Metal compound capable of improving stability and preparation method and application thereof

Abstract

The invention belongs to the field of drug preparation and drug delivery, and particularly relates to a metal compound capable of improving stability and a preparation method and application thereof. A pyridine group is introduced on the basis of the BODIPY diplatinum ligand F1, the conjugation characteristic of the pyridine group can enhance the molecular stability of the metal ring, and the electron-withdrawing characteristic of the pyridine group is also beneficial to enhancing the light absorption capacity of the metal ring.

Description

Technical Field

[0001] The present invention belongs to the fields of drug preparation and drug delivery, and particularly relates to a metal compound capable of improving stability, a preparation method thereof, and an application thereof. Background Art

[0002] Traditional drugs have defects such as poor therapeutic effects, insufficient targeting, and large side effects. Constructing nanoparticles with a drug encapsulated in a biomembrane can effectively solve this problem and reduce immune responses and toxic side effects in the body. Due to the presence of specific receptors, it has specific targeting, so nanoparticles can selectively target diseased tissues or cells, improving the drug delivery efficiency and therapeutic effect.

[0003] Supramolecular Coordination Compounds (SCCs) are supramolecular structures with definite structures and functions formed through the coordination between organic ligands and metal ions. These complexes usually have exquisite structures and show broad application prospects in fields such as catalysis, molecular recognition, drug delivery, and biomedical diagnosis and treatment. Especially in biomedicine, it shows great potential. It can integrate metal drugs and organic ligands in one system to achieve integrated diagnosis and treatment while reducing side effects.

[0004] Boron-dipyrromethene (BODIPY) fluorescent dyes have been widely used in fields such as biomedical research, bioimaging, and photodynamic therapy due to their excellent photochemical and physical properties, such as high molar extinction coefficient, high fluorescence quantum yield, stable spectral properties, narrow fluorescence spectral peak width, good photothermal stability and chemical stability, low toxicity, good biocompatibility, and derivatization and functionalization capabilities.

[0005] Chinese patent document with the publication number CN118388516A discloses an amphiphilic platinum-containing triangular macrocyclic molecule constructed by supramolecular self-assembly, a preparation method thereof, and an application thereof. This amphiphilic platinum-containing triangular macrocyclic molecule is obtained by a self-assembly reaction of a BODIPY-based bipyridine ligand with a coordination angle of 180° and a double-platinum receptor with a coordination angle of 60° in an organic solvent system under stirring. A bipyridine ligand is assembled on the pyridine BODIPY core, and then Pt atoms are introduced. The photothermal conversion efficiency of M1 NPs (nanoparticles obtained by assembling a bipyridine ligand on the pyridine BODIPY core) is 37.91%, and the photothermal conversion efficiency of Mc NPs (nanoparticles obtained by assembling a bipyridine ligand on the pyridine BODIPY core and then introducing Pt atoms) is 34.70%. That is, the photothermal efficiency decreases after introducing Pt atoms. Summary of the Invention

[0006] The object of the present invention is to provide a metal compound capable of improving stability, and its preparation method and application.

[0007] To achieve the above object, in the first aspect of the present invention, the following solution is adopted: A fluoroboron dipyrrole-based bis-platinum ligand, the structural formula is as shown in F1:

[0008]

[0009] In the second aspect of the present invention, a preparation method of a fluoroboron dipyrrole-based bis-platinum ligand is disclosed, including the following steps:

[0010] Add 1-bromooctane, potassium carbonate, potassium iodide, and acetonitrile to p-hydroxybenzaldehyde and reflux at 75 - 85 °C for 10 - 14 h, then add trifluoroacetic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), triethylamine (Et 3 N), boron trifluoride diethyl ether (BF 3 .Et 2 O) and react to obtain Compound 1;

[0011] Add iodine and aqueous iodine acid solution to Compound 1 and react for 7 - 9 h, and obtain Compound 2 after purification;

[0012] Add N,N-diethyl-4-aminobenzaldehyde, piperidine, and acetic acid to Compound 2, use toluene as a solvent and react at 110 - 125 °C for 11 - 13 h to obtain Compound 3;

[0013] Add copper(I) iodide (CuI), tetrakis(triphenylphosphine)palladium Pd(PPh 3 ) 4 , trimethylsilylacetylene to Compound 3, and use Et 3 N as a solvent and react at 45 - 55 °C for 5 - 6 h to obtain Compound 4;

[0014] Add tetrahydrofuran (THF) as a solvent to Compound 4, add tetrabutylammonium fluoride at -75 ~ -80 °C and react for 30 min - 45 min to obtain Compound 5;

[0015] Add Pt(PEt 3 ) 2 I 2 , copper(I) iodide (CuI) to Compound 5, use THF as a solvent, add Et 3 N at -75 ~ -80 °C and stir for 0.5 - 1.5 h, then stir at room temperature overnight to obtain Compound 6;

[0016] Add silver nitrate to Compound 6, use dichloromethane as a solvent, stir and react under an ice-water bath for 18 - 20 h, remove the solvent to obtain Compound F1.

[0017] The third aspect of the present invention is to provide a metal compound that can improve stability. The structure of the compound is as shown in M1:

[0018]

[0019] The fourth aspect of the present invention discloses a preparation method of a metal compound that can improve stability, including the following steps:

[0020] 1) Preparation of the aforementioned fluoroboron dipyrrolyl double platinum ligand F1;

[0021] 2) Preparation of the bipyridine receptor S1 with a coordination angle of 60°;

[0022]

[0023] 3) Preparation of a metal compound that can improve stability by coordinative self-assembly of the fluoroboron dipyrrolyl double platinum ligand F1 and the bipyridine receptor S1:

[0024] Dissolve the fluoroboron dipyrrolyl double platinum ligand F1 and the bipyridine receptor S1 in dimethyl sulfoxide (DMSO) according to a molar ratio of 1:3 - 3.5, react at 63 - 68 °C for 3 - 5 h, adjust the polarity ratio with a mixed solution of dichloromethane and petroleum ether, and wash away the fluoroboron dipyrrolyl double platinum ligand F1 and the bipyridine receptor S1 with a polarity gradient of the volume ratio of dichloromethane to petroleum ether = 1:40, 1:36, 1:32, 1:28, 1:24, 1:20 respectively to obtain the metal compound M1 that can improve stability.

[0025] Furthermore, in step 2), the preparation process of the bipyridine receptor S1 is as follows:

[0026] Add 3,6-dibromophenanthrene-9,10-dione to a mixed solution of tetrahydrofuran (THF) and water, add sodium dithionite (Na 2 S 2 O 4 ) and stir for 20 - 30 min. After extraction, a pale white solid substance is obtained, and then add potassium carbonate and 1-bromooctane, and reflux and react at 110 - 130 °C for 8 - 12 h to obtain compound a;

[0027] Add 4-ethynylpyridine, Pd(PPh 3 ) 4 and CuI to compound a, use triethylamine (Et 3 N) as the solvent, stir and react at 45 - 55 °C for 20 - 28 h to obtain compound S1.

[0028] The fifth aspect of the present invention discloses a photothermal agent, including the aforementioned metal compound M1 that can improve stability.

[0029] Preferably, it is formed by self-assembly of a metal compound M1 (abbreviated as metal ring M1) that can improve stability and an amphiphilic block copolymer PEG-PLA in a solvent in a mass ratio of 1:7-9.

[0030] The fifth aspect of the present invention is to provide an application of a metal compound that can improve stability in the preparation of an anti-cancer phototherapeutic agent, or in the preparation of a phototherapeutic agent that improves photostability, photothermal conversion efficiency, absorption wavelength, or cell uptake ability.

[0031] The present invention obtains an amphiphilic platinum-containing triangular macrocyclic molecule through coordination-driven self-assembly of a fluoroboron dipyrrole-based bisplatinum ligand with a 180° coordination angle and a bipyridine receptor with a coordination angle of 60°.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] 1) Based on the fluoroboron dipyrrole-based bisplatinum ligand F1, the present invention introduces a pyridine group. Compared with the prior art, its conjugated property can enhance the molecular stability of the metal ring (under the excitation irradiation of a laser with a wavelength of 808 nm and a power of 1.5 W / cm 2 , there is no obvious change in the ultraviolet absorption under continuous irradiation for 14 minutes, proving its photostability). Its electron-withdrawing property is also beneficial to enhancing the light absorption ability of the metal ring. The absorption wavelength of the metal ring in the present invention redshifts to more than 900 nm.

[0034] In the prior art, a BODIPY-pyridine ligand is usually used to combine with a platinum-containing receptor to prepare a supramolecular coordination complex, while the combination method of a BODIPY-bisplatinum ligand and a bipyridine receptor has not been reported. The connection method between the receptor and the ligand synergistically affects the overall properties of the compound. After the connection method is changed, the electron delocalization changes spatially, and the electronic structure, photophysical properties, chemical reactivity, and spatial structure of the compound change significantly; the electron-withdrawing effect of the receptor and the electron-donating effect of the ligand will jointly regulate the electron distribution of the BODIPY core and the platinum center, thereby affecting the energy difference between HOMO and LUMO; this change may affect its application performance in the fields of photosensitive materials, photocatalysis, or photodynamic therapy, and even make it unable to be used as a photosensitive material or for photodynamic therapy. Therefore, the change in the connection method poses technical challenges to the synthesis, electronic structure, photophysical properties, spatial structure, characterization, and verification of the compound.

[0035] 2) The introduction of the biomimetic membrane can enhance the targeting ability of the nanoparticles to the target and show enhanced photothermal therapy performance in phototherapy.

[0036] 3) In CN118388516A, the absorption wavelength is about 770 nm. Due to the short wavelength, the tissue penetration depth and light energy utilization rate are limited. In the present invention, the absorption wavelength of the metal ring is redshifted to over 900 nm, which can enhance the tissue penetration depth of treatment, improve the light energy utilization rate, and enhance the treatment effect.

[0037] 4) In CN118388516A, the photothermal conversion efficiency of M1 NPs is 37.91%, and that of Mc NPs is 34.70%. That is, after introducing Pt atoms, the photothermal conversion efficiency decreases instead. In the present invention, the photothermal conversion efficiency of M1 NPs is better than that of F1 NPs, and the photothermal conversion efficiency of M1 NPs is 48.35%, which is significantly higher than 34.70%.

[0038] 5) In CN118388516A, the particle size of the nanoparticles is close to 200 nm. In the present invention, the particle size of the nanoparticles is 160 nm. The nanoparticles prepared in the present invention have a smaller size and improved cell uptake ability. In the present invention, there is a change in the position of Pt-N coordination in the structure of M1. Due to the change in the charge distribution density of the molecular system after exchange, the size of the nanoparticles prepared is smaller.

[0039] 6) When synthesizing compound 6, the conventional method is to directly add silver trifluoromethanesulfonate and then stir for reaction. However, the present invention finds that compound 6 cannot be prepared by this method. After the reaction ends, there is an obvious color change of compound decomposition after a period of time. This is because compound 5 has a large steric hindrance in its structure, resulting in difficulty in the reaction between compound 5 and silver trifluoromethanesulfonate and significant influence of light on it after partial successful reaction, leading to its decomposition. It is impossible to obtain a compound 6 with high purity under normal temperature and light conditions. Therefore, the present invention improves the preparation method by replacing silver trifluoromethanesulfonate with silver nitrate and reacting in a brown bottle under nitrogen gas, and the reaction conditions are carried out in an ice bath.

[0040] 7) When synthesizing compound M1, the conventional method is to react the receptor and the ligand in equal amounts to complete the preparation, and the yield is relatively high. In the present invention, when using the conventional method for preparation, there are problems of low yield and poor reactivity. It is necessary to feed the ligand F1 and the receptor S1 in a molar ratio of 1:3 or more, and control the temperature at about 65 °C. However, this makes the metal ring M1 and the unreacted receptor S1 present in the DMSO system, and the separation is relatively difficult. If column chromatography is used for separation, the product loss is extremely large. The present invention adjusts the solvent polarity ratio, continuously separates the receptor S1 with small polarity, and determines whether the separation is complete by spotting plates, and adjusts the solvent polarity and monitors by spotting plates to obtain a relatively pure M1. Description of the Drawings

[0041] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for the embodiments will be briefly introduced below. It should be understood that the following accompanying drawings only show some schematic diagrams of the embodiments of the present invention, and therefore should not be regarded as a limitation of the scope;

[0042] Figure 1 Dynamic light scattering and transmission electron microscopy images of M1 NPs;

[0043] Figure 2 Dynamic light scattering and transmission electron microscopy images of BM1 NPs;

[0044] Figure 3 Temperature change and cooling situation of 20 mg / L F1 NPs irradiated at 808 nm, 1 W / cm 2 for 10 min and cooled for 20 min;

[0045] Figure 4 Temperature change and cooling situation of 20 mg / L M1 NPs irradiated at 808 nm, 1 W / cm 2 for 10 min and cooled for 20 min;

[0046] Figure 5 UV absorption change of 2 mg / L F1 NPs and DPBF under laser irradiation at 808 nm, 100 mW / cm 2 conditions;

[0047] Figure 6 UV absorption change of 2 mg / L M1 NPs and DPBF under laser irradiation at 808 nm, 100 mW / cm 2 conditions;

[0048] Figure 7 Schematic diagram of cell viability of M1 NPs and BM1 NPs;

[0049] Figure 8 Live and dead cell staining images of M1 NPs and BM1 NPs in MTT experiments;

[0050] Figure 9 Schematic diagram of the results of the photostability determination of M1 NPs and F1 NPs, A, M1 NPs; B, F1 NPs;

[0051] Figure 10 Test result diagram of the cell uptake experiment of BM1 NPs and BF1 NPs;

[0052] Figure 11 Schematic diagram of the TLC detection of Process 3 in Comparative Example 2. Detailed implementation manners

[0053] In order to make the objectives, technical solutions and advantages of the present invention clearer, the following further details the present invention in conjunction with embodiments. Of course, the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0054] Unless otherwise specified, the chemical reagents and materials in the present invention are all purchased through market channels or synthesized from raw materials purchased through market channels.

[0055] Example 1

[0056] Step 1: Preparation of BODIPY-based bis-platinum ligand F1

[0057]

[0058] Synthesis method of Compound 1: Add 1 g (8.2 mmol) of p-hydroxybenzaldehyde, 14 mL (82 mmol) of 1-bromooctane, 4 mg (1.8 mmol) of k 2 CO 3 , 0.07 mg (0.03 mol) of potassium iodide, and finally add 150 mL of acetonitrile as a solvent. Reflux under condensation at 80 °C for 12 h. After the reaction is completed, spin-dry the solvent to obtain the product. Under the action of nitrogen, add dichloromethane (50 mL) and 2,4-dimethylpyrrole (4.5 g, 25.5 mmol) to the product to obtain a mixture. Drop trifluoroacetic acid (126 μL, 1.7 mmol) into the mixture. After stirring in an ice bath for 1 hour, add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DDQ (2.3 g, 10.2 mmol), and stir at room temperature for another 1 h. Then add triethylamine Et 3 N (12 mL, 85 mmol) and BF 3 ·Et 2 O (21.5 mL, 170 mmol), stir in an ice bath for 12 h, wash the reaction mixture with dichloromethane, dry with anhydrous sodium sulfate, and purify the mixture by column chromatography with PE / CH 2 Cl 2 (4 / 1, v / v) to obtain a dark red solid compound 1 (1.85 g, yield 42.85%). 1 H NMR (500 MHz, CDCl 3)δ 7.12 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 5.99 (s, 2H), 4.00 (t, J = 6.6 Hz, 2H), 2.55 (s, 6H), 1.84 - 1.79 (m, 2H), 1.52 - 1.47 (m, 2H), 1.44 (s, 6H), 1.41 - 1.30 (m, 8H), 0.94 (t, J = 6.9 Hz, 3H).

[0059] Synthesis method of compound 2: Dissolve compound 1 (100 mg, 0.2 mmol) and I 2 (60 mg, 0.24 mmol) in 30 mL of a mixed solution of CH 3 CH 2 OH and THF (2 / 1, v / v). Slowly add 2 mL of an aqueous solution of iodic acid (80 mg, 0.24 mol) and stir for 8 h. Wash and extract the mixture with CH 2 Cl 2 and purify by filtration with PE / CH 2 Cl 2 to obtain compound 2 (139.5 mg, yield 92%). 1 1H NMR (400 MHz, Chloroform-d) δ 7.12 - 7.09 (m, 2H), 7.04 - 7.00 (m, 2H), 4.02 (t, J = 6.6 Hz, 2H), 2.64 (s, 6H), 1.83 (p, J = 6.7 Hz, 2H), 1.55 - 1.46 (m, 2H), 1.45 (s, 6H), 1.42 - 1.16 (m, 6H), 0.93 - 0.88 (m, 3H).

[0060] Synthesis method of compound 3: Add compound 2 (100 mg, 0.13 mmol) and N,N-diethyl-4-aminobenzaldehyde (59 mg, 0.39 mmol) to a 100 mL Schlenk flask. Use 20 ml of anhydrous toluene as the solvent. Under nitrogen protection, add acetic acid (0.6 mL) and piperidine (0.6 mL) dropwise. Condense and reflux at 120 °C for 12 h. After extracting the product with dichloromethane and water, evaporate the solvent. Purify by column chromatography with PE / CH 2 Cl 2 to obtain a brown product e (34 mg, yield 24.29%). 1HNMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 16.5 Hz, 2H), 7.59 - 7.49 (m, 6H), 7.17 - 7.10 (m, 2H), 7.05 - 6.97 (m, 2H), 6.70 (d, J = 8.6 Hz, 4H), 4.03 (t, J = 6.6 Hz, 2H), 3.43 (q, J = 7.1 Hz, 8H), 1.84 (p, J = 6.8 Hz, 2H), 1.59 (s, 6H), 1.38 - 1.30 (m, 10H), 1.21 (t, J = 7.0 Hz, 12H), 0.92 - 0.89 (m, 3H).

[0061] Synthesis method of Compound 4: Add Compound 3 (100 mg, 0.098 mol), CuI (2 mg, 0.01 mmol), and Pd(PPh 3 ) 4 (7.6 mg, 0.07 mmol) into a 50 mL Schlenk flask, and then add THF (10 mL), triethylamine Et 3 N (10 mL), and trimethylsilylacetylene (35 mg, 0.05 mmol). Freeze-pump-thaw 3 times under nitrogen protection, and then react the resulting solution at 50 °C for 5 h. Extract the reaction mixture with dichloromethane, dry it over anhydrous sodium sulfate, and concentrate it under reduced pressure. Purify it by column chromatography with PE / CH 2 Cl 2 (2 / 1, v / v) to obtain brown solid Compound 4 (30.8 mg, yield 72%). 1 H NMR (500 MHz, Chloroform-d) δ 8.40 (d, J = 16.2 Hz, 2H), 7.64 - 7.52 (m, 7H), 7.18 - 7.11 (m, 2H), 7.03 - 6.96 (m, 2H), 6.73 - 6.67 (m, 4H), 4.02 (t, J = 6.6 Hz, 2H), 3.43 (q, J = 7.1 Hz, 8H), 1.84 (q, J = 7.6, 7.1 Hz, 2H), 1.58 (s, 2H), 1.55 (s, 6H), 1.55 - 1.45 (m, 2H), 1.44 - 1.24 (m, 6H), 1.22 (t, J = 7.1 Hz, 12H), 0.94 - 0.87 (m, 3H), 0.27 (s, 18H). 1313C NMR (126 MHz, Chloroform-d) δ 152.40, 148.48, 144.87, 139.09, 132.57, 129.73, 129.48, 124.52, 114.85, 113.93, 112.81, 111.39, 103.00, 99.92, 77.11, 68.09, 44.42, 31.72, 29.30, 29.14, 25.97, 22.56, 14.02, 13.18, 12.60. 19 19F NMR (471 MHz, CDCl 3 ) δ -145.56, -145.63, -145.70, -145.77.

[0062] Synthetic method of Compound 5: Add Compound 4 (200 g, 1.9 mmol) into a 50 mL Schlenk flask, use 20 mL of THF as the solvent, and slowly add TBAF (1.2 mL, 1.2 mol) at -78 °C under nitrogen conditions and react for 35 min. After completion, extract with dichloromethane, dry with anhydrous sodium sulfate, and purify by column chromatography with PE / CH 2 Cl 2 (2 / 1, v / v) to obtain Compound 5 as a brownish solid (62.9 mg, yield 37%). 1 1H NMR (500 MHz, Chloroform-d) δ 8.32 (d, J = 16.2 Hz, 2H), 7.62 - 7.51 (m, 6H), 7.21 - 7.12 (m, 2H), 7.04 - 6.97 (m, 2H), 6.72 - 6.66 (m, 4H), 4.03 (t, J = 6.6 Hz, 2H), 3.42 (q, J = 7.1 Hz, 8H), 1.83 (p, J = 6.7 Hz, 2H), 1.59 (s, 7H), 1.55 (s, 6H), 1.42 - 1.24 (m, 7H), 1.21 (t, J = 7.1 Hz, 12H), 0.94 - 0.85 (m, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 152.68, 148.66, 145.59, 139.29, 132.59, 129.82, 129.73, 124.51, 115.06, 113.84, 111.85, 111.47, 85.68, 77.23, 68.23, 44.54, 31.83, 29.43, 29.28, 29.26, 26.08, 22.68, 14.13, 13.19, 12.71. 19 19F NMR (471 MHz, CDCl 3)δ - 139.15, - 139.22, - 139.29, - 139.36.

[0063] Synthesis method of Compound 6: Add Compound 5 (200 mg, 0.24 mmol), Pt(PEt 3 ) 2 I 2 (534 mg, 0.78 mmol), CuI (5 mg, 0.024 mmol) and 10 mL of THF into a 50 mL Schlenk flask. Freeze - pump - thaw three times under N 2 protection, add 10 mL of triethylamine at - 78 °C, stir the reaction for 1 h, and stir overnight at room temperature. Purify by column chromatography with PE / EA (5 / 1, v / v) to obtain brown solid Compound 6 (300.73 mg, yield 66%). 1 H NMR (500 MHz, Chloroform - d) δ 8.73 (s, 2H), 7.72 - 7.43 (m, 7H), 7.18 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 6.65 (d, J = 7.3 Hz, 4H), 4.01 (t, J = 6.7 Hz, 2H), 3.40 (qt, J = 14.2, 8.2, 7.5 Hz, 9H), 2.28 - 2.04 (m, 24H), 1.82 (p, J = 6.9 Hz, 2H), 1.49 (d, J = 14.0 Hz, 10H), 1.31 (dd, J = 18.2, 8.1 Hz, 6H), 1.20 (t, J = 7.0 Hz, 12H), 1.11 (p, J = 8.0 Hz, 36H), 0.90 (t, J = 6.8 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 190.16, 189.97, 159.39, 153.47, 152.24, 148.12, 132.26, 130.43, 130.14, 129.34, 125.33, 124.59, 115.16, 114.66, 112.00, 111.69, 111.41, 111.31, 110.57, 110.16, 77.37, 77.12, 76.91, 76.86, 68.14, 53.68, 44.67, 44.50, 37.81, 31.84, 31.73, 31.46, 30.22, 29.72, 29.44, 29.38, 29.36, 29.26, 26.13, 22.69, 16.75, 16.61, 16.47, 14.48, 14.16, 12.88, 12.74, 12.65, 12.50, 8.43, 8.28, 8.13. 31P NMR (162 MHz, CDCl 3 ) δ 15.97, 8.76, 1.60.

[0064] Synthesis method of compound F1: Add compound 6 (20 mg, 0.01 mmol) and AgNO 3 (1.69 mg, 0.01 mmol) into a 10 mL vial, and then add about 9 mL of ultradry dichloromethane. Wrap the vial completely with tin foil to prevent light, stir the reaction for 20 h under an ice-water bath condition, filter out the precipitate through a glass fiber filter under a light-free condition, then dry the filtrate under a nitrogen flow to obtain light brown solid compound F1 (19.46 mg, 95%), and store it refrigerated (0 - 4 °C) under dark conditions and in a nitrogen atmosphere. 1 H NMR (500 MHz, Chloroform-d) δ 8.66 (d, J = 16.3 Hz, 2H), 7.48 (dd, J = 54.0, 12.3 Hz, 6H), 7.10 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 7.9 Hz, 2H), 6.58 (d, J = 8.4 Hz, 4H), 3.93 (t, J = 6.8 Hz, 2H), 3.33 (q, J = 8.0 Hz, 8H), 1.75 (p, J = 7.1 Hz, 2H), 1.40 (s, 10H), 1.33 - 1.15 (m, 6H), 1.03 (p, J = 8.0 Hz, 36H), 0.81 (d, J = 8.7 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 190.16, 189.97, 159.39, 153.47, 152.24, 148.12, 132.26, 130.43, 130.14, 129.34, 125.33, 124.59, 115.16, 114.66, 112.00, 111.69, 111.41, 111.31, 110.57, 110.16, 77.37, 77.12, 76.91, 76.86, 68.14, 53.68, 44.67, 44.50, 37.81, 31.84, 31.73, 31.46, 30.22, 29.72, 29.44, 29.38, 29.36, 29.26, 26.13, 22.69, 16.75, 16.61, 16.47, 14.48, 14.16, 12.88, 12.74, 12.65, 12.50, 8.43, 8.28, 8.13. 31 P NMR (162 MHz, CDCl 3 ) δ 15.91, 8.73, 1.58.

[0065] Step 2: Preparation of S1

[0066]

[0067] Synthetic method of compound a: Add 3,6-dibromophenanthrene-9,10-dione (9 g, 24.5 mmol) into 500 mL of THF / water (1:1, v / v). After stirring vigorously, slowly add Na 2 S 2 O 4 (25 g, 143 mmol) to this orange suspension. Stir the mixture under a nitrogen atmosphere for 30 min, quench with a large amount of water and then extract with ethyl acetate. Wash the organic layer with water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a pale white powder. Quickly mix the pale white powder solid with potassium carbonate (10 g, 72.5 mmol) in DMF (120 mL) under a nitrogen atmosphere, and add 1-bromobutane (15 mL, 110 mmol). Heat the reaction mixture to reflux at 120 °C for 10 h, then pour it into water and extract with dichloromethane. Wash with water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography using PE / CH 2 Cl 2 (10 / 1, v / v) as the eluent to obtain the white solid product compound a (8.05 g, yield 68.4%). 1 H NMR (500 MHz, Chloroform-d) δ 8.51 (s, 2H), 8.00 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 4.14 (t, J = 6.6 Hz, 4H), 1.91 (d, J = 7.3 Hz, 3H), 1.66 (h, J = 7.5 Hz, 4H), 1.52 (d, J = 7.6 Hz, 0H), 1.12 (t, J = 7.5 Hz, 6H).

[0068] Synthetic method of compound S1: Add compound a (0.9 mmol, 430 mg), 4-ethynylpyridine (3.8 mmol, 390 mg), Pd(PPh 3 ) 4 (0.1 mmol, 110 mg), and copper(I) iodide (0.06 mmol, 12 mg) into a 50 mL Schlenk flask. Add 30 mL of Et 3 N, and repeatedly freeze-pump-thaw 3 times under nitrogen conditions. Stir the reaction mixture at 50 °C for 24 h under nitrogen protection. Remove the solvent under reduced pressure, wash and extract with water and dichloromethane, and dry over anhydrous sodium sulfate. Rotavap the solvent and dissolve it in CH 3The desired brown solid product Compound S1 (339.7 mg, yield 72%) was obtained by purification of OH / PE (1 / 50, v / v) through column chromatography. 1 H NMR (500 MHz, Chloroform-d) δ 8.44 (s, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.17 (t, J = 6.7 Hz, 4H), 2.28 (ddq, J = 11.5, 7.9, 3.8 Hz, 24H), 1.90 - 1.83 (m, 4H), 1.59 (q, J = 7.5 Hz, 4H), 1.22 (h, J = 7.8, 7.0 Hz, 38H), 1.01 (t, J = 7.4 Hz, 6H).

[0069]

[0070] Step 3: Preparation of M1

[0071] Synthesis method of Compound M1

[0072] Dissolve F1 (6.4 mg, 66 μmol) and S1 (30 mg, 198 μmol) in 1.5 mL DMSO, stir at 65 °C for 4 h, adjust the polarity ratio with a mixed solution of dichloromethane and petroleum ether, and wash away DMSO and Compound S1 with a polarity gradient of (V1 / V2, DCM / PE = 1:40, 1:36, 1:32....1:20) respectively. The specific method is to first add 10 mL of the mixed solution of dichloromethane and petroleum ether (V1 / V2, DCM / PE = 1:40) to the reaction solution bottle of 1.5 mL DMSO. After centrifuging for 2 min with a low-speed centrifuge (3000 r / min), it is found that M1 is basically insoluble in this mixed solvent, F1 is slightly soluble in this solvent, and S1 can be mostly dissolved in this solvent system. At this time, after sucking the solvent with a pipette, continue to increase the ratio of dichloromethane to petroleum ether, and repeat the above operation with (V1 / V2, DCM / PE = 1:36) until F1 and S1 are completely washed away (specifically, add 10 mL of the mixed solution of dichloromethane and petroleum ether (V1 / V2, DCM / PE = 1:36), centrifuge at 3000 r / min for 2 min, suck the solvent with a pipette, and then continue to increase the ratio of dichloromethane to petroleum ether, and so on. M1 and F1 have a large difference in molecular polarity. By adjusting the polarity, the more polar M1 cannot be dissolved in the new solvent system, while F1 and S1 can be dissolved in the new solvent system, thus enabling the washing away of F1 and S1). Finally, during the process, silica gel plate spotting is used to detect whether S1 and F1 are completely washed away, and finally Compound M1 (13.6 mg, yield 94%) is obtained.

[0073] 11H NMR (CDCl3, 500 Hz) δ: 9.09 (s, 6H), 8.55 - 7.98 (m, 18H), 7.58 (d, J = 7.9 Hz, 6H), 7.36 - 6.68 (m, 36H), 4.16 - 4.06 (m, 18H), 3.42 (m, 12H), 3.17 (t, J = 8.2 Hz, 6H), 2.68 (t, J = 7.1 Hz, 6H), 2.46 - 2.39 (m, 12H), 2.12 (s, 18H), 1.72 - 1.12 (m, 132H), 0.96 (t, J = 8 Hz, 126H), 0.88 (t, J = 7.62 Hz, 9H). 31 31P NMR (202 MHz, CDCl3) δ 21.38, 15.72, 9.96.

[0074] Synthesis of Comparative Example 1 F1

[0075] Process Method 1: Prepared by feeding Compound 6 and silver trifluoromethanesulfonate in an equivalent ratio of 1:1. Dissolve Compound 6 (20 mg) and silver trifluoromethanesulfonate (2.57 mg) in 9 mL of dichloromethane, stir and react at room temperature for 12 h. After the reaction, it is a brown system. Filter out the white precipitate with a glass fiber filter, and then blow dry the solvent in the filtrate with flowing nitrogen. After about 30 min, the brown solid turns green, F1 deteriorates, and the reaction fails. This method is not feasible (method reference: existing literature DOI: 10.1021 / acs.macromol.4c01689).

[0076] Process Method 2: Prepared by feeding Compound 6 and silver trifluoromethanesulfonate in an equivalent ratio of 1:1. Dissolve Compound 6 (20 mg) and silver trifluoromethanesulfonate (2.57 mg) in 9 mL of tetrahydrofuran, stir and react at room temperature for 12 h. After the reaction, it is a brown system. Filter out the white precipitate with a glass fiber filter, and then blow dry the solvent in the filtrate with flowing nitrogen. The solvent volatilizes slowly, and the system turns green during the solvent evaporation process.

[0077] Process Method 3: Prepared by feeding Compound 6 and silver nitrate in an equivalent ratio of 1:1. Dissolve Compound 6 (20 mg) and AgNO 3 (1.69 mg, 0.01 mmol) in 9 mL of dichloromethane, stir and react at room temperature for 12 h. After the reaction, it is a brown system. Filter out the white precipitate with a glass fiber filter, and then blow dry the solvent in the filtrate with flowing nitrogen. It turns slightly colored within 4 hours at room temperature, and the sample is severely damaged within 24 hours. It is proved that whether the reaction is protected from light and the storage method have a great impact on the sample.

[0078] Synthesis of Comparative Example 2 M1

[0079] Process 1: F1 (6.4 mg, 66 μmol) and S1 (10 mg, 66 μmol) were fed in a 1:1 equivalent ratio for reaction. Specifically, F1 and S1 were dissolved in 1.5 mL of acetone as the solvent and stirred at 50 °C for 4 h. S1 is a brown solid and slightly soluble in acetone. After stirring, some undissolved S1 could still be seen, making it impossible to determine the reaction amount and difficult to separate.

[0080] Process 2: F1 (6.4 mg, 66 μmol) and S1 (10 mg, 66 μmol) were fed in a 1:1 equivalent ratio for reaction and dissolved in 1.5 mL of DMSO. Both F1 and S1 are soluble in DMSO (synthesis method reference: DOI: 10.1021 / jacs.8b04929). The reaction was stirred at 50 °C for 4 h. After stirring, the reactants were taken and detected by silica gel plate. Three substance spots were found, two of which corresponded to the polar spots of F1 and S1, indicating incomplete reaction. The reaction time was extended to 8 h, but the reaction was still incomplete.

[0081] Process 3: F1 (6.4 mg, 66 μmol) and S1 (30 mg, 198 μmol) were fed in a 1:3 equivalent ratio for reaction. At 50 °C, 1.5 mL of DMSO was used as the solvent and stirred for 4 h. The reactants were taken and detected by silica gel plate, still showing unreacted F1 and S1. As Figure 11 shown.

[0082] Example 2

[0083] Preparation of biomimetic nanoparticles:

[0084] Under normal temperature conditions, metal ring M1 (1 mg) was dissolved in 0.5 mL of THF, and amphiphilic block copolymer mPEG-PLA with a molecular weight of 20k purchased from Xi'an Kaixin Biotech Co., Ltd. (8 mg) was dissolved in 20 mL of water. Under stirring conditions, the THF solution of metal ring M1 was slowly added dropwise to the aqueous solution of mPEG-PLA and stirred until THF was completely volatilized (the volatilization of THF can be judged by smelling). The aqueous solution of nanoparticles with the solvent volatilized was dried in a freeze dryer to obtain M1 nanoparticles M1 NPs. F1 NPs were prepared in the same way.

[0085] Preparation of F1 NPs: F1 (1 mg) was dissolved in 0.5 mL of THF, and amphiphilic block copolymer mPEG-PLA with a molecular weight of 20k (8 mg) was dissolved in 20 mL of water. Under stirring conditions, the THF solution of F1 was slowly added dropwise to the aqueous solution of mPEG-PLA and stirred until THF was completely volatilized. The aqueous solution of nanoparticles with the solvent volatilized was dried in a freeze dryer to obtain F1 nanoparticles F1 NPs.

[0086] Extract the cell membrane of A549 cells (human alveolar basal epithelial cells of lung cancer) and count the membrane proteins (the method is to freeze-thaw the cells, add liquid nitrogen and freeze-thaw repeatedly to break the cells, and then obtain the crude component containing membrane proteins through gradient centrifugation; add protease inhibitors, and then obtain the membrane component through differential centrifugation). The membrane proteins are stored in a refrigerator at -78 °C. Take 10 mg of M1 NPs and 0.5 mg of A549 cell membrane proteins, and mix them according to the mass ratio of M1 NPs to A549 cell membrane of 20:1. The mixture is repeatedly extruded 30 times in a special extruder at room temperature to obtain biomimetic membrane nanoparticles BM1 NPs.

[0087] Example 3

[0088] Dissolve M1 NPs and BM1 NPs in deionized water respectively, filter out larger impurities through a 1 μm filter head, and measure the particle size of M1 NPs to be about 92 nm and that of BM1 NPs to be about 160 nm under a dynamic light scattering particle size analyzer ( Figure 1 、 2 on the right side). Judging from the measured results, the particle size of M1 NPs becomes significantly larger after being modified with the biomimetic membrane, which proves the successful preparation of the biomimetic membrane.

[0089] Dissolve M1 NPs and BM1 NPs in deionized water respectively, take a little and drop it on a copper sheet, dry the water in an oven at 50 °C, and observe the nanoparticle size under a transmission electron microscope ( Figure 1 、 2 on the left side). Judging from the observation results, it is consistent with the results measured by the dynamic light scattering particle size analyzer.

[0090] Example 4

[0091] The 20 mg / L M1 NPs solution is obtained by dissolving M1 NPs in deionized water, and the 20 mg / L F1 NPs solution is obtained by dissolving F1 NPs in deionized water. Place 1 mL of F1 NPs and M1 NPs solutions in 1.5 mL centrifuge tubes respectively, and under the irradiation of 808 nm laser, record the temperature change after continuous irradiation for 10 min and then cooling for 20 min under the condition of 20 mg / L (1 W / cm 2 ), where 20 mg / L is the concentration of F1 NPs or M1 NPs. Finally, the photothermal conversion efficiency of F1 NPs is measured to be 40.02% (as Figure 3 ), and the photothermal conversion efficiency of M1 NPs is 48.35% (as Figure 4 ). The experimental results show that the photothermal efficiency is significantly improved after constructing the metal ring.

[0092] Example 5

[0093] 1 mL of M1 NPs (10 mg / L, the 10 mg / L M1 NPs solution was obtained by dissolving M1 NPs in deionized water) and F1 NPs (30 mg / L, the 30 mg / L F1 NPs solution was obtained by dissolving F1 NPs in deionized water) solutions were respectively placed in 1.5 mL centrifuge tubes. As Figure 9 shown, under the laser irradiation at 808 nm, for 14 min, and 1.5 W / cm 2 , the ultraviolet absorption of M1 NPs showed no obvious change, proving its good photostability, while the maximum absorbance of F1 NPs at 768 nm gradually decreased with the prolongation of the irradiation time. One M1 molecule was assembled by 3 F1 molecules, and the photothermal ability was mainly related to the structure of F1 molecules. Therefore, the concentration of F1 NPs was 3 times that of M1 NPs during measurement. The above results indicate that after being prepared into metal rings, its special Pt-N structure has a great influence on the stability of the molecular system.

[0094] Due to the insufficient photostability of F1 NPs, they are easily decomposed under light irradiation, so it is difficult to kill tumor cells in practical applications.

[0095] Example 6

[0096] 1,3-Diphenylisobenzofuran (DPBF) was used to detect the generation of reactive oxygen species. DPBF will be oxidized after binding with 1 O2, and the absorption intensity at ultraviolet-visible light (416 nm) will rapidly decrease. At the nanoparticle concentration of 2 mg / L (the 2 mg / L M1 NPs or F1 NPs solution was obtained by dissolving M1 NPs or F1 NPs in deionized water), the solutions of F1 NPs and M1 NPs were continuously irradiated with a laser at 808 nm and 100 mW / cm 2 for 40 s respectively. The change of absorbance at 416 nm was observed every 5 s. Using indocyanine green (ICG) as a reference substance, the singlet oxygen quantum yield of F1 NPs was measured to be 2.57% (as Figure 5 ), and the singlet oxygen quantum yield of M1 NPs was 3.08% (as Figure 6 ). The results prove that the introduction of the electron-withdrawing group pyridine can significantly enhance the ability to generate reactive oxygen species.

[0097] Example 7

[0098] The in vitro anti-cancer effects of M1 NPs and BM1 NPs on A549 cells were detected by MTT. The A549 cells were seeded at a density of 1×10 4Inoculated at a density into a 96-well plate, for each type of nanoparticle, a light-irradiated group L and a dark group D were set up, incubated in a constant-temperature incubator for 18 h, and then 100 μL of M1 NPs, BM1 NPs (50 nmol / L, 100 nmol / L, 150 nmol / L, 200 nmol / L, 300 nmol / L, 500 nmol / L) were added to each well respectively. Specifically, after the nanoparticles were dissolved in a small amount of deionized water, they were dispersed and dissolved in cell culture medium to obtain a nanoparticle solution, so that the concentrations of the nanoparticles in the nanoparticle solution were 50 nmol / L, 100 nmol / L, 150 nmol / L, 200 nmol / L, 300 nmol / L, 500 nmol / L respectively, and then 100 μL of the nanoparticle solution was added to each well and co-incubated with A549 cells for 24 h. Among them, the light-irradiated group started light irradiation 4 h after adding the nanomaterial, and each well was irradiated for 3 min under a laser irradiation of 808 nm and 1 W / cm 2 After co-incubation for 24 h, the medium was replaced with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution, and incubation was continued for 4 h. The original MTT solution was replaced with dimethyl sulfoxide, and after complete dissolution, its absorbance was measured. The cells treated without adding nanoparticles were used as a full-viability control (adding 100 μL of cell culture medium without adding nanoparticles), and the cells treated with water (without adding cell culture medium, under dark conditions, adding 100 μL of water) were used as a full-mortality control and the cell viability at each concentration was calculated (as Figure 7 shown in Table 1).

[0099] Table 1 Cell viability at each concentration under different treatments

[0100]

[0101] Calcein-AM and propidium iodide (PI) were used to stain the cells incubated with nanoparticles for live and dead cell staining to verify their in vitro anti-tumor effects. A549 cells were seeded into a 24-well plate at a density of 4×10 4 per well, a light-irradiated group L and a dark control group D were set up, cultured for 18 h, the medium was removed, 400 μL of material M1 NPs or BM1 NPs (1.5 mg / L) was added and incubation started. After incubation for 4 h, the light-irradiated group was irradiated with a laser (808 nm, 1.0 W / cm 2 , 3 min), and after light irradiation, incubation was continued for 24 h. The medium was removed and gently washed 3 times with PBS, then Calcein-AM and PI were added for staining for 30 min. Finally, it was washed 3 times with PBS again, and imaging was observed and recorded under a fluorescence microscope (as Figure 8 ).

[0102] As Figure 7 shown in 8As shown, under dark conditions, with the increase in the concentration of nanoparticles, there was no obvious death of A549 cells. Under light conditions, it could be seen that the biomimetic nanoparticles after wrapping the cell membrane had better cell killing effects compared with the non-coated nanoparticles. At the same time, BM1 NPs wrapped with the biomimetic membrane showed better anti-tumor effects than M1 NPs without the wrapped nanoparticles. It was speculated that the modification of the biomimetic membrane enhanced the drug targeting and thus enhanced the tumor killing effect.

[0103] Example 8

[0104] The test results of the uptake experiment are as Figure 10 shown. The ordinate represents the relative intensity of the fluorescence signal, and the abscissa is the number of cells. The uptake of BM1 NPs by A549 cells was detected by flow cytometry. A549 cells were seeded in 96-well plates at a density of 10×10 4 cells per well and cultured for 14 h. Then, 800 μL of BM1 NPs (10 mg / L) was added. After uptake for different times (1 h, 2 h, 3 h, 4 h), the culture medium was removed and the cells were washed 3 times with PBS. All cells were collected and the fluorescence signal was measured by flow cytometry. From the results in the figure, it could be seen that with the increase in the culture time, BM1 NPs were continuously taken up by the cells. Similarly, the biomimetic nanoparticles BF1 NPs of F1 were prepared and the uptake experiment was carried out in the same manner as above at a concentration of 30 mg / L. The experimental results showed that the uptake ability of BF1 NPs was not as good as that of BM1 NPs.

[0105] As Figure 10 shown in the average fluorescence intensity of the nanoparticles in the cells after 4 h, for BF1 NPs it was 4.2×1000, and for BM1 NPs it was 9.16×1000. The larger the fluorescence intensity number, the stronger the uptake ability.

[0106] The preparation process of BF1 NPs was as follows: The cell membrane of A549 cells (human lung alveolar basal epithelial cells of lung cancer) was extracted and the membrane proteins were counted. The membrane proteins were stored in a refrigerator at -78 °C. 10 mg of F1 NPs and 0.5 mg of A549 cell membrane proteins were taken, and the mixture was repeatedly extruded 30 times in a special extruder at room temperature to obtain the biomimetic membrane nanoparticles BF1 NPs.

[0107] As mentioned above, the above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, which are all covered by the protection scope of the present invention.

Claims

1. A fluoroborane dipyrrolyl platinum ligand, characterized in that: The structural formula is shown in F1:

2. The method for preparing a fluoroboron dipyrrolyl platinum ligand according to claim 1, characterized in that: The steps include: Add 1-bromooctane, potassium carbonate, potassium iodide and acetonitrile to p-hydroxybenzaldehyde and reflux at 75-85°C for 10-14h, add trifluoroacetic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), triethylamine (Et3N) and boron trifluoride etherate (BF3.Et2O) to react to obtain compound 1; Add iodine and iodic acid aqueous solution to compound 1 and react for 7-9 hours to obtain compound 2 after purification; Add N,N-diethyl-4-aminobenzaldehyde, piperidine and acetic acid to compound 2, use toluene as solvent and react at 110-125° C. for 11-13 hours to obtain compound 3; Add cuprous iodide (CuI), tetrakis(triphenylphosphine)palladium Pd(PPh3)4, and trimethylethynylsilane to compound 3, and use Et3N as solvent to react at 45-55°C for 5-6h to obtain compound 4; Tetrahydrofuran (THF) was added to compound 4 as a solvent, and tetrabutylammonium fluoride was added at -75 to -80°C for 30 min to 45 min to obtain compound 5; Pt(PEt3)2I2 and cuprous iodide (CuI) were added to compound 5, triethylamine (Et3N) was added at -75 to -80°C with THF as solvent, and the mixture was stirred for 0.5 to 1.5 h, and then stirred at room temperature overnight to obtain compound 6; Silver nitrate was added to compound 6, and dichloromethane was used as solvent. The reaction was stirred in an ice-water bath for 18-20 h, and the solvent was removed to obtain compound F1.

3. A metal compound capable of improving stability, characterized in that: The structure of the compound is shown in M1:

4. A method for preparing a metal compound with improved stability, characterized in that: The steps include: 1) Preparation of the fluoroboron dipyrrolyl platinum ligand F1 according to claim 1; 2) Preparation of bipyridine receptor S1 with a coordination angle of 60°; 3) The fluoroborane dipyrrolyl platinum ligand F1 and the bipyridine receptor S1 are used for coordination-driven self-assembly to prepare a metal compound with improved stability.

5. The method for preparing a metal compound with improved stability according to claim 4, characterized in that: The fluoroborane dipyrrolyl platinum ligand F1 and the bipyridine receptor S1 are dissolved in dimethyl sulfoxide (DMSO) at a molar ratio of 1:3-3.5, reacted at 63-68°C for 3-5 hours, and the polarity ratio is adjusted with a mixed solution of dichloromethane and petroleum ether. The fluoroborane dipyrrolyl platinum ligand F1 and the bipyridine receptor S1 are washed away with a polarity gradient of dichloromethane and petroleum ether with a volume ratio of 1:40, 1:36, 1:32, 1:28, 1:24, and 1:20, respectively, to obtain a metal compound M1 with improved stability.

6. The method for preparing a metal compound with improved stability according to claim 5, characterized in that: In step 2), the preparation process of the bipyridine receptor S1 is as follows: Add 3,6-dibromophenanthrene-9,10-dione to a mixed solution of tetrahydrofuran (THF) and water, add sodium dithionite (Na2S2O4) and stir for 20-30 minutes, extract to obtain a pale white solid substance, then add potassium carbonate and 1-bromooctane, reflux at 110-130°C for 8-12 hours to obtain compound a; 4-Alkynylpyridine, Pd(PPh3)4 and CuI are added to compound a, and triethylamine (Et3N) is used as solvent. The reaction is stirred at 45-55°C for 20-28h to obtain compound S1.

7. A photothermal agent, characterized in that: The present invention comprises the metal compound M1 capable of improving stability as claimed in claim 3.

8. A photothermal agent according to claim 7, characterized in that: The metal compound M1 capable of improving stability as claimed in claim 3 and the amphiphilic block copolymer PEG-PLA are mixed and self-assembled in a solvent in a mass ratio of 1:7-9.

9. Use of a metal compound with improved stability as claimed in claim 3 in the preparation of an anti-cancer phototherapy agent.

10. Use of a metal compound capable of improving stability as claimed in claim 3 in the preparation of a phototherapy agent with improved photostability, photothermal conversion efficiency, absorption wavelength or cellular uptake capacity.

Images