CN114478581B - NIR-II small molecule, compound and complex for phototherapy, and preparation method and application thereof - Google Patents
NIR-II small molecule, compound and complex for phototherapy, and preparation method and application thereof Download PDFInfo
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- CN114478581B CN114478581B CN202210005209.1A CN202210005209A CN114478581B CN 114478581 B CN114478581 B CN 114478581B CN 202210005209 A CN202210005209 A CN 202210005209A CN 114478581 B CN114478581 B CN 114478581B
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- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
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Abstract
The invention provides a phototherapeutic NIR-II small molecule represented by formula 3:
the complex is a brand new compound with the maximum emission wavelength of more than 1000nm, the quantum yield in aqueous solution is 0.42%, the photothermal conversion efficiency is 41.77%, and the complex has good light stability and biocompatibility, is easy to be used for easily preparing a complex by modifying polypeptide, protein, polyethylene glycol, aptamer or folic acid and derivatives thereof at an adjustable site and reacting with rare metal salt to form the complex, and can be used for near-infrared two-zone tumor imaging, preparing anti-tumor drugs and the likeAbsorbed and metabolized by organism, and has obvious cytotoxic effect on tumor cells.
Description
Technical Field
The invention relates to the technical field of biomedical fluorescence imaging application, in particular to NIR-II small molecules, compounds and complexes for light therapy, and a preparation method and application thereof.
Background
Chemotherapy, one of the most convenient and promising treatments, has successfully increased the survival of cancer patients over the past few years. Since the first application of cisplatin in tumor therapy, there has been a growing effort to explore potential therapeutic applications of transition metal complexes. Among them, organic ruthenium (II/III) complexes, a new generation of anticancer candidate compounds, are attracting attention due to their interesting optical properties and strong interactions with cellular DNA and proteins. However, the course of therapy is greatly hampered by severe systemic toxicity due to natural or acquired resistance and nonspecific distribution. NAMI-A, the first clinically approved ruthenium complex, was found to bind to DNA, RNA and histidine residues of serum albumin, but eventually failed due to its low therapeutic efficacy.
New treatment modalities such as photothermal therapy (PTT) or photodynamic therapy (PDT) have synergistic effects with chemotherapy, improving overall therapeutic efficacy while minimizing side effects. Therefore, ru (II) polypyridine complexes with a variety of photophysical properties and biological activities are the best candidates to combine these therapeutic modalities. In addition, due to the presence of fluorescence, ru (II) polypyridine complexes have a variety of photophysical properties and biological activities. Ru (II) polypyridine complex [ Ru (Phen) 2 dppz] 2+ And [ (bpy) 2 Ru(tpphz)Ru(bpy) 2 ] 4+ Has great potential in visualizing drug delivery and image-guided therapy. However, the emission wavelengths of the Ru (II) complexes present lie predominantly in the strongly reflecting visible region (390 to 780 nm). Therefore, it cannot be used for in vivo bioimaging and converts Ru (II) complexes to therapeuticsThe platform remains a challenge. In addition, in order to optimize the solubility, pharmacokinetics, toxicity and biodistribution of Ru (II) complexes, nanocarriers including selenium, gold nanomaterials, silica, carbon nanotubes have been used, but the particle size, complexity and poor metabolism and biodegradability of nanosystems have been a major concern.
Therefore, it is important to develop a small molecule with better light stability and photo-thermal conversion efficiency, no toxicity, good biocompatibility, easy absorption and metabolism by organisms, obvious cytotoxicity to tumor cells, and near-infrared two-region fluorescence emission.
Disclosure of Invention
The present invention aims to address, at least to some extent, one of the technical problems of the prior art and thus, in a first aspect of the invention, the invention provides a phototherapeutic NIR-II small molecule according to formula 3:
in a second aspect of the present invention, there is provided a phototherapeutic NIR-II compound having the structure shown in formula 4,
wherein R1 and R2 are respectively and independently selected from-NH-PEG-OCH 3 One of folic acid, iRGD, CREKA and oligopeptide PPSHTPT;
preferably, the structure of the light-treated NIR-II compound is as shown in formula H7-PEG 2K As shown in the drawings, the above-described,
in a third aspect of the present invention, there is provided a phototherapeutic NIR-II complex having the structure shown in formula 5,
r1 and R2 are respectively and independently selected from-NH-PEG-OCH 3 One of folic acid, iRGD, CREKA and oligopeptide PPSHTPT; r3 is selected from one of Ru and Ir; n and a are respectively and independently taken from 1, 2, 3 and 4; m is selected from Cl, SO 4 (ii) a R3 is selected from one of Ru and Ir; n is selected from 1, 2, 3 and 4; m is selected from Cl, SO 4 ；
Preferably, the structure of the light-treated NIR-II complex is as shown in formula HL-PEG 2K As shown in the drawings, the above-described,
in one or more embodiments of the invention, the phototherapeutic NIR-II complex self-assembles in water to form nanoparticles having an average particle size of 125 to 130nm, preferably 127.15nm.
In one or more embodiments of the invention, the fluorescence emission wavelength of the phototherapeutic NIR-II complex is 1028nm.
In a fourth aspect of the invention there is provided the use of a phototherapeutic NIR-II small molecule according to the first aspect of the invention and/or a phototherapeutic NIR-II compound according to the second aspect of the invention and/or a phototherapeutic NIR-II complex according to the third aspect of the invention for near infrared two-zone tumour imaging.
In a fifth aspect, the present invention provides the use of a small phototherapeutic NIR-II molecule according to the first aspect of the present invention and/or a phototherapeutic NIR-II compound according to the second aspect of the present invention and/or a phototherapeutic NIR-II complex according to the third aspect of the present invention in the preparation of an anti-tumour medicament.
In a sixth aspect of the present invention, the present invention provides a method for preparing a phototherapeutic NIR-II small molecule according to the first aspect of the present invention, wherein the phototherapeutic NIR-II small molecule is prepared from compound 1, and the reaction formula for preparing the phototherapeutic NIR-II small molecule from compound 1 is as follows:
step 1): taking compound 1,4, 7-dibromo-5, 6-dinitrodiazosulfide and K 2 CO 3 、Pd(PPh 3 ) 4 Adding the mixture into a reaction container, stirring the mixture in an oil bath at 100-130 ℃ for reaction under the protection of nitrogen, cooling the mixture after the reaction is finished, diluting the mixture with water, extracting the mixture with EA, and purifying the extract to obtain a mauve compound 2;
step 2): adding the compound 2 obtained in the step 1) into a mixed solvent of DCM, methanol and water, adding 95 (w/w)% of ammonium chloride and zinc powder, placing the mixture into a reaction vessel, reacting for 1-3 h at 20-30 ℃, filtering, washing a filter cake with DCM, and carrying out rotary drying on the filtrate to obtain a yellow crude product;
and step 3): dissolving 1, 10-phenanthroline-5, 6-diketone and the yellow crude product obtained in the step 2) in acetic acid, adding the solution into a reaction container, refluxing in an oil bath at the temperature of 110-130 ℃ for 3-6H, cooling, concentrating to obtain a residue, and purifying to obtain a green solid compound, namely H7;
step 4): dissolving H7 in DCM at 0 ℃, slowly adding 1mL of TFA, adding the mixture into a reaction container, preserving at room temperature for 30min, and concentrating to obtain a compound 3, namely the light-treated NIR-II micromolecule;
preferably, in the step 1), the compound 1,4, 7-dibromo-5, 6-dinitrobenzothiadiazole, K 2 CO 3 、Pd(PPh 3 ) 4 1, 3.2;
preferably, in the step 2), the molar ratio of the compound 2 to the ammonium chloride to the zinc powder is 0.028; the volume ratio of DCM, methanol and water is 1.
In a seventh aspect of the present invention, the present invention provides a method for preparing a phototherapeutic NIR-II compound according to the second aspect of the present invention, wherein the phototherapeutic NIR-II compound is prepared from the phototherapeutic NIR-II small molecule of claim 1, the phototherapeutic NIR-II small molecule is prepared by the following reaction formula:
preferably, the phototherapeutic NIR-II compound is obtained from a therapeutic NIR-II small molecule according to the first aspect of the invention modifying a polypeptide, protein, polyethylene glycol, aptamer or folate, and derivatives thereof, at a regulatable site;
preferably, the preparation of the phototherapeutic NIR-II compound by the phototherapeutic NIR-II small molecule comprises the steps of: taking-NH-PEG-OCH 3 Or folic acid, iRGD, CREKA, oligopeptide PPSHTPT, DIPEA and HATU are added into the DMSO solution of the NIR-II micromolecules for the phototherapy, and the mixture is stirred for 5 to 8 hours at the temperature of between 20 and 30 ℃ and purified, so that the NIR-II compound for the phototherapy is obtained;
preferably, -NH-PEG-OCH 3 Or folic acid or iRGD or CREKA or oligopeptide PPSHTPT, DIPEA, HATU molar ratio of 0.028.
In an eighth aspect of the present invention there is provided a process for the preparation of a phototherapeutic NIR-II complex according to the third aspect of the present invention, wherein the phototherapeutic NIR-II complex is prepared from a phototherapeutic NIR-II compound according to the second aspect of the present invention, the reaction for preparing the phototherapeutic NIR-II complex by the phototherapeutic NIR-II compound is as follows:
the preparation of the phototherapeutic NIR-II complex from the phototherapeutic NIR-II compound comprises the following steps: treating the lightNIR-II Compound of (3), ru (bpy) 2 Cl 2 Or Ru (II) -bis (4, 4'-dimethyl-2,2' -dipyridine) or Ru (phen) 2 Cl 2 、Ru(dppz) 2 Cl 2 Or cis- [ Ir (2, 2' -dipyridine) 2 D 2 ]PF 6 Placing the mixture into a reaction container, adding 40-60 (v/v)% of methanol, refluxing for 8-10 hours at 80-100 ℃, concentrating reaction liquid to obtain residue after the reaction is finished, and purifying the residue to obtain the light-treated NIR-II complex;
preferably, the phototherapeutic NIR-II compound is reacted with Ru (bpy) 2 Cl 2 Or Ru (II) -bis (4, 4'-dimethyl-2,2' -dipyridine) or Ru (phen) 2 Cl 2 Or Ru (dppz) 2 Cl 2 Or cis- [ Ir (2, 2' -dipyridine) 2 D 2 ]PF 6 Is 1.
The invention has the beneficial effects that:
1. the invention provides NIR-II small molecules, compounds and complexes capable of realizing fluorescence emission above 1000nm and used for synergistic phototherapy, which are novel compounds with the maximum emission wavelength exceeding 1000nm, have good quantum yield (QY = 0.42%) above 1000nm, are nontoxic, have good biocompatibility, and are easy to absorb and metabolize by organisms;
2. the invention provides application of the NIR-II small molecules, compounds and complexes for the phototherapy in tumor imaging of a near-infrared region II.
3. The invention provides application of the light-treated NIR-II small molecules, compounds and complexes in preparation of antitumor drugs.
4. The invention provides a preparation method of the NIR-II small molecules, the compounds and the complexes for the phototherapy, which has the advantages of simple synthetic route, high reaction efficiency, high yield and higher industrial application prospect
Drawings
FIG. 1 shows HL-PEG 2K MALDI-TOF-MS characterization of (matrix-assisted laser Desorption-time of flight-Mass Spectrometry);
FIG. 2 shows HL-PEG 2K The high performance liquid chromatography characterization of (3);
FIG. 3 shows H7-PEG 2K And absorbance and fluorescence of HL-PEG2K in aqueous solution (10. Mu.M)Emitting light;
FIG. 4 shows HL-PEG 2K And ICG photostability in H2O, FBS and PBS;
FIG. 5 shows HL-PEG 2K The light stability of (2);
FIG. 6 shows HL-PEG 2K Cytotoxicity to U87 cells;
FIG. 7 shows HL-PEG 2K The photothermal conversion efficiency of;
FIG. 8 shows HL-PEG 2K (iii) apoptosis and cell cycle assays of; wherein (a) AM and PI (scale bar: 200 μ M) staining of U87 MG cells treated with different treatment groups (control, laser irradiation, HL-PEG2K (60 μ M) + laser irradiation and cisplatin (60 μ M)); (b) Flow cytometry analysis of control, laser irradiation, HL-PEG2K (60 μ M) treated U87 MG apoptosis; (c) quantitative analysis results of flow cytometry; (d) Flow cytometry analysis of the cell cycle of control, laser irradiated, HL-PEG2K (60 μ M) plus laser irradiated and cisplatin (60 μ M) treated U87 MG cells;
FIG. 9 shows HL-PEG 2K Viable and dead cell staining of U87 cells was treated;
FIG. 10 shows HL-PEG 2K Determination of J-aggregates after treatment of U87 cells;
FIG. 11 shows HL-PEG 2K Measurement of NADH after treatment of U87 cells;
FIG. 12 shows HL-PEG 2K Immunoblot analysis after treatment of U87 cells;
FIG. 13 shows HL-PEG 2K Fluorescence imaging and CPTT in glioma model mice. (a) Horizontal position (808nm, 90mW cm) -2 1000lp, 30ms) near infrared image of HL-PEG2K in subcutaneous/in situ glioma model and its quantitative signal intensity; (b) HL-PEG2K is in the supine position (808nm, 90mW cm) -2 1000lp, 30ms) and their quantitative signal intensity; (c) And (d) representative IR photographs and HL-PEG2K solution at 808nm laser (1W cm) 2 ) In vivo heating profile of U87 MG tumor bearing mice under irradiation; (e) tumor weight excision in a U87 MG mouse model; (f) PBS and laser (1W cm) were used respectively 2 5 min), cis-platinum (200. Mu.L, 2mg/kg Pt) and HL-PEG2K (200. Mu.L, 2mg/kg Ru) with 808nm laser(1W cm 2 Average weight of mice after 5 min); (g) PBS and laser (1W cm) were used respectively 2 5 min), cis-platinum (200. Mu.L, 2mg/kg Pt) and HL-PEG2K (200. Mu.L, 2mg/kg Ru) with 808nm laser (1W cm) 2 5 min) relative tumor volume of mice;
FIG. 14 shows HL-PEG 2K The biocompatibility analysis of (a);
FIG. 15 shows HL-PEG 2K Fluorescence signals in different pH buffers;
FIG. 16 shows HL-PEG 2K Fluorescence imaging of major organs in glioma model mice;
FIG. 17 is a photograph of mice during treatment;
FIG. 18 shows HL-PEG collection of mouse blood over a predetermined time 2K The intensity of fluorescence;
FIG. 19 shows HL-PEG 2K TEM image and DLS of (a);
FIG. 20 shows HL-PEG 2K The photothermal curve of (c);
FIG. 21 shows IR-26 (IR series dyes), H7-PEG 2K ，HL-PEG 2K Quantum yield in dichloromethane.
Detailed Description
The scheme of the invention will be explained with reference to the following examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The following examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer, by using conventional methods known in the art without specific descriptions, and by using consumables and reagents which were commercially available without specific descriptions. Unless otherwise defined, technical and scientific terms used herein have the same meaning as is familiar to those skilled in the art. In addition, any methods or materials similar or equivalent to those described herein can also be used in the present invention.
Examples 1-3 below are methods for the synthesis of light-treated NIR-II small molecules (compound 3), the reaction formula is shown below:
example 1: synthesis of Compound 2
The preparation method of the compound 2 comprises the following steps:
in the presence of 1,4, 7-dibromo-5, 6-dinitrobenzothiadiazole (296.7mg, 0.77mmol) and K 2 CO 3 (342mg, 2.5 mmol) in solution, pd (PPh) was added 3 ) 4 (89.3mg, 0.077mmol) were stirred in an oil bath at 115 ℃ under nitrogen. After completion of the reaction, the mixture was cooled and diluted with water (100 mL), extracted with EA (50 mL × 3), and further purified by a conventional procedure to obtain magenta compound 2 (160 mg, yield 20%). 1 H NMR(400MHz,CDCl 3 )δ7.45–7.39(m,4H),7.33(dd,J＝20.2,12.8Hz,5H),7.25–7.09(m,17H),4.24–4.18(m,4H),2.97(t,J＝7.8Hz,4H),2.65(t,J＝7.8Hz,4H),1.06–0.96(m,4H),0.07(s,18H). 13 C NMR(101MHz,CDCl 3 )δ173.1,153.2,149.8,146.7,144.8,142.3,137.0,130.2,129.6,129.5,127.8,126.2,125.8,124.3,122.1,120.4,62.8,36.0,30.4,17.3,1.4.
Example 2: synthesis of Compound H7
The preparation method of the compound H7 comprises the following steps:
compound 2 (80mg, 0.076 mmol) obtained in example 1 was added to 5mL of EDC and 5mL of methanol, and 95 (w/w)% ammonium chloride (146mg, 2.73mmol.) and zinc powder (594 mg, 9.08mmol.) were added. The mixture was reacted at 25 ℃ for 2h, then filtered, the filter cake was washed with 20ml of lcm and the filtrate was spin dried to give a yellow crude product (80 mg) which was used directly in the subsequent synthesis. 1, 10-phenanthroline-5, 6-dione (20mg, 0.09mmol) and the above crude product were dissolved in 5mL of acetic acid, refluxed in an oil bath at 120 ℃ for 4 hours, and then cooled and concentrated under a rotary evaporator to give a residue. The above residue was purified to obtain desired compound H7 (35 mg, yield 39.3%) as a green solid. 1 H NMR(400MHz,CDCl 3 )δ9.23-9.21(m,4H),8.00(d,J＝8.4Hz,4H),7.70(dd,J＝7.7,4.6Hz,2H),7.39-7.29(m,12H),7.28-7.25(m,4H),7.21-7.19(m,4H),7.12(t,J＝6.8Hz,2H),4.20(t,J＝7.8Hz,4H),2.97(t,J＝7.8Hz,4H),2.65(t,J＝7.8Hz,4H),0.99(t,J＝7.8Hz,4H),0.04(s,18H). 13 C NMR(101MHz,CDCl 3 )δ173.1,153.0,152.9,149.4,148.3,147.5,145.6,142.1,137.3,136.2,134.4,134.1,129.5,129.4,129.2,128.1,127.9,125.6,125.2,124.6,123.6,121.1,62.8,36.1,30.5,17.3,1.4.
Example 3: synthesis of light-treated NIR-II small molecule compound 3
Compound H7-PEG 2K The preparation method comprises the following steps:
1mL of TFA was slowly added to 2mL of a solution of H7 (10mg, 8.54mmol) obtained in example 2 in DCM, and the mixture was stored at room temperature for 30min at 0 ℃. And concentrating the crude product to obtain a compound 3, namely the NIR-II micromolecule for phototherapy.
Example 4 below illustrates the synthesis of a light-treatable NIR-II compound exemplified by H7-PEG2k
The reaction formula is shown as follows:
example 4: compound H7-PEG 2K Synthesis of (2)
NH was added to a 250. Mu.L solution of the phototherapeutic NIR-II small molecules (10 mg, 10.3. Mu. Mol) obtained in example 3 in dimethyl sulfoxide 2 PEG-OME (61.8mg, 30.9. Mu. Mol, M.W.2000, ponscure Biotechnology), DIPEA (13.3mg, 103.2. Mu. Mol), HATU (39.2mg, 103.2. Mu. Mol). The above solution was stirred at 25 ℃ for 6h and then purified with Amicon Ultra-0.5ml 3.5K (6 washes). The green compound H7-PEG2k was obtained in 83% yield (42.2 mg). The purity of H7-PEG2k was analyzed by using a high performance liquid chromatography column (Thermo Science Hypersil Gold C8). 1 H NMR(400MHz,CDCl 3 )δ9.32(d,J＝8.2Hz,2H),9.25(s,2H),8.07(d,J＝8.7Hz,4H),7.79(s,3H),7.42–7.30(m,12H),7.24(m,J＝8.1Hz,6H),7.14(t,J＝6.8Hz,2H),6.59(s,2H),3.66(m,354H),3.40(s,6H),3.04–2.96(t,4H),2.61–2.52(t,4H),2.27–2.20(t,4H).
Example 5 below is with HL-PEG 2K For the purpose of illustrationSynthesis method of NIR-II complex for bright light treatment
The reaction formula is shown as follows:
example 5: HL-PEG 2K Synthesis of (2)
HL-PEG 2K The preparation method comprises the following steps:
the compound H7-PEG prepared in example 3 was weighed 2K (10mg,2.03μmol)、Ru(bpy) 2 Cl 2 (7.8 mg, 16.21. Mu. Mol) in a single-neck flask, adding 2mL of 50 (v/v)% methanol, refluxing at 90 ℃ for 8 to 10 hours, concentrating to remove the solvent, and purifying the residue by HPLC to obtain HL-PEG 2K (5.8 mg, 53% yield). FIG. 1 shows HL-PEG 2K And (3) MALDI-TOF-MS characterization. FIG. 2 shows HL-PEG 2K And (4) performing high performance liquid chromatography characterization. FIG. 3 shows H7-PEG 2K And absorbance and fluorescence emission of HL-PEG2K in aqueous solution (10. Mu.M). Measurement of HL-PEG 2K With a maximum emission wavelength of 1028nm and a tail of 1400nm. Therefore, the nano particles have the near-infrared two-region emission characteristic and can be used for imaging research of the near-infrared two-region. FIG. 15 shows HL-PEG 2K Fluorescence signals in different pH buffers. FIG. 19 shows HL-PEG 2K TEM image and DLS of (a); FIG. 20 shows HL-PEG 2K The photothermal curve of (a); FIG. 21 shows IR-26,H7-PEG 2K ,HL-PEG 2K Quantum yield in dichloromethane. HL-PEG 2K The quantum yield in aqueous solution was 0.42%
Example 6
The following experiment is the HL-PEG obtained in example 5 2K The light stability test of (2).
HL-PEG 2K The light stability test of (2).
The method comprises the following specific steps:
mixing HL-PEG 2k ICG (indocyanine green), was dissolved in FBS, H2O and PBS respectively. Using 808nm laser (180 mW cm) 2 ) After 60min of continuous irradiation, the fluorescence intensity was calculated using ImageJ software and the time-dependent fluorescence intensity of each group was compared.
FIG. 4 shows HL-PEG 2K And ICG at H 2 Graph comparing light stability in O, FBS and PBS. As can be seen, 808nm laser continuously irradiates HL-PEG in different media 2K One hour for the nanoparticles and ICG, and a laser power density of 0.09W/cm 2 ICG fluorescence signals in PBS, water and fetal calf serum are obviously attenuated, and HL-PEG 2K The fluorescent signal of the nanoparticles remained good. The above results show that the prepared HL-PEG 2K Has superior light stability compared with ICG. FIG. 5 shows HL-PEG 2K Graph of photostability results.
Example 7
The following experiment was conducted for HL-PEG obtained in example 5 2K Cytotoxicity assay on U87 cells.
HL-PEG 2K Cytotoxicity assay on U87 cells.
The method comprises the following specific steps:
u87 MG cells were seeded on 96-well plates, cultured in a cell incubator for 12 hours, and then separately incubated with a cell culture medium containing HL-PEG 2k And replacing the cell culture solution with the cisplatin cell culture solution. After 24 hours, respectively measuring HL-PEG by using a CCK-8 colorimetric method 2K HL-PEG under laser irradiation 2K Viability of cell cultures under cisplatin treatment.
FIG. 6 shows HL-PEG 2K HL-PEG under laser irradiation 2K Comparative results of the cytotoxicity test of cisplatin on U87 cells are shown. As shown in the figure, HL-PEG 2K Is significantly less cytotoxic than cisplatin.
Example 8
The following experiment is the HL-PEG obtained in example 5 2K The photothermal properties of (1).
HL-PEG 2K The photothermal properties of (a).
The method comprises the following specific steps:
taking HL-PEG 2K Placing 300 mu L of sample in an EP tube, continuously irradiating the sample by using 808nm laser, removing a laser light source when the temperature of the sample reaches a constant temperature, simultaneously recording the temperature of the sample by using a photo-thermal camera in the process, recording the temperature once every 30s, and drawing a temperature-rise cooling curve. Simultaneously testing the ultraviolet absorption emission curve of the sample, and recording the absorption under 808nmThe luminosity a808. The photothermal conversion efficiency (η) is calculated by the following equation:
hs can be calculated by using an hs = mc/tau formula, m refers to the mass of a test sample, c refers to the specific heat capacity of water, tau is a cooling coefficient and can be obtained by fitting the relation between a cooling curve and temperature, Δ Tmax refers to the difference value of the highest temperature and the ambient temperature, and Qs is the heat dissipation capacity of pure water, so that the temperature rise of the pure water sample is not obvious and can be ignored here. A808 is the absorbance of the sample at 808nm. Substituting the above result into formula to obtain HL-PEG 2K The light-heat conversion efficiency. FIG. 7 shows HL-PEG 2K The light-heat conversion efficiency. As can be seen, HL-PEG 2K The photothermal conversion efficiency was 41.77%.
Example 9
The following experiment is the HL-PEG obtained in example 5 2K Apoptosis and cell cycle assays of (1).
HL-PEG 2K Apoptosis and cell cycle assays of (1).
The method comprises the following specific steps:
with 60 μ M HL-PEG 2k And 60 μ M cisplatin in 1W cm under the condition of 808nm laser irradiation or not 2 Irradiating U87 MG cells for 5min with laser power density, incubating in cell incubator for 12 hr, and culturing with 60 μ MHL-PEG 2k And 60 mu M cisplatin in a novel DMEM medium for 24h. Cells were then harvested and stored in PBS. The cells were stained with Annexin V-FITC/PI apoptosis kit (China Multi science) and PI cell cycle staining kit (China Multi science) respectively, and apoptosis and cell cycle were detected using a Beckman CytExpert flow cytometer. FIG. 8 shows HL-PEG 2K Apoptosis and cell cycle assays of (1). Wherein (a) different treatment groups (control group, laser irradiation, HL-PEG) 2K AM and PI (scale bar: 200 μm) staining; (b) Flow cytometry analysis of control group,Laser irradiation, HL-PEG 2K (60μM)、HL-PEG 2K Apoptosis of (60 μ M) treated U87 MG cells; (c) quantitative analysis results of flow cytometry; (d) Flow cytometer analysis control group, laser irradiation and HL-PEG 2K (60μM)、HL-PEG 2K (60 μ M) cell cycle of U87 MG cells irradiated with laser and treated with cisplatin (60 μ M).
Example 10
The following experiment is the HL-PEG obtained in example 5 2K Staining experiments of live and dead cells after treatment of U87 cells.
HL-PEG 2K Live and dead cell staining experiments after treatment of U87 cells.
The method comprises the following specific steps:
cells were washed with assay buffer, treated with 60. Mu.M HL-PEG2k and 60. Mu.M cisplatin for 24h, and laser irradiated at 808nm. The cell cultures of all samples were then partitioned and the cells were further fixed with paraformaldehyde for 10min. Subsequently, cells were gently washed and stained with 100 μ L of working solution containing calcein-AM/PI kit. After culturing U87 MG cells in a cell culture chamber (37 ℃) for 30min, live/dead cells were detected by an inverted fluorescence microscope (Olympus, USA). FIG. 9 shows the results of different treatment groups (control group, laser irradiation, cisplatin (60. Mu.M), HL-PEG 2K (60. Mu.M) and HL-PEG 2K Graph showing the results of comparison of staining of viable and dead cells after treating U87 cells (60. Mu.M) + laser irradiation).
Example 11
The following experiment is the HL-PEG obtained in example 5 2K Mitochondrial membrane potential measurements after treatment of U87 cells.
HL-PEG 2K Mitochondrial membrane potential measurements after treatment of U87 cells.
The method comprises the following specific steps:
u87 MG cells were treated with 60. Mu.M HL-PEG 2k And 60 μ M cisplatin for 24h, irradiating with 808nm laser with power density of 1W/cm2 for 5min, collecting cell sample, washing with PBS, and treating with JC-1 dark for 0.5h. Subsequently, the green fluorescence representing JC-1 monomer and the intensity of red fluorescence representing J-aggregates in the above cell samples were measured by a spark fluorescence microplate reader (TECAN). By calculating the red/green of each groupThe rate of decrease in color fluorescence intensity further yields Matrix Metalloproteinase (MMP). FIG. 10 shows the results of different treatment groups (control group, laser irradiation, cisplatin (60. Mu.M), HL-PEG 2K (60. Mu.M) and HL-PEG 2K Graph comparing the results of the measurement of J-aggregates after treatment of U87 cells (60. Mu.M) + laser irradiation).
Example 12
The following experiment is the HL-PEG obtained in example 5 2K Intracellular NADH determination after U87 cells were treated.
HL-PEG 2K Intracellular NADH measurement after U87 cells were treated.
The method comprises the following specific steps:
u87 MG cells were treated with 60. Mu.M HL-PEG2k and 60. Mu.M cisplatin for 24h, irradiated for 5min with or without laser irradiation at 808nm and a power density of 1W cm-2, and then injected with the same amount of NAD +/NADH detection reagent (Beyotime, china) in the cell lysate, respectively. Storing at 25 deg.C for 10min, and measuring fluorescence intensity with spark fluorescence microplate reader. FIG. 11 shows the results of different treatment groups (control group, laser irradiation, cisplatin (60. Mu.M), HL-PEG 2K (60. Mu.M) and HL-PEG 2K Graph showing the results of NADH measurement after treatment of U87 cells (60. Mu.M) + laser irradiation).
Example 13
The following experiment was conducted for HL-PEG obtained in example 5 2K Immunoblot analysis after treatment of U87 cells.
HL-PEG 2K Immunoblot analysis after treatment of U87 cells.
The method comprises the following specific steps:
each group of cell cultures was washed 3 times with cold PBS and then 100. Mu.l of lysis buffer was added. The lysates were incubated for half an hour on ice, centrifuged at 12000 Xg for 25min to extract the protein, and their content was determined by BCA method. The protein sample is then loaded onto a gel for separation. The gel was then transferred to a filter, which was finally blocked with 5% skim milk and incubated with the following antibodies: β -actin (1. The film was then treated with enhanced ECL reagent and further developed after rinsing. FIG. 12 is an immunoblot analysis of different treated groups (control, laser irradiation, HL-PEG2K (60. Mu.M) + laser irradiation and cisplatin (60. Mu.M)) after treatment of U87 cells.
Example 14
The following experiment was conducted for HL-PEG obtained in example 5 2K Fluorescence imaging in mice.
HL-PEG 2K Fluorescence imaging in mice.
The method comprises the following specific steps:
u87 MG tumor model mice were anesthetized with pentobarbital sodium solution (50 MG/kg), fixed under laser irradiation after anesthesia, and injected into tail vein with HL-PEG 2K Probe (200. Mu.L, 2mg/kg Ru) with laser (90 mW cm) at 808nm 2 ) NIR-II imaging was performed with different wavelength filters (1000 nm and 1250 nm) in prone position at predetermined time points under illumination. FIG. 13 shows HL-PEG 2K Fluorescence imaging and CPTT in glioma model mice. Wherein, (a) the near infrared image of HL-PEG2K in a decubitus (808nm, 90mW cm-2,1000LP, 30ms) in a subcutaneous/in-situ glioma model and the quantitative signal intensity thereof; (b) HL-PEG2K is in the supine position (808nm, 90mW cm) -2 1000lp, 30ms) and their quantitative signal intensity; (c) And (d) representative IR photograph and HL-PEG2K solution at 808nm laser (1W cm) 2 ) In vivo heating profile of U87 MG tumor-bearing mice under irradiation.
Example 15
The following experiment was conducted for HL-PEG obtained in example 5 2K CPTT under live NIR-II image guidance.
HL-PEG 2K CPTT under live NIR-II image guidance. FIG. 13 (e) U87 MG mouse model tumor weight resection; (f) Separately using PBS and laser (1W cm) 2 5 min), cisplatin (200. Mu.L, 2mg/kg Pt) and HL-PEG2K (200. Mu.L, 2mg/kg Ru) irradiated with 808nm laser (1W cm) 2 Average weight of mice after 5 min); (g) PBS and laser (1W cm) were used respectively 2 5 min), cis-platinum (200. Mu.L, 2mg/kg Pt) and HL-PEG2K (200. Mu.L, 2mg/kg Ru) with 808nm laser (1W cm) 2 5 min) post-mouse relative swellingTumor volume. Figure 17 is a photograph of mice during treatment. FIG. 16 shows HL-PEG 2K Fluorescence imaging of major organs in glioma model mice; FIG. 18 shows HL-PEG collection of mouse blood over a predetermined time 2K Fluorescence intensity.
The method comprises the following specific steps:
u87 MG mice were randomized into 5 groups (n = 4): (A) a control group, (B) a808 nm laser group, (C) a cisplatin injection group (200. Mu.L, 2mg/kg Pt), (D) HL-PEG 2k Injection group (200. Mu.L, 2mg/kg Ru), (E) HL-PEG2k injection group (200. Mu.L, 2mg/kg Ru), given 808nm laser irradiation. (B) Group (E) has a power density of 1W/cm for 12h after injection 2 The 808nm laser continuously irradiates the tumor for 5min. The length and width of the mouse tumor was measured with digital calipers every 4d throughout the treatment period (22 d). And tumor volume (mm 3) was calculated according to the following formula. Tumor volume = length × width 2 /2. Organs were isolated from the tumor model, fixed with tissue fixative and analyzed by HE staining.
FIG. 14 shows HL-PEG 2K The biocompatibility analysis of (1). Acute toxicity tests were performed by intravenous injection. PBS (200. Mu.L), HL-PEG were administered separately 2K (200. Mu.L, 2mg/kg Ru), cisplatin (200. Mu.L, 2mg/kg Pt), 3 per group. Mice were sacrificed after 7d of treatment and HE staining was observed for histopathological changes. PBS or HL-PEG 2k No obvious inflammatory lesions or injuries were observed in the group, while renal tubular epithelial cell edema, cytoplasma loosening or vacuolization was observed in the cisplatin group. In addition, biochemical markers were also analyzed to assess liver and kidney toxicity. ALP, ALT, AST and T-Bil of each group have no significant difference, but BUN (reflecting the sensitive index of renal insufficiency) of the cis-platinum group is reduced by about 6.49 times compared with that of the control group, which indicates that cisplatin causes severe renal insufficiency. And HLPEG 2k The treatment group has no abnormal index. ICR mice treated 3d after injection with 1mg/kg Ru and 2mg/kg Ru, respectively, had 3 weights per group, and recorded every 2d, with no statistical difference (P) from the control group>0.05). Studies have shown that HL-PEG2K has non-negligible toxicity and good pharmacokinetic properties.
Although the embodiments of the present invention have been shown and described, it should be understood that the above embodiments are illustrative and not restrictive, and that various changes, modifications, substitutions and alterations may be made therein by those skilled in the art without departing from the scope of the present invention.
Claims (15)
1. A phototherapeutic NIR-II small molecule according to formula 3:
2. a phototherapeutic NIR-II compound having the structure shown in formula 4,
wherein R1 and R2 are respectively and independently selected from-NH-PEG-OCH 3 Folic acid, iRGD, CREKA, oligopeptide PPSHTPT.
3. The phototherapeutic NIR-II compound of claim 2, wherein the structure of said phototherapeutic NIR-II compound is of formula H7-PEG 2K As shown in the drawings, the above-described,
4. a phototherapeutic NIR-II complex, wherein the structure of the phototherapeutic NIR-II complex is shown as formula 5,
r1 and R2 are respectively and independently selected from-NH-PEG-OCH 3 One of folic acid, iRGD, CREKA and oligopeptide PPSHTPT; r3 is selected from one of Ru and Ir; n and a are respectively and independently taken from 1, 2, 3 and 4; m is selected from Cl, SO 4 。
5. Phototherapeutic NIR-II complex according to claim 4, wherein the structure of the phototherapeutic NIR-II complex is of formula HL-PEG 2K As shown in the drawings, the first and second,
6. the phototherapeutic NIR-II complex of claim 4, wherein the phototherapeutic NIR-II complex self-assembles in water to form nanoparticles having an average particle size of 125 to 130nm.
7. The phototherapeutic NIR-II complex of claim 4, wherein the phototherapeutic NIR-II complex has a fluorescence emission wavelength of 1028nm.
8. Use of a phototherapeutic NIR-II small molecule according to claim 1 and/or a phototherapeutic NIR-II compound according to claim 2 and/or a phototherapeutic NIR-II complex according to claim 4 for the preparation of a near-infrared two-zone tumor imaging agent.
9. Use of a phototherapeutic NIR-II small molecule according to claim 1 and/or a phototherapeutic NIR-II compound according to claim 2 and/or a phototherapeutic NIR-II complex according to claim 4 for the preparation of an anti-tumor medicament.
10. A method for preparing a small phototherapeutic NIR-II molecule of claim 1, wherein said small phototherapeutic NIR-II molecule is prepared from compound 1, and the reaction formula for preparing said small phototherapeutic NIR-II molecule from compound 1 is as follows:
compound 1 preparation of the phototherapeutic NIR-II small molecule comprises the following steps:
step 1): taking compound 1,4, 7-dibromo-5, 6-dinitrodiazosulfide and K 2 CO 3 、Pd(PPh 3 ) 4 Adding the mixture into a reaction container, stirring the mixture in an oil bath at 100-130 ℃ for reaction under the protection of nitrogen, cooling the mixture after the reaction is finished, diluting the mixture with water, extracting the mixture with EA, and purifying the extract to obtain a mauve compound 2;
step 2): adding the compound 2 obtained in the step 1) into a mixed solvent of DCM and methanol, adding 95 (w/w)% of ammonium chloride and zinc powder, placing the mixture into a reaction vessel, reacting for 1-3 h at 20-30 ℃, filtering, washing a filter cake with DCM, and carrying out rotary drying on the filtrate to obtain a yellow crude product;
step 3): dissolving 1, 10-phenanthroline-5, 6-diketone and the yellow crude product obtained in the step 2) in acetic acid, adding the solution into a reaction container, refluxing in an oil bath at the temperature of 110-130 ℃ for 3-6H, cooling, concentrating to obtain a residue, and purifying to obtain a green solid compound, namely H7;
step 4): dissolving H7 in DCM at 0 ℃, slowly adding 1mL of TFA, adding the mixture into a reaction container, preserving at room temperature for 30min, and concentrating to obtain a compound 3, namely the light-treated NIR-II micromolecule.
11. The method for preparing phototherapy NIR-II small molecule as claimed in claim 10, wherein in step 2), the molar ratio of compound 2, ammonium chloride and zinc powder is 0.028.
12. A method of preparing a phototherapeutic NIR-II compound according to claim 2, wherein the phototherapeutic NIR-II compound is prepared from the phototherapeutic NIR-II small molecule of claim 1, and wherein the phototherapeutic NIR-II small molecule is prepared by the reaction of:
the preparation of the phototherapeutic NIR-II compounds by using the phototherapeutic NIR-II small molecules comprises the following steps: taking NH 2 PEG-OME or folic acid or iRGD or CREKA or oligopeptide PPSHTPT, DIPEA and HATU are added into the DMSO solution of the light-treated NIR-II micromolecule, stirred for 5 to 8 hours at the temperature of between 20 and 30 ℃, and purified to obtain the light-treated NIR-II compound.
13. A process for the preparation of a phototherapeutic NIR-II compound of claim 12 wherein NH 2 -the molar ratio of PEG-OME or folic acid or iRGD or CREKA or oligopeptide PPSHTPT, DIPEA, HATU is 0.028.
14. A method of preparing a phototherapeutic NIR-II complex according to claim 4, wherein the phototherapeutic NIR-II complex is prepared from the phototherapeutic NIR-II compound according to claim 2, wherein the phototherapeutic NIR-II compound is prepared as follows:
the preparation of the phototherapeutic NIR-II complex from the phototherapeutic NIR-II compound comprises the following steps: applying said photo-therapeutic NIR-II compound, ru (bpy) 2 Cl 2 Or Ru (II) -bis (4, 4'-dimethyl-2,2' -dipyridine) or Ru (phen) 2 Cl 2 Or Ru (dppz) 2 Cl 2 Or cis- [ Ir (2, 2' -dipyridine) 2 D 2 ]PF 6 Placing the mixture into a reaction container, adding 40-60 (v/v)% of methanol, refluxing for 8-10 hours at 80-100 ℃, and concentrating the reaction solution after the reaction is finishedObtaining a residue and purifying the residue to obtain the light-treated NIR-II complex.
15. A method of preparing a phototherapeutic NIR-II complex of claim 14, wherein the phototherapeutic NIR-II compound is reacted with Ru (bpy) 2 Cl 2 Or Ru (II) -bis (4, 4'-dimethyl-2,2' -dipyridine) or Ru (phen) 2 Cl 2 Or Ru (dppz) 2 Cl 2 Or cis- [ Ir (2, 2' -dipyridine) 2 D 2 ]PF 6 Is 1.
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