Composite nanoparticles for chemiluminescence excitation light-powered therapy, and preparation method and application thereof
By utilizing composite nanoparticles of chemiluminescent substrate and photosensitizer within tumor cells, the limitations of traditional photodynamic therapy in penetration depth and the shortcomings of existing chemiluminescent systems have been overcome, achieving highly efficient treatment of deep tumors.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
- Filing Date
- 2024-06-05
- Publication Date
- 2026-05-19
AI Technical Summary
Traditional photodynamic therapy has limited penetration depth of externally excited light, which limits its therapeutic effect on deep tumors. Existing chemiluminescence-excited photodynamic therapy systems suffer from system complexity, hydrogen peroxide supplement toxicity, and insufficient targeting, which affect their clinical application.
The method employs composite nanoparticles containing chemiluminescent substrates, amphiphilic molecules, and photosensitizers. By utilizing the response of hydrogen peroxide within tumor cells, chemiluminescence is generated through a chemical reaction to excite photodynamic therapy, and the oxidation of NADH to generate hydrogen peroxide is catalyzed, thus promoting the continuous chemiluminescence process.
This study achieved highly efficient chemiluminescence-excited photodynamic therapy for subcutaneous tumors and lung metastases, demonstrating excellent therapeutic effects and highly effective cancer cell targeting.
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Figure CN118717711B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the fields of nanomaterials and biomedicine. More specifically, it relates to a composite nanoparticle for chemiluminescence-excited photodynamic therapy, its preparation method, and its applications. Background Technology
[0002] Cancer is a major threat to human health, with up to 90% of cancer patients dying from tumor metastasis. Traditional cancer treatments, such as surgery, chemotherapy, and radiotherapy, have drawbacks such as significant side effects, high risks, and extensive trauma, hindering their clinical application. Photodynamic therapy (PDT) is a novel drug-device combined treatment for tumors. Its mechanism of action involves photoexcitation of a photosensitizer to generate reactive oxygen species that kill tumor cells. Although PDT has advantages such as high selectivity, low toxicity, and low likelihood of developing drug resistance, traditional PDT suffers from limited penetration depth of external excitation light. Even with near-infrared light excitation, tissue penetration depth is only a few millimeters, making it difficult to reach deep into the patient's body and deep tumor lesions. Therefore, PDT is generally limited to treating superficial tumors, such as skin cancer, restricting its clinical application.
[0003] To address the issue of low penetration depth of external excitation sources, a promising approach is to utilize in-situ chemiluminescence in tumor cells to excite photosensitizers, thereby eliminating dependence on external excitation sources—a method known as chemiluminescent photodynamic therapy (CPT). In CPT, the unique high concentration of hydrogen peroxide within tumor cells allows the chemiluminescent substrate to react with the hydrogen peroxide, generating chemical energy. Therefore, the simultaneous presence of sufficient chemiluminescent substrate and hydrogen peroxide in tumor cells is essential for effective CPT. Although the concentration of hydrogen peroxide within tumor cells (0.1-100 μM) is higher than in normal cells, this is insufficient to sustain high chemiluminescence efficiency; it only provides targeted initiation for cancer treatment. As the reaction progresses, if the intracellular H2O2 is rapidly depleted and cannot be replenished in time, the chemical reaction may be rapidly inhibited, leading to poor therapeutic efficacy and limited sustained treatment effectiveness.
[0004] Currently reported chemiluminescence-excited photodynamic therapy systems suffer from drawbacks such as system complexity, the toxicity of hydrogen peroxide supplements, and insufficient targeting, which limit their clinical application. Summary of the Invention
[0005] To address the aforementioned problems, the first objective of this invention is to provide a composite nanoparticle for chemiluminescence-excited photodynamic therapy. This composite nanoparticle responds to overexpressed hydrogen peroxide in vivo, initiating chemiluminescence-excited photodynamic therapy. Simultaneously, the excited-state photosensitizer catalyzes the oxidation of overexpressed NADH in tumor cells and generates H2O2 in situ, providing an H2O2 source for chemiluminescence and promoting its continuous occurrence.
[0006] A second objective of this invention is to provide a method for preparing the composite nanoparticles as described above.
[0007] The third objective of this invention is to provide a photodynamic therapy drug for metastatic tumors.
[0008] The fourth objective of this invention is to provide the application of composite nanoparticles in the preparation of photodynamic therapy drugs for metastatic tumors.
[0009] To achieve the first objective mentioned above, the present invention adopts the following technical solution:
[0010] This invention discloses a composite nanoparticle for chemiluminescence-excited photodynamic therapy, comprising the following three raw material components:
[0011] Chemiluminescent substrates are selected from bis[2,4,5-trichloro-6-(pentoxycarbonyl)phenyl]oxalate and / or diphenyloxalate;
[0012] The amphiphilic molecule is selected from one or more of the following: hyaluronic acid and folic acid with a molecular weight of 50,000-100,000 g / mol; phospholipid-polyethylene glycol with a molecular weight of 2,000-10,000 g / mol; and polyvinylpyrrolidone with a molecular weight of 500-10,000 g / mol. The amphiphilic molecule used in this invention primarily serves a loading function; and
[0013] Photosensitizer, selected from any one of the following structures:
[0014] i) Metal Ru-based photosensitizers
[0015]
[0016] R1 is selected from any one of H, C1-C4 alkoxy groups, and NO2;
[0017] ii) Organic non-metallic photosensitizers
[0018]
[0019] The R2 is selected from any one of H, C1-C4 alkoxy groups, NO2, and NH2;
[0020] The chemiluminescent substrate and photosensitizer are co-encapsulated within the amphiphilic molecule.
[0021] In this invention, the composite nanoparticles utilize hydrogen peroxide overexpressed within tumor cells to induce a chemical reaction between the peroxate ester group and hydrogen peroxide in the chemiluminescent substrate, generating a high-energy intermediate. This reaction responds to the overexpressed hydrogen peroxide in vivo. The chemical reaction excites a photosensitizer via an electron exchange mechanism, achieving indirect luminescence and enabling chemiluminescence-excited photodynamic therapy. Simultaneously, the excited-state photosensitizer catalyzes the oxidation of NADH overexpressed within tumor cells, generating H2O2 in situ. This provides an H2O2 source for chemiluminescence, promoting its continuous progression. Therefore, these composite nanoparticles exhibit highly efficient chemiluminescence-excited photodynamic activity against cancer cells and demonstrate excellent therapeutic effects on subcutaneous tumors and lung metastases at the in vivo level.
[0022] Furthermore, R1 is selected from C1-C4 alkoxy groups, and for example, it can be methoxy, ethoxy, etc.
[0023] To achieve the second objective mentioned above, the present invention adopts the following technical solution:
[0024] This invention discloses a method for preparing the composite nanoparticles as described above, comprising the following steps:
[0025] The chemiluminescent substrate, photosensitizer, and amphiphilic molecule were dissolved in organic solvents to obtain solutions A, B, and C, respectively.
[0026] Add solutions A, B, and C to water, and after sonication, stirring, and dialysis, the solution is obtained and stored at 4°C or below.
[0027] Furthermore, the molar ratio of the chemiluminescent substrate to the photosensitizer is 40-60:1, and can be, for example, 40:1, 45:1, 50:1, 55:1, 60:1, etc.; the mass ratio of the photosensitizer to the amphiphilic molecule is 1:15-25, and can be, for example, 1:15, 1:20, 1:25, etc.
[0028] Furthermore, ultrasonic treatment was performed using an ultrasonic cell disruptor for 10-15 minutes.
[0029] Furthermore, the stirring rate is 1500-3000 r / min, the stirring time is 24-48 h, and the stirring temperature is 37℃.
[0030] Furthermore, the dialysis is to remove organic solvents and excess small molecules. The dialysis bag used has a molecular weight cutoff of 2000-3500 Da, and the dialysis time is 36-72 hours.
[0031] Furthermore, the organic solvent is selected from methanol, ethanol, acetonitrile, and dimethyl sulfoxide.
[0032] Furthermore, the concentration of solution A is 4-10 mg / mL, the concentration of solution B is 1-5 mg / mL, and the concentration of solution C is 5-10 mg / mL.
[0033] Furthermore, the volume ratio of solution A, solution B, and solution C is 1:0.1:10.
[0034] To achieve the third objective mentioned above, the present invention adopts the following technical solution:
[0035] This invention discloses a photodynamic therapy drug for metastatic tumors, wherein the effective components of the photodynamic therapy drug for metastatic tumors include the composite nanoparticles as described above or the composite nanoparticles prepared by the preparation method described above.
[0036] Furthermore, photodynamic therapy drugs for metastatic tumors can be administered via injection, intravenous infusion, or oral administration.
[0037] To achieve the fourth objective mentioned above, the present invention adopts the following technical solution:
[0038] This invention discloses the application of composite nanoparticles prepared using the composite nanoparticles described above or by the preparation method described above in the preparation of photodynamic therapy drugs for metastatic tumors.
[0039] Furthermore, the metastatic tumor is a lung metastatic tumor.
[0040] Furthermore, the lung metastases originate from the metastasis of breast cancer cells. In one specific embodiment, the present invention constructs a research model using lung metastases derived from mouse breast cancer cells.
[0041] The beneficial effects of this invention are as follows:
[0042] This invention provides a composite nanoparticle for chemiluminescence-excited photodynamic therapy. The composite nanoparticle comprises three raw material components: a chemiluminescent substrate, an amphiphilic molecule, and a photosensitizer. The chemiluminescent substrate reacts with H₂O₂ to generate a high-energy intermediate, which then excites the photosensitizer via an electron exchange mechanism to achieve indirect luminescence. This enables responsiveness to overexpressed hydrogen peroxide in vivo and chemiluminescence-excited photodynamic therapy. Simultaneously, the excited-state photosensitizer catalyzes the oxidation of overexpressed NADH in tumor cells and generates H₂O₂ in situ, providing an H₂O₂ source for chemiluminescence and promoting its continuous progression. Therefore, this composite nanoparticle exhibits highly efficient chemiluminescence-excited photodynamic activity against a range of cancer cells and demonstrates excellent therapeutic effects on subcutaneous tumors and lung metastases at the in vivo level. These encouraging results provide guidance for the development of highly effective anti-metastatic agents. Attached Figure Description
[0043] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.
[0044] Figure 1 The transmission electron microscope image of NP3 in Example 2 is shown.
[0045] Figure 2 The absorption spectrum of NADH catalytic oxidation by NP3 in Example 3 is shown.
[0046] Figure 3 The graph shows the changes in NADH, ATP, and H2O2 levels in A549 cells treated with NP3 in Example 4. Figure 3 In the diagram, A represents the change in NADH content, B represents the change in ATP content, and C represents the change in H2O2 content.
[0047] Figure 4 The diagram shows the cytotoxicity test results of NP1, NP2, and NP3 against cancer cells in Example 5. Figure 4 In this case, A is NP1, B is NP2, and C is NP3.
[0048] Figure 5 The following diagram illustrates the therapeutic effects of the control group and the target group on metastatic tumors in Example 6. Figure 5 In the figure, A shows lung nodule photos of different groups, B shows the number of nodules in different groups, and C shows the nodule inhibition rate in different groups. Detailed Implementation
[0049] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments and accompanying drawings, further explains the invention. Similar components in the drawings are indicated by the same reference numerals. Those skilled in the art should understand that the specific description below is illustrative rather than restrictive and should not be construed as limiting the scope of protection of the present invention.
[0050] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.
[0051] Example 1
[0052]
[0053] This embodiment provides a method for preparing composite nanoparticles, including the following steps:
[0054] Phospholipid-polyethylene glycol 2000 (DSPE-PEG 2000, 100 mg) and bis[2,4,5-trichloro-6-(pentoxycarbonyl)phenyl] oxalate (CPPO, 4 mg) were dissolved in 10 mL and 1 mL of tetrahydrofuran, respectively.
[0055] Ru(phen)2(PIP-OCH3) 2+ (Ru3, 400 μM) dissolved in dimethyl sulfoxide (0.1 mL);
[0056] The above solution was mixed evenly and added to ultrapure water (20 mL). The mixture was then sonicated for 10 minutes using an ultrasonic cell disruptor, followed by stirring at 37°C for 24 hours (2000 r / min). Organic solvents and excess small molecules were removed by dialysis. The dialysis bag used had a molecular weight cutoff of 3500 Da, and the dialysis time was 48 hours. The resulting composite nanoparticle solution was stored at 4°C for later use and designated as NP3.
[0057] Comparative Example 1
[0058]
[0059] This comparative example provides a method for preparing composite nanoparticles, comprising the following steps:
[0060] Phospholipid-polyethylene glycol 2000 (DSPE-PEG 2000, 100 mg) and bis[2,4,5-trichloro-6-(pentoxycarbonyl)phenyl] oxalate (CPPO, 4 mg) were dissolved in 10 mL and 1 mL of tetrahydrofuran, respectively.
[0061] photosensitizer Ru(phen)3 2+ (Ru1, 400 μM) dissolved in dimethyl sulfoxide (0.1 mL);
[0062] The above solution was mixed evenly and added to ultrapure water (20 mL). The mixture was then sonicated for 10 minutes using an ultrasonic cell disruptor, followed by stirring at 37°C for 24 hours (2000 r / min). Organic solvents and excess small molecules were removed by dialysis. The dialysis bag used had a molecular weight cutoff of 3500 Da, and the dialysis time was 48 hours. The resulting composite nanoparticle solution was stored at 4°C for later use and designated as NP1.
[0063] Comparative Example 2
[0064]
[0065] This comparative example provides a method for preparing composite nanoparticles, comprising the following steps:
[0066] Phospholipid-polyethylene glycol 2000 (DSPE-PEG 2000, 100 mg) and bis[2,4,5-trichloro-6-(pentoxycarbonyl)phenyl] oxalate (CPPO, 4 mg) were dissolved in 10 mL and 5 mL of tetrahydrofuran, respectively.
[0067] The photosensitizer Ru(phen)2(PIP) 2+ (Ru2, 400 μM) dissolved in dimethyl sulfoxide (1 mL);
[0068] The above solution was mixed evenly and added to ultrapure water (20 mL). Then, it was sonicated for 10 minutes using an ultrasonic cell disruptor, followed by stirring at 37°C for 24 hours (2000 r / min). Organic solvents and excess small molecules were removed by dialysis. The molecular weight cutoff of the dialysis bag was 3500 Da, and the dialysis time was 48 hours. The resulting composite nanoparticle solution was stored at 4°C for later use and designated as NP2.
[0069] Example 2
[0070] The particle size of NP3 in Example 1 was measured to be 60 nm using transmission electron microscopy. Figure 1 Dynamic light scattering (DLS) revealed a hydrodynamic diameter of 110 nm. Due to the presence of a hydration layer, the particle size measured by DLS was higher than that obtained by transmission electron microscopy. Elemental imaging and energy-dispersive X-ray spectroscopy confirmed the presence of Ru-based signals, as well as signals based on C, O, Cl, and N elements. These results demonstrate the successful synthesis of the composite nanoparticles.
[0071] Example 3: Chemiluminescent catalytic oxidation of NADH
[0072] The changes in the absorption spectrum during the oxidation of chemically excited NADH were detected using an ultraviolet absorption spectrometer.
[0073] Before each experiment, 3 mL of a mixed aqueous solution containing 2 μM NP1-NP3 and 200 μM NADH was added to a cuvette, followed by the addition of 200 μM H2O2 to indicate the start of the reaction. During the experiment, the absorption spectrum of the mixed solution was measured every 30 minutes, and the reaction time was monitored for 4.5 hours. After the reaction was completed, the amount of hydrogen peroxide in the mixed solution was detected using hydrogen peroxide test paper.
[0074] See results Figure 2 This indicates that in the NP3 system containing Example 1, the absorption peak of NADH gradually decreased throughout the reaction. Compared with NP1 and NP2, NP3 has excellent chemiluminescent catalytic efficiency. In the NP1 system containing Comparative Example 1, the absorption peak of NADH showed almost no significant change after 4.5 hours of reaction. In the NP2 system containing Comparative Example 2, the absorption peak of NADH decreased by about 30% after 4.5 hours of reaction, indicating that the NP2 system can oxidize NADH to a certain extent through chemiluminescent catalysis.
[0075] Example 4: Changes in NADH, ATP, and H2O2 levels at the cellular level
[0076] A549 cells were seeded into 60 mm diameter cell culture dishes and incubated at 37°C for 24 hours. NP3 nanoparticles were added at concentrations of 0 μM, 2 μM, 4 μM, and 6 μM, respectively, and co-cultured with A549 cells for 4 hours. The culture medium was then discarded, and the cells were washed three times with sterile PBS buffer. A suitable amount of 0.25% trypsin was added for digestion, followed by the addition of an appropriate volume of PBS buffer for collection and resuspending. Tests were then performed according to the instructions of commercial NADH, ATP, and H2O2 kits.
[0077] See results Figure 3 , Figure 3 China A 实验 A represents the absorbance value in the experiment. 控制 Indicates the absorbance value without the addition of nanoparticles, A 实验 / A 控制 The introduction of nanoparticles indicated a change in related quantities, with results showing that NADH levels in A549 cells treated with 6 μM NP3 decreased by approximately 60%. Figure 3 The results (A) indicate that chemically induced NADH oxidation can also occur in cancer cells. NADH depletion is detrimental to intracellular ATP production; ATP levels in A549 cells treated with 6 μM NP3 decreased by approximately 70%. Figure 3 (Middle B). It is noteworthy that with increasing NP3 concentration, the intracellular H2O2 content in A549 cells gradually increased; 6 μM NP3 increased the H2O2 content by 2.1 times. Figure 3 (C)
[0078] Example 5: Cytotoxicity Experiment
[0079] The inhibitory effect of composite nanoparticles on the proliferation of various tumor cells (including human lung cancer cells A549, human ovarian cancer cells SKOV-3, and human cisplatin-resistant lung cancer cells A549 / DDP) was detected by the MTT assay.
[0080] Tumor cells in good growth condition and in the logarithmic growth phase were washed three times with sterile PBS buffer, then digested with an appropriate amount of 0.25% trypsin, and the digestion was terminated by adding an appropriate volume of culture medium. The liquid was transferred to centrifuge tubes and centrifuged at 1000 rpm for 4 minutes. The culture medium was discarded, and the cells were resuspended in fresh culture medium. Cells were then cultured at 1 × 10⁶ cells per well. 4 Cells were seeded at a density of 1000 μL in 96-well plates and incubated at 37°C for 24 hours. Then, different concentrations of NP1-NP3 were co-cultured with the cells for 4 hours, followed by changing the culture medium and incubating for another 24 hours. The culture medium was then discarded, and 200 μL of 0.5 mg / mL 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (MTT) solution was added and incubated for 4 hours. The liquid was then aspirated, and 200 μL of a mixture of DMSO and methanol was added to each well. The absorbance of each well at 570 nm was measured using a microplate reader.
[0081] The cytotoxicity results of NP1-NP3 on different cell types are as follows: Figure 4 As shown, the results indicate that NP3 exhibits highly efficient chemically activated PDT activity against various cancer cells. Figure 4 (C), its IC 50 The values were approximately 3.9 μM, 3.6 μM, and 4.5 μM (based on Ru3 concentration). NP1 exhibited lower cytotoxicity. Figure 4 (A), its IC50 for three types of cancer cells 50 The values were all greater than 20 μM (based on the concentration of Ru1), indicating that NP2 had some cytotoxicity against cancer cells. Figure 4 (B), its IC50 against various cancer cells 50 The values were approximately 15.8 μM, 18.6 μM, and 19.1 μM (based on the concentration of Ru2), but these values were much higher than those of NP3.
[0082] Example 6: In vivo antitumor experiment
[0083] Six-week-old female BalB / C mice (approximately 20g) were used in the experiment. They were fed under normal conditions with a 12-hour alternating dark and day cycle, and provided with ample food and water. To establish a lung metastasis model, 4T1 cancer cells were injected intravenously. From the fifth day after injection, the formation of lung metastases was observed daily. By the eighth day, the lung metastasis model had been established. At this point, all mice were randomly divided into four groups: PBS group (control), NP1 group, NP2 group, and NP3 group (the latter three being the target groups), with five mice in each group. Each group received 100 μL of the corresponding composite nanoparticles at a concentration of 18 mg / kg or an equal volume of PBS via tail vein injection. After administration, the mice were observed every other day, and their weight was recorded. After all mice in the control group had been sacrificed, the mice were dissected, and the heart, liver, spleen, lungs, and kidneys were removed and fixed with paraformaldehyde. The number of lung nodules in each group was recorded and photographed. Samples were then sent for H&E, ESR1 (estro receptor 1), and Caspase-3 (cysteine protease-3) staining of tissue sections. Mice in the target group were observed for 30 days, and their survival rate was recorded. The inhibition rate of lung metastases = (number of nodules in the PBS group - number of nodules in the target group) / number of nodules in the target group × 100%.
[0084] See results Figure 5 The results showed that the PBS, NP1, and NP2 groups had a greater number of metastatic nodules in the lungs, while the NP3 group had almost no metastatic nodules, indicating that NP3 has excellent therapeutic effects on metastatic tumors. Statistical analysis of lung metastatic nodules in each group showed that the NP3 group had an average of approximately 2 metastatic nodules, with an inhibition rate of approximately 97% compared to the PBS group. The nodule inhibition rates in the NP1 and NP2 groups were only 8% and 36%, respectively. During the treatment period, the PBS control group, NP1 group, and NP2 group experienced varying degrees of weight loss due to the rapid growth of metastatic tumors, while the mice treated with NP3 showed a slight increase in weight over time. More importantly, during the 30-day treatment period, the survival rate of mice in the NP3 treatment group was 100%, while no mice in the other groups survived after 14 days of treatment, further demonstrating the good therapeutic effect of NP3.
[0085] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all the implementation methods here. All obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.
Claims
1. A composite nanoparticle for chemiluminescence-excited photodynamic therapy, characterized in that, It includes the following three raw material components: Chemiluminescent substrates are selected from bis[2,4,5-trichloro-6-(pentoxycarbonyl)phenyl]oxalate and / or diphenyloxalate; The amphiphilic molecule is selected from one or more of the following: hyaluronic acid with a molecular weight of 50,000-100,000 g / mol, folic acid, phospholipid-polyethylene glycol with a molecular weight of 2,000-10,000 g / mol, and polyvinylpyrrolidone with a molecular weight of 500-10,000 g / mol; and Photosensitizer, selected from any one of the following structures: i) Metal-based Ru-based photosensitizers R1 is selected from any one of H, C1-C4 alkoxy groups, and NO2; The chemiluminescent substrate and the photosensitizer are co-encapsulated within the amphiphilic molecule; The composite nanoparticles were prepared according to the following steps: The chemiluminescent substrate, photosensitizer, and amphiphilic molecule were dissolved in organic solvents to obtain solutions A, B, and C, respectively. Solution A, solution B and solution C are added to water, and after sonication, stirring and dialysis, the solution is obtained. The molar ratio of the chemiluminescent substrate to the photosensitizer is 40-60:1; the mass ratio of the photosensitizer to the amphiphilic molecule is 1:15-25.
2. A method for preparing composite nanoparticles as described in claim 1, characterized in that, Includes the following steps: The chemiluminescent substrate, photosensitizer, and amphiphilic molecule were dissolved in organic solvents to obtain solutions A, B, and C, respectively. Solution A, solution B and solution C are added to water, and after sonication, stirring and dialysis, the solution is obtained. The molar ratio of the chemiluminescent substrate to the photosensitizer is 40-60:1; the mass ratio of the photosensitizer to the amphiphilic molecule is 1:15-25.
3. The preparation method according to claim 2, characterized in that, The stirring rate is 1500-3000 r / min, and the stirring time is 24-48 h.
4. The preparation method according to claim 2, characterized in that, The dialysis bags used had a molecular weight cutoff of 2000-3500 Da, and the dialysis time was 36-72 h.
5. A photodynamic therapy drug for metastatic tumors, characterized in that, The effective component of the photodynamic therapy drug for metastatic tumors includes the composite nanoparticles as described in claim 1 or the composite nanoparticles prepared by the preparation method as described in any one of claims 2-4.
6. The photodynamic therapy drug for metastatic tumors according to claim 5, characterized in that, Photodynamic therapy drugs for metastatic tumors are administered into the body via injection, intravenous infusion, or oral administration.
7. The application of the composite nanoparticles as described in claim 1 or the composite nanoparticles prepared by the preparation method according to any one of claims 2-4 in the preparation of photodynamic therapy drugs for metastatic tumors, characterized in that, The metastatic tumor is a lung metastatic tumor.