CN 114539232 A CN114539232 A CN 114539232A
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王东
肖培宏
唐本忠
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Abstract

The invention discloses a pH reversibly activated near-infrared two-region aggregation-induced emission I-type photosensitizer and application thereof, wherein the pH reversibly activated near-infrared two-region aggregation-induced emission I-type photosensitizer is one of the following chemical structural formulas:
Figure DDA0003490984370000011
Figure DDA0003490984370000012
and
Figure DDA0003490984370000013
wherein R is1And R2One selected from hydrogen, methyl and methoxy, R3Is composed of
Figure DDA0003490984370000014
One kind of (1). The pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer provided by the invention has the following advantages: the tumor cell targeting ability is very excellent when the phototoxicity to normal tissues and cells is low; aggregation in physiological environment but no fluorescence quenching problem exists, and the active oxygen generating capacity is enhanced; the near-infrared light is excited, the tissue penetration capability is deeper, and the photothermal and photodynamic synergistic treatment effect is very good on a human-derived tumor xenograft (PDX) model and bacterial infection.

Description

pH reversible activation near-infrared two-region aggregation-induced emission I type photosensitizer and application thereof
Technical Field
The invention relates to the technical field of photosensitizers, in particular to a pH reversibly activated near-infrared two-region aggregation-induced emission I-type photosensitizer and application thereof.
Background
Photodynamic therapy (PDT) and photothermal therapy (PTT) are highly effective malignant tumor treatment modalities emerging in recent years, and have attracted wide attention of medical researchers due to their advantages of non-invasiveness, low drug resistance, and controllable treatment region selection, as compared with conventional chemotherapy, radiotherapy, and the like. PDT generally consists of three parts: photosensitizer, light and oxygen, all of which are not indispensable. The photosensitizer absorbs a photon under the irradiation of an excitation light source with a specific wavelength and then moves from the ground state (S)0) Transition to singlet excited state (S)1). Excited molecules are very unstable and can fluoresce by radiative transitions back to the ground state; can also be transferred to a relatively long-lived excited triplet state (T) by intersystem crossing1) Subsequent interaction with biological substrates or molecular oxygen produces Reactive Oxygen Species (ROS) that are cytotoxic; or by means of non-radiative transitions back to the ground state, releasing heat (PTT). Compared with single PDT or PTT treatment, the two synergistic treatments can overcome the problems of poor treatment effect caused by tumor hypoxia existing in PDT treatment, tumor heat resistance caused by heat shock protein generated in PTT treatment and the like.
The current commonly used photosensitizers mainly comprise hematoporphyrin derivatives, phthalocyanine derivatives, chlorophyll a degradation products and the like, and most of the photosensitizers have the problem of aggregation-induced quenching (ACQ), so that the generation capacity of fluorescence and active oxygen is reduced, and the clinical treatment effect is seriously influenced. In 2001, the hong Kong science and technology university, Tang Ben loyal professor, first proposed a new concept of "aggregation-induced emission (AIE)" and led to the revolution of luminescent materials. Unlike conventional organic fluorescent dyes, this particular class of compounds does not emit light or fluoresces very weakly in solution, but emits intense fluorescence in the aggregated state. The appearance of the aggregation-induced emission photosensitizer overcomes the limitation of the traditional organic micromolecular photosensitizer, and shows a plurality of advantages in the fields of tumor fluorescence imaging and treatment. First, aggregation-induced emission photosensitizers generally have good biocompatibility. Secondly, the aggregation-induced emission photosensitizer has high general luminous efficiency, large Stokes shift, good light stability and enhanced active oxygen generation capability in an aggregation state. Although the aggregation-induced emission photosensitizer has made breakthrough progress in PDT and PTT treatment in recent years, the practical clinical application of the aggregation-induced emission photosensitizer is seriously hindered by the problems of normal tissue damage and skin photosensitivity caused by the short excitation wavelength and poor tumor targeting.
The current focus of photosensitizer research is how to further improve tumor targeting and reduce the side effects of phototherapy. The construction of an 'intelligent' activated photosensitizer in a tumor microenvironment is one of effective strategies for improving tumor targeting. The pH value of the tumor extracellular fluid is between 6.5 and 6.8, which is slightly lower than the pH value of the microenvironment of blood and normal tissues (about 7.4), so that the development of tumor pH activated photosensitizer is possible. The near infrared region II (NIR-II) has longer emission wavelength (1000-1700nm), so that the influence of light scattering and auto-fluorescence effect when penetrating biological tissues can be obviously reduced, and the anti-tumor treatment of deeper tissues is realized.
Therefore, the development of the pH reversibly activated near-infrared two-region emission aggregation-induced emission photosensitizer has very important research significance.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a pH reversibly activated near-infrared two-region aggregation-induced emission I-type photosensitizer and application thereof, and aims to solve the problems of poor targeting property and large side effect of the existing photosensitizer when used for treating tumors.
The technical scheme of the invention is as follows:
a pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer is one of the following chemical structural formulas:
Figure BDA0003490984350000031
Figure BDA0003490984350000032
wherein R is1And R2One selected from hydrogen, methyl and methoxy, R3Is composed of
Figure BDA0003490984350000033
One kind of (1). .
The pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer has an absorption wavelength of 660nm to 750 nm.
The pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer is characterized in that the emission wavelength of the pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer is 1000-1500 nm.
The application of a pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer is characterized in that the pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer is used for preparing a medicine for treating tumor or bacterial infection diseases.
The application of the pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer is characterized in that mPEG is adopted as the medicine2000-PLGA encapsulates nanoparticles formed by the infrared two-domain aggregation-induced emission type I photosensitizer.
Use of a pH reversibly activated near infrared two-domain aggregation-induced emission type I photosensitizer, wherein the drug is present in the blood and normal tissues in a non-conjugated basic form and in a fully conjugated acidic form at a tumor site.
Has the advantages that: compared with the traditional photosensitizer, the pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer provided by the invention has the following advantages: 1. low phototoxicity to normal tissues and cells; 2. has excellent tumor cell targeting capacity; 3. aggregation in physiological environment but no fluorescence quenching problem exists, and the active oxygen generating capacity is enhanced; 4. near infrared light is used for excitation, and the tissue penetration capability is deeper. Specifically, the present invention provides mPEG for photosensitizers2000PLGA has pH responsiveness after being encapsulated into nanoparticles, exists mainly in a non-conjugated basic form in blood and normal tissues after tail vein injection, has a radiation transition and non-radiation transition channel closed under 808nm laser irradiation, shows lower active oxygen and photo-thermal generation capacity, and has no obvious phototoxicity; after the nanoparticles reach a tumor part through an EPR effect, the photosensitizer mainly exists in a fully conjugated acid form under the condition of pH6.5, a radiation transition channel and a non-radiation transition channel are opened under 808nm laser irradiation, the photosensitizer has stronger I-type superoxide anion free radical and photo-thermal generation capacity, and a very good photo-thermal and photo-dynamic synergistic treatment effect is achieved on a human-derived tumor xenograft (PDX) model and bacterial infection.
Drawings
FIG. 1 is a synthetic route diagram of a novel pH reversibly activated near-infrared two-domain aggregation-induced emission molecule provided by an embodiment of the present invention.
Fig. 2 is a nuclear magnetic resonance hydrogen spectrum of compound 1 prepared in example 1 of the present invention in deuterated chloroform.
Fig. 3 is a nuclear magnetic resonance carbon spectrum of compound 1 prepared in example 1 of the present invention in deuterated chloroform.
FIG. 4 is a NMR spectrum of Compound 2 prepared in example 2 of the present invention in DMSO.
FIG. 5 is a NMR spectrum of Compound 4 prepared in example 3 of the present invention in deuterated chloroform.
FIG. 6 shows the NMR spectrum of Compound 4 prepared in example 3 of the present invention in deuterated chloroform.
FIG. 7 shows the NMR spectrum of Compound 5 prepared in example 4 of the present invention in deuterated chloroform.
FIG. 8 is a NMR spectrum of Compound 5 prepared in example 4 of the present invention in deuterated chloroform.
FIG. 9 shows the NMR spectrum of Compound 6 prepared in example 5 of the present invention in deuterated chloroform.
Figure 10 is the nmr spectrum of compound 6 prepared in example 5 of the invention in deuterated chloroform.
FIG. 11 is a NMR spectrum of Compound 7 prepared in example 6 of the present invention in deuterated chloroform.
Figure 12 is the nmr spectrum of compound 7 prepared in example 6 of the invention in deuterated chloroform.
FIG. 13 is a NMR spectrum of TTVBI prepared in example 7 of the present invention in DMSO.
FIG. 14 shows the NMR C-spectrum of TTVBI prepared in example 7 of the present invention in DMSO.
FIG. 15 shows the NMR spectrum of DTVBI prepared in example 8 of the present invention in DMSO.
FIG. 16 shows the NMR carbon spectrum of DTVBI prepared in example 8 of the present invention in DMSO.
FIG. 17 shows the NMR spectrum of DTTVBI compound prepared in example 9 of the present invention in DMSO.
FIG. 18 shows the NMR carbon spectrum of DTTVBI in DMSO as the compound prepared in example 9 of the present invention.
FIG. 19 is a graph showing UV absorption spectra in DMSO of the pH reversibly activated NIR dimer-inducible luminescence molecules prepared in examples 7, 8 and 9 in accordance with the present invention;
FIG. 20 is a graph showing fluorescence emission spectra of pH reversibly activated NIR two-domain aggregation-inducible light-emitting molecules prepared in examples 7, 8 and 9 of the present invention in DMSO;
FIG. 21 is a drawing showing10X 10 prepared in inventive examples 7, 8 and 9-6A fluorescence emission intensity diagram of M TTVBI, DTVBI and DTTVBI in dimethyl sulfoxide/toluene mixed systems with different proportions;
FIG. 22 is a DLS plot of DTTVBI NPs as nanoparticles prepared from the pH reversibly activated near infrared two-domain aggregation-induced emission molecule prepared in example 9 of the present invention;
FIG. 23 is a spectrum of absorption and fluorescence emission spectra of DTTVBI NPs as nanoparticles prepared from the pH reversibly activated near infrared two-region aggregation induced emission molecule prepared in example 9 of this invention in DMSO;
FIG. 24 is a diagram of UV-VIS absorption spectra of nanoparticles DTTVBI NPs prepared from the pH reversibly activated near-infrared two-region aggregation-induced emission molecule prepared in example 9 of the present invention in PBS buffer solutions with different pH values;
FIG. 25 is a graph of pKa values obtained by nonlinear fitting of DTTVBI NPs as nanoparticles prepared from the pH reversibly activated near-infrared two-domain aggregation-induced emission molecule prepared in example 9 of the present invention;
FIG. 26 is a fluorescence spectrum of DTTVBI NPs (deep double entry fluorescence) nanoparticles with pH6.5 and pH 7.4 prepared from the pH reversibly activated near-infrared two-region aggregation-induced emission molecule prepared in example 9 of the present invention under 808nm laser irradiation using DCFH as an active oxygen indicator;
FIG. 27 is a graph of the temperature change of pH6.5 and pH 7.4DTTVBI NPs prepared from pH reversibly activated near infrared two-region aggregation-induced emission molecules prepared in example 9 of the present invention under laser irradiation at 0.8W 808nm at different concentrations;
FIG. 28 is a graph of temperature changes of 100 μ M nanoparticles of pH6.5 and pH 7.4DTTVBI prepared from the pH reversibly activated near-infrared two-region aggregation-induced emission molecule prepared in example 9 of the present invention under 808nm laser irradiation at different powers;
FIG. 29 is a diagram of the photothermographic effect of DTTVBI NPs at pH6.5 and pH 7.4 nanoparticles prepared from the pH reversibly activated near-infrared two-region aggregation-induced emission molecule prepared in example 9 of the present invention;
FIG. 30 is a graph showing the effect of DTTVBI NPs nanoparticles prepared from the pH reversibly activated NIR two-domain aggregation-induced emission molecules prepared in example 9 of the present invention in PDX model photothermal and photodynamic combined therapy;
FIG. 31 is a graph of bacterial survival rate of nanoparticles BC/DTTVBI NPs prepared from the pH reversibly activated near-infrared two-region aggregation-induced emission molecule prepared in example 9 of the present invention for photothermal and photodynamic combination therapy of E.coli.
Fig. 32 is a schematic diagram of the mechanism of pH reversible activation of the near-infrared two-region aggregation-induced emission molecule prepared in embodiment 9 of the present invention and the preparation of nanoparticles.
Detailed Description
The invention provides a pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer and application thereof, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and more clear. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention provides a pH reversibly activated near-infrared two-region aggregation-induced emission I-type photosensitizer, which is one of the following chemical structural formulas:
Figure BDA0003490984350000071
Figure BDA0003490984350000072
wherein R is1And R2One selected from hydrogen, methyl and methoxy, R3Is composed of
Figure BDA0003490984350000073
One kind of (1).
Specifically, the invention designs and synthesizes three types of near-infrared two-region aggregation-induced emission I-type photosensitizers which can be reversibly activated by tumor pH, the three photosensitizers take differently substituted triphenylamine or diphenylamine as electron donors and rotors in the structure, different quantities of thiophene and double bonds as pi conjugate bridges, and ethyl or propyl sulfonic acid is substituted for [ c, d, e]The benzindole is an electron acceptor, and the constructed photosensitizer has an absorption wavelength range of 660nm-750nm and an emission wavelength range of 1000nm-1500And (5) nm. The mPEG for the photosensitizer provided by the invention2000The PLGA has pH responsiveness after being encapsulated into DTTVBI nanoparticles, wherein the prepared DTTVBI nanoparticles have 694nm of maximum absorption and stronger absorption value at 808nm, mainly exist in a non-conjugated basic DTTVBI-OH structure in blood and normal tissues after tail vein injection, have closed radiation transition and non-radiation transition channels under 808nm laser irradiation, show lower active oxygen and photothermal generation capacity and have no obvious phototoxicity; after the nanoparticles reach a tumor part through an EPR effect, the photosensitizer mainly exists in a fully conjugated acid DTTVBI structure under the condition that the tumor pH is 6.5-6.8 weak acidity, a radiation transition channel and a non-radiation transition channel are opened under 808nm laser irradiation, the photosensitizer has stronger I-type superoxide anion free radical and photothermal generation capacity, and a very good photothermal and photodynamic synergistic treatment effect is achieved on a human-derived tumor xenograft (PDX) model and bacterial infection.
In some embodiments, the application of the pH reversible activation near infrared two-region aggregation-induced emission type I photosensitizer is further provided, wherein the pH reversible activation near infrared two-region aggregation-induced emission type I photosensitizer is used for preparing a medicament for treating tumor or bacterial infection diseases.
In this embodiment, the drug is mPEG2000-PLGA encapsulates nanoparticles of said infrared dimer aggregation-inducing luminescent type I photosensitizer, said drug being present in the blood and normal tissues in a non-conjugated basic form and in a fully conjugated acidic form at the tumor site.
The invention is further illustrated by the following specific examples:
example 1
As shown in FIG. 1 as a, at N2Under the protection of (1), 851mg of NaH is added into a DMF (30ml) solution of 2.0g of 1, 8-naphthalimide, 2.21g of iodoethane is slowly dripped into the reaction system after the reaction liquid is cooled to 0 ℃, the reaction is continuously stirred at room temperature for 3h, after the reaction is completed, ethyl acetate is extracted, organic phases are combined and dried by anhydrous sodium sulfate, and after concentration under reduced pressure, the obtained residue is washed by petroleum ether/ethyl acetate (100:1 → 10:1)The eluent was purified by silica gel column chromatography to give 1.20g of compound 1 as a yellow powdery solid in 52% yield. The nuclear magnetic resonance hydrogen spectrum of the compound 1 in the deuterated chloroform is shown in figure 2, the nuclear magnetic resonance carbon spectrum of the compound 1 in the deuterated chloroform is shown in figure 3, wherein,1H NMR(600MHz,CDCl3)δ8.04(d,J＝6.6Hz,1H),7.98(d,J＝8.4Hz,1H),7.68(dd,J1＝7.8Hz,J2＝6.6Hz,1H),7.50(d,J＝8.4Hz,1H),7.44(dd,J1＝8.4Hz,J2＝7.2Hz,1H),6.89(d,J＝6.6Hz,1H),3.97(q,J＝7.2Hz,2H),1.37(t,J＝7.2Hz,3H).13C NMR(151MHz,CDCl3)δ167.83,139.22,130.76,129.19,128.69,128.55,126.93,125.26,124.22,120.23,104.89,35.03,14.13.HRMS(ESI,positive ion mode)calcd for C13H12NO+198.0913,found 198.0908.
example 2
As shown in FIG. 1 at a, at N2Under the protection of (1), dissolving 1.20g of the compound 1 in 25ml of a dry tetrahydrofuran solution, then dropwise adding 2.43ml of a 3.0M methyl magnesium chloride solution into the reaction solution, stirring at 60 ℃ for reaction for 1 hour after the dropwise addition is finished, cooling the reaction solution to room temperature, adding 12.16ml of a 2M hydrochloric acid solution, concentrating under reduced pressure to remove tetrahydrofuran, then adding 6.08ml of a 1M potassium iodide solution, and continuously stirring for reaction for 30 minutes to precipitate a large amount of red precipitates. After filtration, the obtained solid was washed with water and ethyl acetate in this order, and dried to obtain 1.52g of crude red solid powdery compound 2 in a yield of 70%. The nuclear magnetic resonance hydrogen spectrum of the compound 2 in dimethyl sulfoxide is shown in figure 4, wherein,1H NMR(600MHz,DMSO-d6)δ8.98(d,J＝7.2Hz,1H),8.80(d,J＝7.8Hz,1H),8.55(d,J＝7.2Hz,1H),8.45(d,J＝8.4Hz,1H),8.17(t,J＝8.4Hz,1H),8.01(t,J＝7.8Hz,1H),4.71(q,J＝7.8Hz,2H),3.24(s,3H),1.55(t,J＝7.2Hz,3H).HRMS(ESI,positive ion mode)calcd for C14H14N+196.1121,found 196.1115.
example 3:
as shown in fig. 1 b, at N2Under the protection of (1), 5.8g of 2-bromothiophene, 4.0g of diphenylamine and 3.4g of sodium tert-butoxide are dissolved in 80ml of dry toluene solution, and 432mg of Pd are added in turn2(dba)3And 274mg of tri-tert-butylphosphine tetrafluoroborate. Then the oil bath of the reaction liquid is heated to 120 ℃ for reaction for 16 h. After cooling to room temperature, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (200:1 → 50:1) as an eluent to give 4.20g of compound 4 as a yellow powdery solid in a yield of 71%. The nuclear magnetic resonance hydrogen spectrum of the compound 4 in the deuterated chloroform is shown in figure 5, the nuclear magnetic resonance carbon spectrum of the compound 4 in the deuterated chloroform is shown in figure 6, wherein,1H NMR(400MHz,Methylene Chloride-d2)δ7.29(d,J＝5.2Hz,2H),7.26(d,J＝5.2Hz,2H),7.14(dd,J1＝8.8Hz,J2＝1.2Hz,4H),7.05–7.01(m,3H),6.91(dd,J1＝5.6Hz,J2＝5.2Hz,1H),6.74(dd,J1＝1.2Hz,J2＝3.6Hz,1H).13C NMR(151MHz,CDCl3)δ151.58,148.13,129.25,126.02,122.89,122.44,121.69,120.98.HRMS(ESI,positive ion mode)calcd for C16H14NS+252.0841,found 252.0832.
example 4:
as shown in FIG. 1 b, at N2Under the protection of (1), 2.51g of Compound 4 was dissolved in 50ml of a dry tetrahydrofuran solution, and after cooling and stirring at-78 ℃ for 30 minutes, 5.0ml of 2.4M n-butyllithium was slowly added dropwise to the reaction mixture to continue the reaction at-78 ℃ for 30 minutes. Then 3.65g of DMF was added dropwise to the reaction solution, and after 30min of reaction at-78 ℃, the reaction solution was transferred to room temperature for further reaction for 10 min. The reaction solution was quenched with 20ml of water, extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (50:1 → 10:1) as an eluent to obtain 2.38g of compound 5 as a yellow powdery solid in a yield of 85%. The nuclear magnetic resonance hydrogen spectrum of the compound 5 in the deuterated chloroform is shown in figure 7, the nuclear magnetic resonance carbon spectrum of the compound 5 in the deuterated chloroform is shown in figure 8, wherein,1H NMR(600MHz,CDCl3)δ9.61(s,1H),7.46(d,J＝4.2Hz,1H),7.38–7.35(m,4H),7.28(dd,J1＝9.0Hz,J2＝1.8Hz,4H),7.24–7.21(m,2H),6.39(d,J＝4.2Hz,1H).13C NMR(151MHz,CDCl3)δ181.57,164.42,146.14,138.48,130.59,129.96,126.30,125.64,112.32.HRMS(ESI,positiveion mode)calcd for C17H14NOS+280.0791,found 280.0782.
example 5:
as shown in c in FIG. 1, N is at 0 deg.C2With the protection of (3), 551mg of potassium tert-butoxide was added to a solution of 800mg of Compound 5 and 960mg of diethyl 2- (thienylmethyl) phosphonate in dry tetrahydrofuran (40ml), and the reaction solution was allowed to move to room temperature for 16 hours. After the reaction was complete, the reaction was quenched by addition of 50ml water, extracted with ethyl acetate (75ml x 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (50:1 → 20:1) as eluent to give 1.0g of compound 6 as a yellow powder in 95% yield. The nuclear magnetic resonance hydrogen spectrum of the compound 6 in the deuterated chloroform is shown in figure 9, the nuclear magnetic resonance carbon spectrum of the compound 6 in the deuterated chloroform is shown in figure 10, wherein,1H NMR(600MHz,Chloroform-d)δ7.32–7.28(m,4H),7.20(d,J＝7.3Hz,4H),7.15(d,J＝4.8Hz,1H),7.08(t,J＝7.4Hz,2H),6.98–6.94(m,3H),6.84(d,J＝15.8Hz,1H),6.80(d,J＝3.9Hz,1H),6.54(d,J＝3.8Hz,1H).13C NMR(151MHz,CDCl3)δ150.81,147.64,142.77,135.96,129.36,127.74,125.66,125.62,123.98,123.53,123.14,122.20,120.13,119.83.HRMS(ESI,positive ion mode)calcd for C22H18NS2 +360.0875,found 360.0862.
example 6:
as shown in fig. 1 c, at N2Under the protection of (1), 0.70ml of 2.4M n-butyllithium was slowly added dropwise to a solution of 500mg of Compound 6 in dry tetrahydrofuran (10ml) at-78 ℃ and the reaction was carried out for 30 min. Then 0.54ml DMF was added dropwise to the reaction mixture, reacted at-78 deg.C for 10min, and then moved to room temperature to continue the reaction for 30 min. After the reaction was complete, 10ml of water was added and quenched, extracted with ethyl acetate (20ml × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (50:1 → 10:1) as eluent to give 360mg of compound 7 as a yellow powder in 67% yield. Said compound 7 in deuterated chloroformThe NMR spectrum of the compound 7 in deuterated chloroform is shown in figure 11, and the NMR spectrum of the compound in deuterated chloroform is shown in figure 12, wherein,1H NMR(500MHz,CDCl3)δ9.81(s,1H),7.60(d,J＝4.0Hz,1H),7.32–7.28(m,4H),7.20(d,J＝7.3Hz,4H),7.15(d,J＝15.7Hz,1H),7.10(t,J＝7.4Hz,2H),6.99(d,J＝4.0Hz,1H),6.89(d,J＝3.9Hz,1H),6.71(d,J＝15.7Hz,1H),6.48(d,J＝4.0Hz,1H).13C NMR(151MHz,CDCl3)δ182.47,153.51,152.86,147.33,140.86,137.59,133.28,129.51,128.57,126.71,125.82,124.22,123.79,118.31,117.81.HRMS(ESI,positive ion mode)calcd for C23H18NOS2 +388.0824,found 388.0812.
example 7:
as shown in FIG. 1 at a, at N291mg of Compound 2 and 100mg of Compound 3 are dissolved in 2ml of glacial acetic acid, and then 0.2ml of triethylamine and 0.2ml of acetic anhydride are added in this order and reacted for 1 hour under oil bath conditions at 60 ℃. After the reaction was completed, cooling to room temperature, adding dropwise the reaction solution to 20ml of anhydrous ether to precipitate a large amount of green precipitate, and after filtration, purifying the resulting solid residue by silica gel column chromatography using methylene chloride/methanol (50:1 → 10:1) as an eluent to obtain 95mg of TTVBI as a black powdery solid compound in a yield of 40%. The nuclear magnetic resonance hydrogen spectrum of the compound TTVBI in deuterated chloroform is shown in figure 13, the nuclear magnetic resonance carbon spectrum of the compound TTVBI in deuterated chloroform is shown in figure 14, wherein,1H NMR(600MHz,DMSO-d6)δ9.26(d,J＝7.5Hz,1H),9.03(d,J＝15.4Hz,1H),8.65(d,J＝8.0Hz,1H),8.27(dd,J1＝7.8,J2＝2.6Hz,2H),8.21(d,J＝4.1Hz,1H),8.14(t,J＝7.7Hz,1H),7.94–7.90(m,1H),7.77(d,J＝4.1Hz,1H),7.75–7.72(m,2H),7.56(d,J＝15.4Hz,1H),7.42–7.37(m,4H),7.18(t,J＝7.5Hz,2H),7.14(d,J＝7.3Hz,4H),6.98(d,J＝8.8Hz,2H),4.79(q,J＝7.3Hz,2H),1.51(t,J＝7.3Hz,3H).13C NMR(151MHz,DMSO-d6)δ160.06,154.73,149.09,146.17,145.06,139.93,139.30,138.87,136.15,134.08,130.81,129.97,129.91,129.13,128.90,127.72,127.55,125.67,125.41,125.19,124.57,123.25,121.12,117.96,111.61,40.90,15.33.HRMS(ESI,positive ion mode)calcd for C37H29N2S+533.2046,found 533.2034.
example 8:
as shown in fig. 1 b, at N2Under the protection of (1), 116mg of Compound 2 and 100mg of Compound 5 are dissolved in 2.5ml of glacial acetic acid, and then 0.25ml of triethylamine and 0.25ml of acetic anhydride are added in this order to react for 3 hours under an oil bath at 60 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction mixture was dropwise added to 20ml of anhydrous ether to precipitate a large amount of green precipitate, and the solid residue obtained after filtration was purified by silica gel column chromatography using methylene chloride/methanol (50:1 → 10:1) as an eluent to obtain 45mg of a black powdery solid compound, DTVBI, in a yield of 22%. The nuclear magnetic resonance hydrogen spectrum of the compound DTVBI in the deuterated chloroform is shown in figure 15, the nuclear magnetic resonance carbon spectrum of the compound DTVBI in the deuterated chloroform is shown in figure 16, wherein,1H NMR(600MHz,DMSO-d6)δ8.98(d,J＝7.2Hz,1H),8.88(d,J＝14.4Hz,1H),8.38(d,J＝7.8Hz,1H),8.19(s,1H),7.97–7.92(m,2H),7.78(d,J＝7.8Hz,1H),7.73(t,J＝7.8Hz,1H),7.59(d,J＝4.4Hz,8H),7.49–7.46(m,2H),6.88(d,J＝14.4Hz,1H),6.56(d,J＝4.7Hz,1H),4.47(q,J＝7.3Hz,2H),1.33(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO)δ174.47,170.99,156.73,144.44,144.36,139.66,132.99,130.59,130.55,130.07,129.95,129.58,129.21,128.57,128.53,126.45,124.92,124.00,115.17,112.59,104.97,40.05,14.41.HRMS(ESI,positive ion mode)calcd for C31H25N2S+457.1733,found 457.1722.
example 9:
as shown in fig. 1 c, at N284mg of Compound 2 and 100mg of Compound 7 are dissolved in 2.0ml of glacial acetic acid, and then 0.2ml of triethylamine and 0.2ml of acetic anhydride are added in this order and reacted for 3 hours in an oil bath at 60 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction mixture was dropped into 20ml of anhydrous ether to precipitate a large amount of green precipitate, and the solid residue obtained after filtration was purified by silica gel column chromatography using methylene chloride/methanol (50:1 → 10:1) as an eluent to obtain 81mg of DTTVBI as a black powdery solid compound in a yield of 45%. The nuclear magnetic resonance hydrogen spectrum of the compound DTTVBI in deuterated chloroform is shown in figure 17The carbon nuclear magnetic resonance spectrum of the compound DTTVBI in deuterated chloroform is shown as figure 18, wherein,1H NMR(500MHz,CD3OD-d4:CD2Cl2-d2＝1:1)δ8.89(d,J＝7.5Hz,1H),8.76(d,J＝15.0Hz,1H),8.42(d,J＝8.0Hz,1H),8.06(d,J＝8.0Hz,1H),8.03(d,J＝8.0Hz,1H),7.88–7.85(m,2H),7.80(t,J＝8.0Hz,1H),7.36(d,J＝9.0Hz,1H),7.34–7.31(m,4H),7.23–7.21(m,4H),7.18–7.14(m,3H),7.12(d,J＝15.0Hz,1H),7.04(d,J＝4.1Hz,1H),6.74(d,J＝15.4Hz,1H),6.42(d,J＝4.1Hz,1H),4.61(q,J＝7.3Hz,2H),1.63(t,J＝7.3Hz,3H).13C NMR(126MHz,CD3OD-d4:CD2Cl2-d2＝1:1)δ159.54,158.10,157.69,147.26,144.96,141.67,140.12,139.87,136.14,133.09,132.32,132.12,131.35,131.05,130.52,130.42,130.11,129.09,128.97,126.64,125.73,125.06,124.83,117.06,116.78,116.29,110.03,41.46,15.33.HRMS(ESI,positive ion mode)calcd for C37H29N2S2 +565.1767,found 565.1753。
example 10
The UV absorption spectra of the pH reversibly activated NIR dimer induced emission molecules prepared in examples 7-9 in DMSO were measured separately and shown in FIG. 19. it can be seen from FIG. 19 that the maximum absorption values of TTVBI, DTVBI and DTTVBI in DMSO are at 660nm,694nm and 750nm, respectively.
Fluorescence emission spectra of the pH reversibly activated NIR dimer induced emission molecules prepared in examples 7-9 in DMSO were measured separately and shown in FIG. 20, where it can be seen from FIG. 20 that the emission ranges of TTVBI, DTVBI and DTTVBI in DMSO cover the NIR I region and II region.
The 10x 10 prepared in examples 7, 8 and 9 were tested separately-6The fluorescence emission intensity of M TTVBI, DTVBI and DTTVBI in a dimethyl sulfoxide/toluene mixed system with different ratios is shown in FIG. 21, and the result is shown in FIG. 21, and it can be seen from FIG. 21 that TTVBI, DTVBI and DTTVBI have typical aggregation-induced luminescence effects.
Example 11
With mPEG2000PLGA encapsulates DTTVBI in example 9 into nanoparticles.
The DLS diagram of the nanoparticles in example 11 was tested, and the results are shown in FIG. 22. it can be seen from FIG. 22 that the prepared nanoparticles are dispersed uniformly and have particle sizes between 140 and 165 nm.
The absorption and fluorescence emission spectra of the DTTVBI NPs as nanoparticles in example 11 in dimethyl sulfoxide were tested, and as shown in FIG. 23, it can be seen from FIG. 23 that the maximum absorption value of DTTVBI NPs is 694nm, and the maximum emission is at 1000 nm.
The ultraviolet-visible absorption spectrum of the DTTVBI NPs of the nanoparticle in the test example 11 in PBS buffer solutions with different pH values is shown in FIG. 24, and as shown in FIG. 24, the prepared nanoparticle has an absorption value of about 425nm which is continuously increased along with the increase of the pH value from 4 to 10, and an absorption value of 694nm which is continuously decreased, which shows that the DTTVBI NPs have obvious pH responsiveness.
The graph of pKa values obtained by nonlinear fitting of DTTVBI NPs of the nanoparticles in example 11 was tested, and the results are shown in FIG. 25, from which it can be seen that the pKa value of the nanoparticles is 6.94.
The fluorescence spectrograms of pH6.5 and pH 7.4 nanoparticles DTTVBI NPs prepared from the pH reversibly activated near-infrared two-region aggregation-induced emission molecule prepared in example 9 under 808nm laser irradiation by using DCFH (DCFH) as an active oxygen indicator are tested, and the results are shown in FIG. 26, and it can be seen from FIG. 26 that the pH6.5 DTTVBI NPs have high active oxygen generation capacity, while the active oxygen generation capacity of the pH 7.4DTTVBI NPs is weaker, which indicates that the nanoparticles prepared under physiological conditions have no photosensitivity and have small damage to normal tissues and cells.
The temperature change graphs of different concentrations of pH6.5 and pH 7.4DTTVBI NPs prepared from the pH reversibly activated near-infrared two-zone aggregation-induced emission molecule prepared in the test example 9 under the irradiation of the laser with 0.8W 808nm are shown in the result of FIG. 27, and the pH6.5 DTTVBI NPs have very excellent photo-thermal effect and can be raised to 65 ℃ at the highest temperature as shown in FIG. 27; and the pH value of 7.4DTTVBI NPs is poor in photothermal effect, and the temperature can only be increased to 43 ℃, so that the nano particles prepared under the physiological condition have no photothermal killing effect and have small damage to normal tissues and cells.
The temperature change graphs of 100uM pH6.5 and pH 7.4DTTVBI nanoparticles prepared from the pH reversibly activated near-infrared two-region aggregation-induced emission molecule prepared in example 9 under different power 808nm laser irradiation are tested, and the results are shown in FIG. 28, and it can be seen from FIG. 28 that pH6.5 DTTVBI NPs have more excellent photothermal effects than pH 7.4DTTVBI NPs under the same power.
The photo-thermal imaging effect of the pH6.5 and pH 7.4 nanoparticle DTTVBI NPs prepared from the pH reversibly activated near-infrared two-domain aggregation-induced emission molecule prepared in example 9 was tested, and as shown in fig. 29, it can be seen from fig. 29 that the pH6.5 DTTVBI NPs have a more excellent photo-thermal imaging effect than the pH 7.4DTTVBI NPs.
An experimental graph for testing the effect of the nanoparticle DTTVBI NPs prepared from the pH reversibly activated near-infrared two-region aggregation-induced emission molecules prepared in example 9 on the PDX model photothermal and photodynamic combined treatment is shown in FIG. 30, and the result is shown in FIG. 30, and it can be seen from FIG. 30 that the DTTVBI NPs can effectively inhibit the growth of PDX tumors and have very good tumor targeting property and biocompatibility.
The bacterial survival rate graph of the nanoparticle BC/DTTVBI NPs prepared from the pH reversibly activated near-infrared two-region aggregation-induced emission molecule prepared in the example 9 for the photothermal and photodynamic combined treatment of escherichia coli is tested, and the result is shown in FIG. 31, and it can be seen from FIG. 31 that 150 μ M BC/DTTVBI NPs can achieve high-efficiency killing of escherichia coli, the bacteriostasis rate is as high as more than 95%, and the PDT/PTT synergistic antibacterial effect is very good.
A schematic diagram of a preparation process and a mechanism of the pH reversible activation of the pH reversibly activated near-infrared two-domain aggregation-induced emission molecule nanoparticle DTTVBI NPs prepared in example 9 is drawn, and the result is shown in fig. 32, and it can be seen from fig. 32 that under normal physiological conditions, the photosensitizer mainly exists in a non-conjugated basic DTTVBI-OH structure and does not have obvious photosensitivity; under the slightly acidic condition of tumors, the photosensitizer mainly exists in a fully conjugated acid DTTVBI structure, and has excellent PDT/PTT synergistic 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 (6)

1. The pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer is characterized in that the pH reversibly activated near-infrared two-region aggregation-induced emission type I photosensitizer is one of the following chemical structural formulas:
Figure FDA0003490984340000011
Figure FDA0003490984340000012
wherein R is1And R2One selected from hydrogen, methyl and methoxy, R3Is composed of
Figure FDA0003490984340000013
One kind of (1).
2. The pH reversibly activated near infrared two-region aggregation-induced emission type I photosensitizer according to claim 1, wherein the absorption wavelength of the pH reversibly activated near infrared two-region aggregation-induced emission type I photosensitizer is 660nm to 750 nm.
3. The pH reversibly activated near infrared two-region aggregation-induced emission type I photosensitizer according to claim 1, wherein the emission wavelength of the pH reversibly activated near infrared two-region aggregation-induced emission type I photosensitizer is 1000nm to 1500 nm.
4. Use of the pH-reversibly activated NIR dimer inducible luminescence type I photosensitizer of any one of claims 1 to 3, wherein the pH-reversibly activated NIR dimer inducible luminescence type I photosensitizer is used for the preparation of a medicament for the treatment of neoplastic or bacterial infectious disease.
5. The use of the pH reversibly activated NIR BIO aggregation-induced emission type I photosensitizer as claimed in claim 4, wherein the drug is based on mPEG2000-PLGA encapsulates nanoparticles formed by the infrared two-domain aggregation-induced emission type I photosensitizer.
6. The use of a pH-reversibly activatable NIR dimer aggregation-induced emission type I photosensitizer as claimed in claim 4, wherein said drug is present in a non-conjugated basic form in blood and normal tissues and in a fully conjugated acidic form at the tumor site.
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