Reversible TTET mechanism-based efficient light-controlled drug release nanoparticles and preparation method thereof

Abstract

The invention discloses efficient light-controlled drug release nanoparticles based on a reversible TTET mechanism and a preparation method, and belongs to the technical field of light-controlled drug release. The preparation method comprises the following steps: adding ethyl 4-chloroacetoacetate into methanesulfonic acid dissolved with 4-bromoresorcinol, and stirring; then obtaining a compound 1; the preparation method comprises the following steps: mixing a compound 1, a drug molecule with carboxyl, K2CO3 and ultra-dry DMF, and carrying out a heating reaction in the presence of nitrogen to obtain a prodrug Cu-Dug; the preparation method comprises the following steps: mixing 2-(2, 4-difluorophenyl)-pyridine and IrCl3. 3H2O, adding a mixed solvent in the presence of nitrogen, carrying out a heating reflux reaction, cooling, carrying out suction filtration, washing, drying, mixing with a pyridine-2-formic acid derivative and Na2CO3, adding glycol ether in the presence of nitrogen, and carrying out a heating reaction; then distilling, extracting, drying and purifying to obtain the photosensitizer Ir complex; the preparation method comprises the following steps: adding a co-block polymer, a prodrug Cu-Dug and a photosensitizer Ir complex into THF (tetrahydrofuran), and mixing to obtain a mixed solution; and adding the mixed solution into deionized water, stirring, dialyzing, and filtering to obtain a nanoparticle aqueous solution.

Description

Technical Field

[0001] This invention belongs to the field of photocontrolled drug release technology, specifically relating to a nanoparticle for efficient photocontrolled drug release based on a reversible TTET mechanism and its preparation method. Background Technology

[0002] Photocontrolled drug delivery systems can release drugs under light excitation at specific wavelengths, offering advantages such as non-invasiveness, spatiotemporal controllable release, and targeted release, showing great promise for applications in clinical medicine and pharmacy. Drug release rate and drug release amount are important indicators for evaluating the performance of photocontrolled drug delivery systems. Improving drug release rate and drug release amount is significant for reducing light dose, decreasing phototoxicity, and improving drug utilization.

[0003] Currently, high-efficiency photocontrolled drug release systems primarily improve drug release rate and amount by enhancing the photoresponsiveness of the drug delivery carrier, but this carries the risk of drug leakage. Preparing photoresponsive prodrugs by protecting drug molecules with photocleaving groups can address the problem of premature drug leakage. However, improving the deprotection efficiency of photoresponsive prodrugs has become a key scientific issue determining drug release rate and amount, and related research has not been reported. Therefore, developing novel high-efficiency photolysis drug release systems based on prodrugs is essential.

[0004] To this end, a highly efficient light-controlled drug release nanoparticle based on the reversible TTET mechanism and its preparation method are proposed. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing nanoparticles with efficient photocontrolled drug release based on a reversible TTET mechanism, thereby solving the problems in the prior art.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] A method for preparing nanoparticles includes the following steps:

[0008] S1, Ethyl 4-chloroacetoacetate was added to methanesulfonic acid containing 4-bromo-redophenol and stirred; the reaction solution was then cooled, allowed to stand to precipitate, filtered to retain the solid, and washed and dried to obtain compound 1;

[0009] S2, compound 1, a drug molecule with a carboxyl group, K2CO3 and ultra-dry DMF are mixed and heated under a nitrogen atmosphere to react. After cooling, washing, drying and purification, the prodrug Cou-Drug is obtained.

[0010] S3, 2-(2,4-difluorophenyl)-pyridine and IrCl3·3H2O were mixed, and a mixed solvent of H2O and ethylene glycol ethyl ether was added under nitrogen atmosphere. The mixture was heated to reflux and then cooled to precipitate. The precipitate was filtered and the solid phase was retained. The solid phase was washed and dried and then mixed with pyridine-2-carboxylic acid derivatives and Na2CO3. Ethyl glycol ethyl ether was added under nitrogen atmosphere and the mixture was heated to react. After the reaction was completed, the photosensitizer Ir complexes was obtained by distillation, extraction, drying and purification.

[0011] S4, the coblock polymer, prodrug Cou-Drug, and photosensitizer Ir complexes are added to THF and mixed to obtain a mixed solution; the mixed solution is added to deionized water and stirred, and then dialyzed and filtered to obtain an aqueous solution of nanoparticles.

[0012] Furthermore, the drug molecule containing a carboxyl group is: chlorambucil, indomethacin, naproxen, 2,5-hexanone theobromine, or 3-benzyloxycinnamic acid.

[0013] Further, the pyridine-2-carboxylic acid derivative is: 4-aminopyridine-2-carboxylic acid, 3-hydroxypyridine-2-carboxylic acid, or 5-aminopyridine-2-carboxylic acid.

[0014] Further, the coblock polymer is: PLA5000-mPEG3400, PLA5000-PEG5000-COOH or PLA5000-PEG3400-OH.

[0015] Furthermore, in the mixed solvent of H2O and ethylene glycol ethyl ether, the volume ratio of H2O to ethylene glycol ethyl ether is 1:3.

[0016] Furthermore, in S4, the stirring rate is 1800–2400 r / min.

[0017] Furthermore, in S4, the filtration uses a 0.22 μm aqueous microporous filter membrane.

[0018] Furthermore, the phosphorescence emission peak of the prodrug Cou-Drug is located at 473 nm to 482 nm, and the T1 state energy level is 2.57 eV to 2.62 eV; the phosphorescence emission peak of the photosensitizer Ir complexes is located at 464 nm to 472 nm, and the T1 state energy level is 2.63 eV to 2.67 eV; the T1 state energy level difference between the prodrug Cou-Drug and the photosensitizer Ir complexes is less than 0.1 eV.

[0019] A nanoparticle was prepared using the method described above.

[0020] The above-mentioned nanoparticles are used in the preparation of light-controlled drug release systems.

[0021] A drug carrier comprising the aforementioned nanoparticles.

[0022] The beneficial effects of this invention are:

[0023] (1) The highly efficient light-controlled drug release nanoparticles based on the reversible TTET mechanism prepared by this invention have significantly improved the drug release rate and drug release amount, and solved the risk of drug leakage. They have great application prospects in controlled drug release and clinical treatment.

[0024] (2) The highly efficient light-controlled drug release nanoparticles based on the reversible TTET mechanism prepared in this invention have good water dispersibility and very low cytotoxicity, making them very suitable for biomedical applications. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 This diagram illustrates the mechanism by which the prodrug and iridium complex applicable in Example 1, as well as the efficient photo-controlled drug release nanoparticles based on the reversible TTET mechanism, enhance drug release rate and amount.

[0027] Figure 2 This is a detailed synthetic route diagram of the prodrug Cou-Cb in Example 1;

[0028] Figure 3 For example, the prodrug Cou-Cb in Example 1 1 H NMR spectrum;

[0029] Figure 4 For example, the prodrug Cou-Cb in Example 1 13 C NMR spectrum;

[0030] Figure 5 This is the mass spectrum of the prodrug Cou-Cb in Example 1;

[0031] Figure 6 This is a schematic diagram of the specific synthetic route of photosensitizer Ir2 in Example 1;

[0032] Figure 7 The photosensitizer Ir2 in Example 1 1 H NMR spectrum;

[0033] Figure 8 The photosensitizer Ir2 in Example 1 13 C NMR spectrum;

[0034] Figure 9 This is the mass spectrum of the photosensitizer Ir2 in Example 1;

[0035] Figure 10 The emission spectra of the toluene solution of Cou-Cb in Example 2 at 80 K and the emission spectra of the toluene solution of Ir2 at 298 K are shown.

[0036] Figure 11 The lifetime decay curves at 472 nm are for the photocontrolled drug release nanoparticles (Cou-Cb&Ir2@PLA-PEG) and the nanoparticles coated only with Ir2 (Ir2@PLA-PEG) in Example 4.

[0037] Figure 12 The light-controlled drug release nanoparticles (Cou-Cb & Ir2@PLA-PEG) and nanoparticles coated only with the prodrug Cou-Cb (Cou-Cb@PLA-PEG) in Example 5 were tested at 350 nm (1.27 mW / cm²). 2 Prodrug consumption curves and drug release curves under illumination conditions;

[0038] Figure 13 This is a TEM image of the photocontrolled drug release nanoparticles in Example 6. Detailed Implementation

[0039] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0040] A method for preparing highly efficient photocontrolled drug release nanoparticles based on a reversible TTET mechanism includes the following steps:

[0041] S1, Ethyl 4-chloroacetoacetate was added to methanesulfonic acid containing 4-bromo-redophenol and stirred; the reaction solution was then cooled, allowed to stand to precipitate, filtered to retain the solid, and washed and dried to obtain compound 1;

[0042] S2, Compound 1, a drug molecule with a carboxyl group, and K2CO3 were placed in a reaction flask, and ultra-dry DMF (N,N-dimethylformamide) was added. The reaction was heated under a nitrogen atmosphere. After cooling to room temperature, the drug was washed, dried, and purified to obtain the prodrug Cou-Drug.

[0043] S3, 2-(2,4-difluorophenyl)-pyridine and IrCl3·3H2O were placed in a reaction flask, and a mixed solvent of H2O and ethylene glycol ethyl ether was added under nitrogen atmosphere. The mixture was heated to reflux and then cooled to precipitate. The precipitate was filtered and the solid phase was retained. After washing and drying, the solid phase was placed in a reaction flask with pyridine-2-carboxylic acid derivatives and Na2CO3. Ethyl glycol ethyl ether was added under nitrogen atmosphere and the mixture was heated to react. After the reaction was completed, the photosensitizer Ir complexes was obtained by distillation, extraction, drying and purification.

[0044] S4. The coblock polymer, prodrug Cou-Drug, and photosensitizer Ir complexes were added to a THF (tetrahydrofuran) solution and mixed thoroughly to obtain a mixed solution. The mixed solution was then added to deionized water and stirred (stirring rate of 1800-2400 r / min). After dialysis and filtration, an aqueous solution of Cou-Cb&Ir2@PLA-PEG nanoparticles was obtained.

[0045] Among them, the drug molecules with carboxyl groups are selected from: chlorambucil, indomethacin, naproxen, 2,5-hexanone theobromine, 3-benzyloxycinnamic acid, etc.

[0046] The pyridine-2-carboxylic acid derivatives are selected from: Pic-OH, Pic-NH2, etc., specifically, such as: 4-aminopyridine-2-carboxylic acid, 3-hydroxypyridine-2-carboxylic acid or 5-aminopyridine-2-carboxylic acid.

[0047] The coblock polymers selected are: PLA5000-mPEG3400, PLA5000-PEG5000-COOH, and PLA5000-PEG3400-OH.

[0048] The prodrug Cou-Drug has a phosphorescence emission peak at 473 nm to 482 nm and a T1 state energy level of 2.57 eV to 2.62 eV; the photosensitizer Ir complexes has a phosphorescence emission peak at 464 nm to 472 nm and a T1 state energy level of 2.63 eV to 2.67 eV.

[0049] The technical solution of the present invention will be described in detail below with reference to the embodiments; the sources of the raw materials used in the embodiments are shown in Table 1:

[0050] Table 1. List of Raw Materials for Examples

[0051]

[0052]

[0053] The sources of the instruments used in the embodiments are shown in Table 2:

[0054] Table 2 List of Instruments for Examples

[0055]

[0056] Example 1

[0057] This embodiment provides the preparation of the prodrug Cou-Cb and the photosensitizer Ir2. For example... Figure 1 As shown, Cou-Cb and Ir2 were selected as preferred exemplified molecules in Cou-Drug and Ir complexes, respectively, and were used for illustrative studies.

[0058] like Figure 2 As shown, the preparation process of the prodrug Cou-Cb includes:

[0059] 1) Preparation of compound 1: Ethyl 4-chloroacetoacetate (19.85 mmol) was added to methanesulfonic acid (20 mL) containing 4-bromo-m-diphenol (2.5 g, 13.22 mol) and stirred for 2 days; the reaction solution was poured into ice water, allowed to stand and precipitate, filtered to retain the solid, washed with cold water and dried to give 2.5 g of grayish-white solid, with a yield of 89.3%.

[0060] 1 H NMR(400MHz, DMSO-d6)d(ppm):11.57(s,1H),8.00(s,1H),6.92(s,1H),6.48(s,1H),5.01(s,2H).

[0061] 2) Preparation of the prodrug Cou-Cb: Compound 1 (289.5 mg, 1 mmol), chlorambucil (243.2 mg, 0.8 mmol), and K₂CO₃ (110.4 mg, 0.8 mmol) were placed in a reaction flask, and 8 mL of ultra-dry DMF was added. The reaction was carried out at 80 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was washed with water and ethyl acetate, and the organic phase was retained. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by column chromatography with EA:PE = 1:6 (v / v) as the eluent. 90.3 mg of a white solid was obtained, with a yield of 16.1%.

[0062] like Figure 3 The image shows the prodrug Cou-Cb. 1 H NMR spectrum: 1 H NMR (400MHz, DMSO-d6)d (ppm): 11.55 (s, 1H), 7.89 (s, 1H), 7.02 (d, J = 8.5Hz, 2H), 6.91 (s, 1H), 6. 66(d,J=8.6Hz,2H),6.22(s,1H),5.33(s,2H),3.69(s,8H),2.50-2.43(m,4H),1.87-1.77(m,2H).

[0063] like Figure 4 The image shows the prodrug Cou-Cb. 13 C NMR spectrum: 13 C NMR(101MHz,DMSO-d6)d(ppm):172.73,160.09,157.96,154.28,150.33,144.96,129.80,1 29.02,112.34,110.96,109.60,106.71,103.65,61.48,52.67,41.59,33.69,33.14,26.96.

[0064] like Figure 5 The mass spectrum of the prodrug Cou-Cb is shown below: MALDI-TOF-MS (m / z): calculated

[0065] 557.262 for C 24 H 24 BrCl2NO5; found 557.308.

[0066] like Figure 6 As shown, the preparation process of photosensitizer Ir2 includes:

[0067] 2-(2,4-difluorophenyl)-pyridine (2fppy, 210 mg, 1.1 mmol) and IrCl3·3H2O (176.2 mg, 0.5 mmol) were placed in a reaction flask, and 16 mL of a H2O / ethylene glycol ethyl ether (v / v = 1:3) mixed solvent was added under nitrogen atmosphere. The mixture was heated to 110 °C and refluxed for 24 h. After cooling, the mixture was poured into ice-salt water, and the product precipitated. The product was filtered and the solid phase was retained. The solid was washed with a small amount of ethanol and dried to obtain [(fppy)2Ir2]. [Cl2]; [(fpby)2Ir2Cl2] (60.8 mg, 0.05 mmol), 4-aminopyridine-2-carboxylic acid (Pic-4-NH2, 18.07 mg, 0.13 mmol), and Na2CO3 (58.3 mg, 0.55 mmol) were placed in a reaction flask, and 4 mL of ethylene glycol diethyl ether was added under nitrogen atmosphere. The reaction was carried out at 120 °C for 15 h. The solvent was removed by vacuum distillation, and the product was extracted with water and ethyl acetate. The organic phase was retained and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography with DCM:MeOH = 30:1 (v / v) as the eluent, yielding 28.3 mg of a yellow product, with a yield of 39.8%.

[0068] like Figure 7 The image shows the photosensitizer Ir2. 1 H NMR spectrum: 1H NMR(400MHz,DMSO-d6)d(ppm):8.56(d,J=5.8Hz,1H),8.30-8.20(m,2H),8.09 -7.98(m,2H),7.73(d,J=5.6Hz,1H),7.50(t,J=6.6Hz,1H),7.39(t,J=6.8Hz,1H),7.21(d,J=2.0Hz,1H),7.04(d ,J=6.1Hz,1H),6.97(s,2H),6.85-6.71(m,2H),6.63-6.55(m,1H),5.66(d,J=10.1Hz,1H),5.50(d,J=8.4Hz,1H).

[0069] like Figure 8 The image shows the photosensitizer Ir2. 13 C NMR spectrum: 13 C NMR(101MHz,DMSO-d6)d(ppm):173.03,164.51(d,J=7.2Hz),164.13(dd,J=28.4,13.0Hz),163.5 8(d,J=6.4Hz),162.21(t,J=13.9Hz),161.61(dd,J=29.1,13.2Hz),159.63(t,J=13.8Hz),156.68 ,153.59(d,J=6.6Hz),150.45,149.28,148.36,147.73,139.56(d,J=10.3Hz),128.88,128.27,12 4.24, 123.85, 123.06 (t, J = 18.2Hz), 114.15 (t, J = 15.2Hz), 112.69, 112.46, 97.75 (q, J = 28.4Hz).

[0070] like Figure 9 The mass spectrum of the photosensitizer Ir2 is shown below: MALDI-TOF-MS (m / z): calculated 709.681 for C 28 H 17 F4IrN4O2; found 710.283.

[0071] Example 2

[0072] The prodrug Cou-Cb obtained in Example 1 and the photosensitizer Ir2 were subjected to phosphorescence spectroscopy to determine the T1 state energy level, including the following steps:

[0073] Prepare toluene solutions of Cou-Cb and Ir2 separately (10 -5The emission spectra of the above samples at 80K and 298K were measured using an Edinburgh FLS-980 transient spectrometer (M).

[0074] Phosphorescence spectra of Cou-Cb and Ir2 are as follows Figure 9 As shown, their emission peaks are located at 478 nm and 472 nm, respectively. According to the formula E = 1240 / λ (where E is the excited state energy level in eV; λ is the wavelength in nm), their T1 state energy levels are calculated to be 2.59 eV and 2.63 eV, respectively.

[0075] The energy difference between the lowest triplet excited state (T1 state) of the prodrug Cou-Cb and the photosensitizer Ir2 is less than 0.1 eV. Under environmental thermal activation conditions, reversible triplet-triplet energy transfer between the prodrug Cou-Cb and the photosensitizer Ir2 can be achieved.

[0076] Example 3

[0077] The preparation of highly efficient photocontrolled drug release nanoparticles based on a reversible TTET mechanism includes the following steps:

[0078] PLA5000-mPEG3400 (20 μL, 200 mg / mL) and Cou-Cb (20 μL, 6 × 10⁻⁶ mg / mL) were added. -3 M), Ir2 (40μL, 3×10) -3 M) was added to a 4 μL THF solution and mixed thoroughly to obtain a mixed solution. The mixed solution was then added to 0.8 mL of vigorously vortexed deionized water and dialyzed using a dialysis membrane to remove residual organic solvents. Finally, the solution was filtered using a 0.22 μm aqueous microporous membrane to obtain an aqueous solution of Cou-Cb&Ir2@PLA-PEG nanoparticles.

[0079] In addition, in this embodiment, Cou-Cb@PLA-PEG and Ir2@PLA-PEG nanoparticles were prepared as controls by replacing the Ir2 or Cou-Cb solution with the same volume of THF.

[0080] Example 4

[0081] The photocontrolled drug-releasing nanoparticles (Cou-Cb&Ir2@PLA-PEG) and Ir2-coated nanoparticles (Ir2@PLA-PEG) prepared in Example 3 were subjected to luminescence lifetime testing, including the following steps:

[0082] Using the Cou-Cb&Ir2@PLA-PEG and Ir2@PLA-PEG prepared in Example 3 as test stock solutions, 200 μL of the test stock solution was diluted with deionized water to 2 mL (0.4 mg / mL) to obtain the test sample; the lifetime decay curve of the sample at 472 nm was tested using an Edinburgh FLS-980 transient spectrometer with an excitation wavelength of 375 nm.

[0083] like Figure 11 As shown, the phosphorescence lifetime decay of Cou-Cb&Ir2@PLA-PEG at 472nm is much slower than that of Ir2@PLA-PEG. Fitting the lifetime decay curves of the two, the lifetime components of Cou-Cb&Ir2@PLA-PEG are 0.97ms (72.74%), 2.63ms (21.19%), and 14.52ms (6.07%), while those of Ir2@PLA-PEG are 0.10ms (39.20%), 0.41ms (14.52%), and 1.25ms (46.29%). Compared to Ir2@PLA-PEG, Cou-Cb&Ir2@PLA-PEG exhibits an ultra-long lifetime component of 14.52ms, representing a 10-fold increase in lifetime.

[0084] Example 5

[0085] The light-controlled drug-releasing nanoparticles (Cou-Cb&Ir2@PLA-PEG) and nanoparticles coated only with Cou-Cb (Cou-Cb@PLA-PEG) prepared in Example 3 were analyzed by high-performance liquid chromatography, including the following steps:

[0086] Using the Cou-Cb&Ir2@PLA-PEG and Cou-Cb@PLA-PEG prepared in Example 3 as test solutions, the desired excitation source (1.27mW / cm²) was obtained using a CELHXF 300, P300 W xenon lamp with a 350nm filter. 2 Take 25 μL of the test stock solution (4 mg / mL), irradiate it at room temperature for different times, then add acetonitrile (50 μL), mix well, and analyze it using Shimadzu LC-20A high performance liquid chromatography.

[0087] The results are as follows Figure 12 As shown, among these, Figure 12 In this context, 'a' represents the consumption rate of the prodrug Cou-Cb in Cou-Cb&Ir2@PLA-PEG and Cou-Cb@PLA-PEG. Figure 12In the figure, 'b' represents the drug Cb release rate in Cou-Cb&Ir2@PLA-PEG and Cou-Cb@PLA-PEG. The results show that the consumption rate of the prodrug Cou-Cb and the drug Cb release rate in Cou-Cb&Ir2@PLA-PEG are both much faster than those in Cou-Cb@PLA-PEG. Using a potassium ferric oxalate spectrophotometer, the drug release quantum efficiency of the photocontrolled drug-release nanoparticles Cou-Cb&Ir2@PLA-PEG was measured to be 14.42±1.05%, and the drug release amount was 63.55±2.06%; the drug release quantum efficiency of the nanoparticles Cou-Cb@PLA-PEG coated only with the prodrug was 4.00±0.31%, and the drug release amount was 57.29±1.63%. Compared to the Cou-Cb prodrug alone, the photolysis quantum efficiency of these photocontrolled drug-release nanoparticles increased by 3.6 times, and the drug release amount increased by 6%. These results indicate that the addition of photosensitizer Ir2 to construct the reversible TTET process significantly improves the drug release rate and amount, achieving highly efficient light-controlled drug release.

[0088] Example 6

[0089] The morphology of the light-controlled drug-releasing nanoparticles (Cou-Cb&Ir2@PLA-PEG) prepared in Example 3 was characterized, including the following steps:

[0090] Using the Cou-Cb&Ir2@PLA-PEG prepared in Example 3 as the test stock solution, 20 μL of the test stock solution was dropped onto the copper grid of the carbon support film and dried at room temperature in a dark place for 48 h to obtain the test sample; the particle size of the nanoparticles was tested using a Hitachi HT7700 transmission electron microscope.

[0091] The results are as follows Figure 13 As shown, the average particle size of Cou-Cb&Ir2@PLA-PEG is 37 nm, indicating good dispersibility.

[0092] In the description of this specification, references to terms such as "an embodiment," "example," "specific example," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0093] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the claimed invention.

Claims

1. A method for preparing nanoparticles, characterized in that, Includes the following steps: S1, Ethyl 4-chloroacetoacetate was added to methanesulfonic acid containing 4-bromo-redophenol and stirred; the reaction solution was then cooled, allowed to stand to precipitate, filtered to retain the solid, and washed and dried to obtain compound 1; S2, Compound 1, a drug molecule with a carboxyl group, K2CO3 and DMF are mixed and heated under a nitrogen atmosphere to react. After cooling, washing, drying and purification, the prodrug Cou-Drug is obtained. S3, 2-(2,4-difluorophenyl)-pyridine and IrCl3·3H2O were mixed, and a mixed solvent of H2O and ethylene glycol ethyl ether was added under nitrogen atmosphere. The mixture was heated to reflux and then cooled to precipitate. The precipitate was filtered and the solid phase was retained. The solid phase was washed and dried and then mixed with pyridine-2-carboxylic acid derivatives and Na2CO3. Ethyl glycol ethyl ether was added under nitrogen atmosphere and the mixture was heated to react. After the reaction was completed, the photosensitizer Ir complexes was obtained by distillation, extraction, drying and purification. S4, add the coblock polymer, prodrug Cou-Drug, and photosensitizer Ir complexes to THF and mix to obtain a mixed solution; The mixed solution was added to deionized water and stirred, then dialyzed and filtered to obtain an aqueous solution of nanoparticles.

2. The method for preparing nanoparticles according to claim 1, characterized in that, In S2, the drug molecule with a carboxyl group is chlorambucil, indomethacin, naproxen, 2,5-hexanone theobromine, or 3-benzyloxycinnamic acid.

3. The method for preparing nanoparticles according to claim 1, characterized in that, The pyridine-2-carboxylic acid derivatives are: 4-aminopyridine-2-carboxylic acid, 3-hydroxypyridine-2-carboxylic acid, or 5-aminopyridine-2-carboxylic acid.

4. The method for preparing nanoparticles according to claim 1, characterized in that, The coblock polymer is PLA5000-mPEG3400, PLA5000-PEG5000-COOH, or PLA5000-PEG3400-OH.

5. The method for preparing nanoparticles according to claim 1, characterized in that, In the mixed solvent of H2O and ethylene glycol ethyl ether, the volume ratio of H2O to ethylene glycol ethyl ether is 1:

3.

6. The method for preparing nanoparticles according to claim 1, characterized in that, In S4, the stirring rate is 1800–2400 r / min; the filtration uses a 0.22 μm aqueous microporous filter membrane.

7. The method for preparing nanoparticles according to claim 1, characterized in that, The prodrug Cou-Drug has a phosphorescence emission peak at 473 nm to 482 nm and a T1 state energy level of 2.57 eV to 2.62 eV; the photosensitizer Ir complexes has a phosphorescence emission peak at 464 nm to 472 nm and a T1 state energy level of 2.63 eV to 2.67 eV; the T1 state energy level difference between the prodrug Cou-Drug and the photosensitizer Ir complexes is less than 0.1 eV.

8. A nanoparticle, characterized in that, It was prepared using the preparation method described in any one of claims 1-7.

9. The application of the nanoparticles according to claim 8 in the preparation of a light-controlled drug release system.

10. A drug carrier, characterized in that, Including the nanoparticles as described in claim 8.

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