A pegylated nanoparticle based on pyridyl porphyrin and its preparation method and application

Abstract

The present application relates to a kind of polyglycolated nanoparticles based on pyridyl porphyrin and its preparation method and application.The nanoparticles of the present application are spherical nanoparticles of shell-core structure;The shell is lipid-polyethylene glycol bilayer structure;The core is platinum ion compound based on pyridyl porphyrin;The platinum ion compound based on pyridyl porphyrin is prepared by mixing pyridyl alcohol ligand and PtCl2 (PhCN) 2.The present application solves many problems of traditional platinum drugs by combining platinum drugs and protonated porphyrin through ion pair, mainly including improving the water solubility of platinum drugs and the cytotoxicity to tumor cells, realizing the synergistic anticancer effect of chemotherapy and PDT therapy.Material does not need complex preparation process, simple operation, easy to package.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a polyethylene glycol-based nanoparticle based on pyridylporphyrin, its preparation method, and its application. Background Technology

[0002] Skin cancer is a general term for malignant tumors of the skin, mainly divided into non-melanoma skin cancer and melanoma skin cancer. Non-melanoma skin cancer is further divided into basal cell carcinoma and squamous cell carcinoma, and it commonly occurs on areas frequently exposed to sunlight, such as the cheeks, nose, and eyelids. Ultraviolet radiation is a major cause of skin cancer. Ultraviolet radiation can lead to DNA damage and gene mutations, thus inducing skin cancer. The incidence of skin cancer varies considerably across different regions.

[0003] Compared to non-melanoma, melanoma is a type of malignant tumor with a high recurrence rate, high metastasis rate, and poor prognosis, and its incidence continues to rise globally. Although melanoma is less common than other skin cancers, it is more deadly. Melanoma is one of the most aggressive cancers and is more prone to metastasis. In its early stages, melanoma can spread to other organs such as the liver, lungs, and brain via lymphatic and hematogenous routes, and in its terminal stages, it can metastasize to the brain. Brain metastasis is a rapidly progressing stage and a leading cause of death for patients.

[0004] Treatment options for melanoma include traditional surgical resection, conventional chemotherapy, emerging targeted therapy, and immunotherapy. Photodynamic therapy (PDT) is a new modality for treating malignant tumors that has emerged in recent years and has become a new method in cancer treatment. PDT treatment can be traced back to ancient times. In 1900, German physician Oscar Rabb first reported the chemical sensitization effect of light on tissues. In 1903, Jesionek and Tappeiner used eosin and sunlight to treat skin cancer patients, marking the beginning of PDT therapy. By the 1960s, Lipson and Schwartz discovered HpD (hematoporphyrin derivatives) and isolated and identified the active component of hematoporphyrin derivatives in the early 1980s. Subsequently, scientists discovered that the "active" part of HpD consists of porphyrin dimers and oligomers, where porphyrin units can be linked by ethers, esters, and carbon-carbon bonds. PDT generates reactive oxygen species (ROS), such as singlet oxygen, through the reaction of excited-state photosensitizers and oxygen sources. 1 O2), hydroxyl radicals (·OH) and superoxide radicals (·O2) -Photochemical photochemical reactions (PDTs) kill tumor cells. While most PDT processes are oxygen-dependent and initiated under aerobic conditions, some PDTs occur in hypoxic environments. Based on different photochemical reactions, PDTs are classified into two types: Type I and Type II. Upon photoactivation, the photosensitizer first transitions from the ground singlet state (S0) to the excited singlet state (S1), and then to the electronically excited triplet state (T1). T1 then triggers the photochemical reaction via two different pathways. For Type I PDT, T1 participates in a hydrogen or electron transfer process, directly forming a free radical with the biological substrate. This free radical can then react with triplet oxygen (…). 3 O2) and water further interact to produce ·O2 - And ·OH. In type II PDT, T1 undergoes a type II photochemical reaction, directly transferring energy from the surrounding ·OH. 3 O2 is converted into cytotoxic substances. 1 O2. Currently, most photosensitizers used primarily operate through type II photochemical reactions, and it is generally believed that... 1 O2 is the main destroyer of cancer cells by photodynamic therapy.

[0005] Local lesions selectively absorb photosensitizers and are exposed to light of appropriate wavelengths. Through photosensitizer-mediated oxidative damage and the involvement of oxygen molecules, apoptosis and necrosis of target cells are induced. Because it has almost no side effects of damaging normal tissue cells, it has unique advantages in clinical practice and has been widely used in the treatment of esophageal cancer, non-melanoma skin cancer, cervical cancer, and other tumors, showing promise as a routine adjuvant therapy for various malignant tumors. Simultaneously, PDT treatment can also induce tumor immunity, providing a new strategy for the effective treatment of some refractory malignant tumors. Currently, new molecules with ideal properties have been discovered that can be used as photosensitizers in PDT treatment. Among these characteristics, enhanced photostability, good solubility in physiological media, generation of highly reactive oxygen species (ROS), selectivity, and high phototoxicity are particularly emphasized. Photodynamic therapy offers a wide variety of photosensitizers to choose from. Among them, porphyrins are commonly used photosensitizers due to their excellent photophysical properties caused by their cyclic structure with 18 conjugated π electrons. Examples include photofrin, temoporfin, photochlor, and redaporfin, some of which have been approved by the FDA for clinical cancer treatment. To enhance the effects of these structures, scientists have studied the combination of porphyrins with some inorganic compounds, such as platinum complexes.

[0006] Platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin are widely used to treat bladder cancer, ovarian cancer, head and neck cancer, testicular cancer, and lung cancer. However, although these drugs are first-line treatments in clinical practice, they all have serious side effects, such as nephrotoxicity, ototoxicity, hepatotoxicity, gastrointestinal dysfunction, and cardiotoxicity. Furthermore, many tumors exhibit inherent or acquired resistance to platinum-based drugs, which limits their clinical use. In recent years, researchers have devoted considerable effort to developing new platinum-based anticancer complexes, but to date, only a very small number of platinum-based anticancer complexes have achieved clinical application worldwide. For example, Lipoplatin is a nanomedicine of approximately 110 nm size formed by encapsulating cisplatin in liposomes.

[0007] Coordination of porphyrins with platinum complexes provides an important pathway for generating compounds with both cytotoxicity and photodynamic therapy (PDT) characteristics to achieve synergistic therapeutic effects and reduce the side effects associated with using each drug alone. Currently, many platinum complexes that can be activated by infrared light have been developed. These complexes all exhibit excellent singlet oxygen quantum yields, indicating their potential as PDT drugs. Furthermore, the presence of the heavy metal platinum enhances the number of triplet states in the photoexcited state and promotes the photochemical degradation pathway during photophysical decay. [The text then abruptly shifts to a seemingly unrelated topic:] ...with divalent platinum preparations Pt... (II) In comparison, Pt (IV) The prodrug complexes based on this principle exhibit negligible toxic side effects in vivo because they release only the active platinum(II) analogue into the tumor environment, thereby minimizing interactions with blood proteins or other biomolecules.

[0008] In 1975, scientists first reported the use of HpD (a hematoporphyrin derivative) to inhibit mammary fat tumors in mice. Since then, porphyrins and their derivatives have been used in photodynamic therapy and are considered first-generation photosensitizers. Among these porphyrin derivatives, Photofrin is the most representative and has been approved for clinical use. However, these porphyrin-based photosensitizers have poor selectivity for tumors and accumulate significantly in the skin, causing photosensitivity.

[0009] Second-generation photosensitizers include 5-aminolevulinic acid (5-ALA), phthalocyanine, dihydroporphyrin e6, benzo[a]porphyrin derivatives, and bacterial green analogs. These photosensitizers exhibit high selectivity for tumors and low accumulation in the skin. Their maximum absorption typically falls within the 630-800 nm range, thus extending the depth of photothermal treatment (PDT). However, these hydrophobic photosensitizers have poor circulating half-lives and exhibit significant self-aggregation effects, both of which negatively impact overall therapeutic efficacy.

[0010] With the rapid development of nanomedicine, materials scientists have developed various nanocarriers for photosensitizer delivery, which can enhance the accumulation of photosensitizers within tumors. In 2006, Kono's research group synthesized polyethylene glycol-modified dendritic materials for loading photoporphyrin IX (PpIX) or hydrophobic rose red (RB) for phototherapy treatment (PDT). In 2015, Zhao Yanli's research group utilized the large cavity and high surface area of ​​hollow mesoporous SiO2 nanoparticles (HMSNs) to synthesize folic acid-bound HMSNs to load 5-ALA, thereby achieving targeted PDT for B16F10 (melanoma). In 2009, Wang Kemin's research group used a water-in-oil reverse microemulsion method to co-condense the silanol groups between methylene blue (MB) and tetraethyl orthosilicate (TEOS), obtaining MB-grafted SiO2 nanoparticles that showed almost no MB leakage during in vivo circulation and exhibited strong resistance to myocardial flavoprotein transactivation. However, the long-term biosafety of these nanocarriers needs further evaluation before third-generation photosensitizers can be used clinically.

[0011] Platinum complexes are renowned for their antitumor activity. To date, thousands of platinum complexes have been prepared and evaluated as potential anticancer drugs. However, platinum-based drugs exhibit rather poor tumor selectivity, and systemic toxicity and drug resistance are major drawbacks. Therefore, chemical and biomedical researchers have shown great interest in functionalizing platinum complexes with bioactive molecules, photosensitizers, nanomaterials, and other components. The motivations for functionalization stem from needs such as: improving tumor selectivity or minimizing systemic toxicity, enhancing drug accumulation in cells, overcoming tumor resistance, imaging drug molecules in vitro or in vivo, achieving synergistic anticancer effects across different therapeutic modalities, or adding additional functions to drugs.

[0012] In recent years, scientists have been attempting to link platinum-based drugs to porphyrin derivatives via chemical bonds to obtain synergistic PDT and chemotherapeutic anticancer activities from single prodrugs. For example, the Spingler group reported the synthesis of platinum-based porphyrin compounds from commercially available 5,10,15,20-tetra(4-pyridyl)porphyrins and platinum complexes with different substitutions, and investigated their photophysical characteristics and in vitro photoinduced anticancer properties (Angew. Chem. 2014, 126, 7058-7061). The properties were determined by photobleaching analysis based on 9,10-dimethylanthracene in N,N-dimethylformamide (DMF). 1 The quantum yield of O2 was measured. The results showed that all coordination compounds exhibited excellent quantum yield. 1 The O2 quantum yield indicates that they all possess PDT potential. Furthermore, these complexes are lipophilic cations. The chemoelectric potential between the inner and outer layers of the cell membrane favors the diffusion of cations, thereby enhancing their cellular uptake (passive targeting).

[0013] Li et al. prepared polymer nanoparticles by combining oxaliplatin with a polyethylene glycol-modified porphyrin photosensitizer (photosensitizer), achieving a synergistic anticancer effect of chemotherapy and drug delivery therapy (PDT). The negative charge on the surface of the nanoparticles and the polyethylene glycol (PEG) give them good stability in the bloodstream, minimizing protein adsorption (Adv. Mater. 2019, 31, 1805888). Upon reaching the tumor site, the PEG on the particle surface is decomposed by matrix metalloproteinase MMP-2, and its surface charge changes from negative to positive in the acidic tumor microenvironment (pH = 6.8), thereby improving the penetration of the nanosystem into deep tumors and the efficiency of drug delivery.

[0014] In 2019, Zhao's research group designed a nanomedicine (PEG-Por-CD:oxliPt(IV)-ada), which was synthesized through self-assembly via a host-guest interaction between an oxaliplatin prodrug (oxliPt(IV)-ada) and a porphyrin photosensitizer (PEG-Por-CD) (ACS Appl. Mater. Interfaces 2019, 11, 16391-16401). Amphiphilic host-guest complexes were prepared by modifying porphyrin and oxaliplatin prodrug with β-CD and ada, respectively, followed by self-assembly. This nanomedicine exhibits good biocompatibility, accumulates at tumor sites, and decomposes under reducing conditions, releasing the therapeutic drug.

[0015] However, existing platinum complexes exhibit poor tumor selectivity, and systemic toxicity and drug resistance are major drawbacks. Although various nanoparticle-based platinum-based drug delivery systems for tumor targeting have been proposed, in vivo delivery of these nanostructures to the target site remains suboptimal due to the clearance of the endothelial reticulum system (RES). Furthermore, the supramolecular drug delivery system constructed by Zhao's research group has extremely complex components, limiting its clinical feasibility. Therefore, using porphyrins and other functional molecules as building blocks to form compounds through ion pairs, and then fabricating structurally controllable multifunctional nanoparticles through simple nanoencapsulation techniques, can effectively address these issues. Simultaneously, the prepared nanoparticles possess an EPR effect, which can increase nanoparticle accumulation at tumor cells. The self-assembled nanoparticles exhibit excellent biocompatibility and a long blood circulation time, all of which are beneficial for expanding their biological applications. Summary of the Invention

[0016] To address the aforementioned technical problems, this invention provides polyethylene glycol-based nanoparticles based on pyridylporphyrin, their preparation method, and applications. This invention synthesizes a platinum ion compound [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) based on pyridylporphyrin that is stable under acidic conditions. Due to its broad and strong absorption peak in the 630-660 nm UV absorption spectrum, this invention hypothesizes that it possesses high [potential for] photodynamic therapy within the photodynamic therapy window. 1 O2 quantum yield, which can be used as a photosensitizer in PDT. Furthermore, to improve the stability of this compound and prolong its blood circulation time, polyethylene glycol-modified nanoparticles, abbreviated as [H8TMPP]-Pt-PEG, were obtained by mixing a tetrahydrofuran solution of 1,2-dioleoylglycerol-3-phosphocholine (DOPC), cholesterol, and distearate phosphatidylethanolamine 2000 (DSPE-PEG) in a 2:2:1 molar ratio with an ethanol / water (v / v = 1 / 2) mixture of the ionic compound. Cell viability assays showed that, under light-free conditions, [H8TMPP]-Pt-PEG exhibited strong cytotoxicity against mouse melanoma cells (B16F10), with an IC50 value of [H8TMPP]-Pt-PEG. 50 The value was 11.6 μg / mL. Under 650 nm laser irradiation, a concentration of 0.45 μg / mL could kill more than 90% of B16F10 cancer cells. At the same time, in vivo anti-cancer experiments in mice also fully demonstrated the synergistic anti-cancer efficacy of chemotherapy and PDT therapy.

[0017] This invention is achieved through the following technical solution:

[0018] The first objective of this invention is to provide PEGylated nanoparticles based on pyridylporphyrin, wherein the nanoparticles are spherical nanoparticles with a core-shell structure; the shell is a lipid-polyethylene glycol bilayer structure; and the core is a platinum ion compound based on pyridylporphyrin.

[0019] The platinum ion-type compound based on pyridylporphyrin was prepared by mixing pyridyl alcohol ligands with PtCl2(PhCN)2.

[0020] In one embodiment of the present invention, the lipid-polyethylene glycol bilayer structure is prepared from lipids, stabilizers and distearate phosphatidylethanolamine.

[0021] In one embodiment of the present invention, the lipid is selected from 1,2-dioleoyl-glycerol-3-phosphocholine.

[0022] In one embodiment of the present invention, the stabilizer is selected from one or more of cholesterol, stigmasterol, and β-sitosterol.

[0023] In one embodiment of the present invention, the polyethylene glycol in the distearate has a molecular weight of 500 Da to 5000 Da. Specifically, it is distearate phosphatidylethanolamine 2000, distearate phosphatidylethanolamine 500, distearate phosphatidylethanolamine 750, distearate phosphatidylethanolamine 1000, distearate phosphatidylethanolamine 5000, etc.; preferably, it is distearate phosphatidylethanolamine 2000.

[0024] In one embodiment of the present invention, the molar ratio of the lipid, stabilizer and distearate phosphatidylethanolamine is 2:2:1.

[0025] In one embodiment of the present invention, the pyridine alcohol ligand is selected from one or more of meso-5,10,15,20-tetra(6-methyl-3-pyridine)porphyrin, meso-5,10,15,20-tetra(6-ethyl-3-pyridine)porphyrin, meso-5,10,15,20-tetra(6-isopropyl-3-pyridine)porphyrin, meso-5,10,15,20-tetra(6-tert-butyl-3-pyridine)porphyrin, and meso-5,10,15,20-tetra(6-phenyl-3-pyridine)porphyrin.

[0026] A second objective of this invention is to provide a method for preparing the pyridylporphyrin-based polyethylene glycol nanoparticles, comprising the following steps:

[0027] (1) Pyridine alcohol ligands were mixed with PtCl2(PhCN)2 and acetic acid, benzonitrile was added, and the mixture was heated to obtain a platinum ion compound based on pyridyl porphyrin.

[0028] (2) The lipid and stabilizer are mixed in an organic solvent, and an alcohol solution of the platinum ion compound based on pyridylporphyrin obtained in step (1) is added and mixed with distearate phosphatidylethanolamine to obtain pyridylporphyrin-based polyethylene glycol nanoparticles.

[0029] A third objective of this invention is to provide the application of the aforementioned pyridylporphyrin-based polyethylene glycol-modified nanoparticles in the preparation of antitumor drugs.

[0030] In one embodiment of the present invention, the drug is a drug for combined photodynamic therapy and chemotherapy.

[0031] In one embodiment of the present invention, the tumor is selected from one or more of melanoma, glioma, colon cancer, lung cancer, breast cancer, liver cancer, and ovarian cancer.

[0032] This invention utilizes the hydrothermal reaction of H2TMPP ligand with PtCl2(PhCN)2 to obtain a highly water-soluble salt compound, [H8TMPP]2(PtCl6)5(Cl)2·2(HCl). Due to its strong absorption peak at 630-660 nm, within the phototherapy window, it is speculated that this compound possesses high [potential for phototherapy]. 1 O2 quantum yield can be applied to chemotherapy and PDT combination therapy for tumors. To overcome its limitation of only being stable under strong acid conditions (pH < 1.9) and to expand its biological applications, a polyethylene glycolization scheme was adopted. Utilizing hydrophilic-hydrophobic interactions, [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) was encapsulated with cholesterol / distearate phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) / dioleoyl lecithin (DOPC) to prepare nanoparticles (labeled as [H8TMPP]-Pt-PEG).

[0033] This invention utilizes porphyrins and their derivatives containing varying degrees of protonation as cations, and simultaneously uses bioactive metal ions and compounds (including anticancer activities) as anions to form ion-pair compounds. Based on this, biocompatible polymer materials are used to encapsulate these compounds to prepare nanoparticle materials. The resulting materials are then investigated for synergistic treatment of tumors (such as melanoma, glioma, colon cancer, lung cancer, breast cancer, liver cancer, or ovarian cancer) using chemotherapy and phototherapy (PDT).

[0034] The technical solution of the present invention has the following advantages compared with the prior art:

[0035] (1) This invention solves many problems of traditional platinum-based drugs by combining platinum-based drugs with protonated porphyrins via ion pairs. These problems mainly include improving the water solubility of platinum-based drugs and their cytotoxic effects on tumor cells, thus achieving a synergistic anti-cancer effect of chemotherapy and PDT therapy. The material does not require a complex preparation process, is easy to operate, and is easy to encapsulate.

[0036] (2) In the material of this invention, platinum exhibits a positive tetravalent (Pt) IVThe platinum hexachloroplatinum ions are free on the protonated porphyrin. Utilizing the relatively easy interconversion between platinum oxidation states, the reduction of non-cytotoxic octahedral platinum (IV) compounds into significantly cytotoxic planar square platinum (II) complexes within cells can prevent tumor cell hypoxia and thus sensitize PDT. Furthermore, polyethylene glycol-modified nanoparticles were obtained by mixing a tetrahydrofuran solution of 1,2-dioleoylglycerol-3-phosphocholine (DOPC), cholesterol, and distearate phosphatidylethanolamine 2000 (DSPE-PEG 2000) in a 2:2:1 molar ratio with an ethanol / water (v / v = 1 / 2) mixture of the ionic compound, which improved the stability of the compound and prolonged its blood circulation time.

[0037] (3) The antitumor effects, in vivo distribution, and blood circulation time of cisplatin and [H8TMPP]-Pt-PEG were compared in vitro / in vivo. Compared with cisplatin, [H8TMPP]-Pt-PEG nanoparticles exhibited superior combined chemotherapy and PDT anticancer efficacy at both cellular and animal levels due to their enhanced high-permeability long retention (EPR) effect, prolonged blood circulation time, and increased tumor accumulation. Attached Figure Description

[0038] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings, wherein...

[0039] Figure 1 This is a schematic diagram of the synthesis and crystal structure of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) in this invention;

[0040] Figure 2 This is a schematic diagram illustrating the synthesis of [H8TMPP]-Pt-PEG in this invention;

[0041] Figure 3 This is the PXRD pattern of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) in this invention;

[0042] Figure 4 This is the infrared spectrum of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) in this invention;

[0043] Figure 5 These are the UV-Vis images of H2TMPP and [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) in this invention;

[0044] Figure 6This is the UV absorption spectrum of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) in aqueous solutions at different pH values ​​in this invention;

[0045] Figure 7 The X-ray photoelectron spectroscopy (X-ray photosensitizer) characterization of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) in this invention;

[0046] Figure 8 These are the TEM image and hydrodynamic diameter diagram of [H8TMPP]-Pt-PEG in this invention;

[0047] Figure 9 The graph (a) shows the cell viability of B16F10 cells after 12 hours of treatment with different treatment groups in this invention, and the corresponding half-inhibition concentration curve (b).

[0048] Figure 10 These are fluorescence micrographs of B16F10 cells incubated with [H8TMPP]-Pt-PEG in this invention; cell nuclei were stained with Hoechst 33258.

[0049] Figure 11 In this invention, B16F10 cells are treated with [H8TMPP]-Pt-PEG and DCFH-DA and then subjected to laser treatment (650nm, 25mW cm⁻¹). -2 Fluorescence microscope images after irradiation;

[0050] Figure 12 The following are flow cytometry images of (a) cell uptake and (b) intracellular ROS after B16F10 was incubated with [H8TMPP]-Pt-PEG for 2 hours in this invention.

[0051] Figure 13 This is a graph showing the relationship between the concentration of [H8TMPP]-Pt-PEG and the hemolysis rate in this invention;

[0052] Figure 14 This describes the in vivo anti-tumor effect of the present invention. (a) Tumor growth inhibition curve; (b) Mouse weight change curve; (c) Survival rate curve of mice in each treatment group; (d) Tumor weight graph of each treatment group; (e) Tumor photograph of each treatment group;

[0053] Figure 15 This is the tissue distribution of (a) [H8TMPP]-Pt-PEG and (b) cisplatin after intravenous injection of the material in this invention. Organs: heart (H), lung (Lu), liver (Li), kidney (K), spleen (Sp), tumor (T), (c) in vitro fluorescence imaging of mice 2 h (left) and 8 h (right) after injection of porphyrin;

[0054] Figure 16 This is the time-dependent curve of plasma platinum concentration after intravenous injection of cisplatin and [H8TMPP]-Pt-PEG nanoparticles in this invention. Detailed Implementation

[0055] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0056] This invention synthesizes a platinum-based ionic compound, [H8TMPP]2(PtCl6)5(Cl)2·2(HCl), which is stable under acidic conditions. Its structure and composition were determined using X-ray single-crystal diffraction, elemental analysis, X-ray powder diffraction, Fourier transform infrared spectroscopy, energy-dispersive spectroscopy, and ultraviolet-visible spectrophotometry. Due to a strong broad absorption peak in the 630-660 nm ultraviolet absorption spectrum, within the PDT therapeutic window, it is presumed to possess high [potential for high-concentration ionization]. 1 The O2 quantum yield can be applied to the combined chemotherapy and photodynamic therapy (PDT) for tumors. In subsequent studies, this invention used DOPC / cholesterol / DSPE-PEG 2000 as a raw material and PEGylated it to obtain a water-soluble PEGylated product, [H8TMPP]-Pt-PEG, which is stable under neutral conditions. In a series of in vitro and in vivo experiments, this invention found that compared with the common anticancer drug cisplatin, [H8TMPP]-Pt-PEG exhibits a longer blood circulation time and increased tumor accumulation due to the enhanced EPR effect. After combined with 650nm laser therapy, tumor growth was completely inhibited, fully demonstrating the combined anticancer effect of [H8TMPP]-Pt-PEG in chemotherapy and photodynamic therapy. The material used in this invention is simple to prepare, has a high yield, and exhibits good synergistic effects between PDT and chemotherapy, making it a potentially valuable antitumor material.

[0057] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials and reagents used are commercially available.

[0058] B16F10 cells (mouse melanoma cells) were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). The culture medium was DMEM supplemented with 10% FBS and 1% penicillin / streptomycin. The cells were cultured in a cell incubator at 37°C and 5% CO2. Cells in the logarithmic growth phase were used for experiments.

[0059] BALB / c nude mice, female, 6–8 weeks old, 18–22 grams, were purchased from the Zhejiang Academy of Medical Sciences. The animals were housed in a sterile, closed environment with a constant temperature of 18–22℃ and a constant humidity of 50–80%. Animal experiments were conducted in accordance with the Animal Protection Law of the People's Republic of China (CAPN). All animal experiments complied with the relevant regulations of the Laboratory Animal Management Committee.

[0060] Statistical processing of data: Experimental data are expressed as mean ± standard deviation. Analysis of variance (ANOVA) and Student's t-test were used to determine significant differences between groups. * P<0.05 ** P<0.01 *** P<0.001 and **** P<0.0001).

[0061] Example 1: Synthesis and Physicochemical Characterization of [H8TMPP]-Pt-PEG Material

[0062] 1. Synthesis of compound PtCl2(PhCN)2

[0063] Add K₂PtCl₄ (0.100 g, 0.241 mmol) and 10 mL of distilled water to a round-bottom flask and stir to obtain a clear solution. Add benzonitrile (0.120 g, 1.163 mmol) to the above solution and stir the mixture at room temperature for three days until the initial solution changes from red to colorless. After stirring, a green solid precipitates, which is then extracted with CH₂Cl₂. The extract is dried over anhydrous sodium sulfate, filtered, and the liquid is removed by evaporation under reduced pressure to obtain a bright green crude solid product. Wash the crude product with diethyl ether 2-3 times and dry under vacuum to obtain pure PtCl₂(PhCN)₂ (0.097 g, yield 85%).

[0064] 1 H NMR (400MHz, CDCl3): δ7.88-7.78(m,4H), 7.78-7.71(m,2H), 7.61-7.52(m,4H).

[0065] Synthesis of compound [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) (synthesis schematic diagram shown) Figure 1 As shown; the preparation method of H2TMPP refers to patent CN107903272B)

[0066] Meso-5,10,15,20-tetra(6-methyl-3-pyridine)porphyrin (H₂TMPP, 1.0 mg, 0.0015 mmol), PtCl₂(PhCN)₂ (2.0 mg, 0.0042 mmol), and acetic acid (20 μL) were placed in a Pyrex glass tube, dissolved in benzonitrile, and transferred to a programmable oven. The mixture was heated to 120 °C over 3 hours and maintained at this temperature for 48 hours, then cooled to room temperature over 12 hours to obtain purplish-black rod-shaped crystals. The solid product was collected by centrifugation, washed three times with diethyl ether, and dried under vacuum to obtain the solid product [H₈TMPP]₂(PtCl₆)₅(Cl)₂·2(HCl).

[0067] 3. Synthesis of [H8TMPP]-Pt-PEG (synthesis schematic diagram shown in Figure 1) Figure 2 (As shown)

[0068] DOPC (30.1 mg, 0.038 mmol) and cholesterol (13.0 mg, 0.034 mmol) were mixed in 20 mL of THF, stirred until homogeneous, and then transferred to a 50 mL round-bottom flask and stirred under reflux. Separately, [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) (30.8 mg, 0.0176 mmol) was added to a mixed solvent of H2O / EtOH (20 mL / 10 mL). Initially, dissolution was slow, but the solid dissolved immediately after the addition of a few drops of concentrated HCl. The [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) solution was added to the above THF solution and refluxed for 1 h. Then, DSPE-PEG 2000 (16.3 mg, 0.00815 mmol) was added to the above mixed solution and refluxed at 80 °C overnight. After dialysis with a dialysis bag with a molecular weight cutoff of 3500 for 48 h, an aqueous solution of the product [H8TMPP]-Pt-PEG was obtained and stored in a -80 °C refrigerator for later use.

[0069] 4. Material Characterization

[0070] The platinum porphyrin ionic compounds [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) and the polyethylene glycol-modified [H8TMPP]-Pt-PEG were characterized by X-ray single crystal diffraction (SCXRD), elemental analysis, X-ray powder diffraction (PXRD), Fourier transform infrared (FT-IR), ultraviolet-visible absorption (UV-Vis), and transmission electron microscopy (TEM) to determine their structural characteristics. The specific characterization is summarized below:

[0071] (1) The X-ray single-crystal diffraction (SCXRD) data of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) are as follows: Molecular formula C 88 H 80 Cl 33 N 16 Pt5; molecular weight 3506.98; crystal system orthorhombic; space group Pbam; 15.0532(8); 30.0670(17); 13.9586(8);α / °90;β / °90;γ / °90; 6317.7(6); Z 2; D c / (g cm -3 1.844; μ(Mo-Kα) / mm -1 6.260; F(000) 3342; Total number of diffraction points 177306; Number of independent diffraction points 7894; Number of observable diffraction points (I>2σ(I)) 4178; R index [I>2σ(I)] R1=0.0953, wR2=0.2491; GOF 1.136.

[0072] (2) Structural description of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl).

[0073] A purplish-black rod-shaped ionic platinum-based porphyrin compound, [H8TMPP]2(PtCl6)5(Cl)2·2(HCl), was prepared by hydrothermal method, and its structure was determined by X-ray single-crystal diffraction. From the single-crystal structure... Figure 2 As can be seen, the four pyridine N atoms in the H2TMPP ligand and the two pyrrole N atoms at the center of the porphyrin skeleton are completely protonated, forming a +6 valent cation structure. In this structure, the porphyrin skeleton undergoes deformation due to the lack of conjugation. [PtCl6] 2- Ions are free outside the protonated porphyrin ring, thus maintaining the valence equilibrium of the entire ionic compound.

[0074] (3) Powder diffraction pattern of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl):

[0075] like Figure 3 As shown, the actual powder diffraction pattern of the crystal generated by the reaction of H2TMPP and PtCl2(PhCN)2 is basically consistent with the powder diffraction pattern generated by fitting the single crystal structure, proving that the structure of the obtained crystal powder is consistent with the single crystal structure, which is [H8TMPP]2(PtCl6)5(Cl)2·2(HCl).

[0076] (4) Elemental analysis (%) of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl): C 88 H 80 Cl 33 N 16 Pt5: Theoretical values: C 30.11, H 2.28, N 6.39; Actual measured values: C 29.74, H 2.75, N 6.60.

[0077] (5) Infrared spectrum of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl) Figure 4 ) and data: 3440.85(m),3098.53(m),3031.48(m),2906.38(w),2839.29(w),2579.16(w),2 162.94(w),2046.08(w),1638.56(s),1601.99(vs),1545.78(s),1494.69(s),1450.5 6(m),1380.49(w),1288.66(s),1234.5(s),1142.64(s),1084.21(m),1043.81(s),98 4.39(vs),882.46(s),853.73(s),823.98(vs),801.71(vs),714.17(vs),643.34(s).

[0078] (6) UV absorption spectrum of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl):

[0079] Figure 5 These are the UV absorption spectra of H2TMPP and [H8TMPP]2(PtCl6)5(Cl)2·2(HCl). It can be observed that the UV absorption peak of the protonated platinum porphyrin ion compound exhibits a red shift, and the Q band decreases. Furthermore, a strong absorption peak appears at a wavelength of 635 nm, within the corresponding PDT therapeutic window, suggesting that this compound has the potential for photodynamic therapy.

[0080] During the experiment, it was found that the compound dissolved in aqueous solutions of different pH values ​​produced different colors of solutions. Therefore, the ultraviolet absorption spectra of the solutions were measured to determine their stability conditions. Figure 6 It can be seen that this compound can only exist stably under strongly acidic conditions with a pH not greater than 1.91, and its ultraviolet absorption spectrum remains unchanged.

[0081] (7) X-ray photoelectron spectroscopy of [H8TMPP]2(PtCl6)5(Cl)2·2(HCl).

[0082] To determine the valence state of platinum in [H8TMPP]2(PtCl6)5(Cl)2·2(HCl), X-ray photoelectron spectroscopy (X-ray photosensitizer) was performed. Figure 7 a is the Pt 4f spectrum of compound [H8TMPP]2(PtCl6)5(Cl)2·2(HCl). By comparing it with the X-ray photosensitizer spectrum of platinum complex in the literature, it was found that 72.6 eV and 75.9 eV correspond to the 4f spectrum of Pt(II), respectively. 7 / 2 and 4f 5 / 2 74.2 eV and 77.5 eV correspond to the 4f of Pt(IV), respectively. 7 / 2 and 4f 5 / 2 . Figure 7 b is the Cl 2p spectrum of compound [H8TMPP]2([PtCl6])5(Cl)2, where 198.0 eV corresponds to the Pt(IV)-Cl bond and 199.5 eV corresponds to the Pt(II)-Cl bond. Overall analysis indicates that Pt(II) and Pt(IV) coexist in [H8TMPP]2(PtCl6)5(Cl)2·2(HCl).

[0083] (8) TEM analysis of polyethylene glycolated [H8TMPP]-Pt-PEG.

[0084] By encapsulating [H8TMPP]-Pt-PEG nanoparticles with cholesterol / DOPC / DSPE-PEG2000 through non-covalent interactions, polyethylene glycol-modified [H8TMPP]-Pt-PEG nanoparticles were prepared. This method utilizes the hydrophobic / hydrophobic interactions between DOPC / cholesterol / DSPE-PEG2000 to form a self-assembled asymmetric lipid-polyethylene glycol bilayer on the surface of a platinum ion compound, in which cholesterol acts as a stabilizer. Figure 8 The TEM image obtained by dropping the prepared [H8TMPP]-Pt-PEG aqueous solution onto a copper grid shows that the polyethylene glycol-modified material forms spherical nanoparticles with a core-shell structure, approximately 200 nm in size. Furthermore, it was found that the hydrodynamic diameter measured by DLS is 10-20 nm larger than the particle size determined by TEM. Figure 8 (b illustration) This can be attributed to the lipid layer of DOPC / cholesterol / DSPE-PEG2000 on the particle surface and the swelling of the particle core.

[0085] Example 2: Cellular Experiments with [H8TMPP]-Pt-PEG

[0086] 1. Cytotoxicity assay

[0087] The MTT assay was used to evaluate the cytotoxicity of the material to B16F10 cells. Two 96-well plates were prepared for phototoxicity and dark toxicity experiments. (The last sentence appears to be incomplete and possibly refers to a specific assay or method.) 4 B16F10 cells were seeded at a cell / well density and cultured at 37°C and 5% CO2 for 16 h. For phototoxicity assays, cells were co-incubated for 6 h with serum-free DMEM solution of [H8TMPP]-Pt-PEG containing gradient platinum ion concentrations (0.5 μg / mL, 1.0 μg / mL, 2.0 μg / mL, 4.0 μg / mL, 8.0 μg / mL), followed by irradiation at 650 nm (25 mW cm⁻¹). -2 Cells were incubated for 2 min, and then cultured for another 6 h. For the dark toxicity assay, cells were co-incubated directly with cisplatin and [H8TMPP]-Pt-PEG for 12 h. Then, MTT solution (200 μL, 0.5 mg / mL) was added. -1 Add the solution to each well and culture the cells at 37°C. After 4 hours, discard the MTT solution by flipping the plate. Add 100 μL of DMSO to dissolve the formazan crystals, shake on a shaker for 5 minutes, and then measure the absorbance at 570 nm using a microplate reader. Untreated cells were used as a control.

[0088] To investigate the synergistic anticancer efficacy of [H8TMPP]-Pt-PEG, cytotoxicity and PDT experiments were conducted. First, 2 mL of the original solution obtained after dialysis in the previous synthesis steps was placed in a centrifuge tube, and 2 mL of 0.1 M PBS sample solution was added to obtain a 4 mL solution. 1 mL of this solution was then taken, and 2 mL of DMEM was added, and the solution was serially diluted to prepare five samples with varying concentrations.

[0089] Approximately 2 million B16F10 cells were suspended in DMEM medium containing 10% FBS (fatal bovine serum) and 1% photosensitizer (Penicillin-streptomycin; antagonist). The cells were transferred to culture dishes, and 10 mL of DMEM (10% FBS + 1% photosensitizer) was added. The cells were incubated at 37.5°C with 5% CO2 for two days. The culture medium was then removed. The cells were rinsed with 0.5 mL of trypsin (containing 0.25% EDTA), followed by digestion with 2 mL of trypsin (containing 0.25% EDTA) for 3 minutes in an incubator. The trypsin was neutralized with 3 mL of DMEM medium, followed by centrifugation at 1000 rpm for 3 minutes. The solution was removed, and the cells were resuspended in 3 mL of DMEM medium, centrifuged again, and the DMEM was removed.

[0090] The obtained cells were remixed with DMEM (6 mL), and 10 μL was taken to count approximately 1 million cells per mL. 1 mL of cells was diluted with 12 mL of DMEM (10% FBS + 1% photosensitizer), thoroughly mixed, and plated in a 96-well MTT plate. Cells were added to each well of the 96-well MTT plate at 200 μL (B1-F12). After incubation for 16 h, the culture medium was removed, and different concentrations of the drug were added. The PDT group was incubated for another 12 h, then irradiated with PDT light (650 nm, 100 mW; 6 min) and incubated for 9 h. The group without PDT was incubated for 21 h. Both groups were then incubated for 4 h after removing the drug and adding 100 μL of MTT solution to each well. The MTT was then removed, and the resulting formazan was dissolved in 100 μL of DMSO per well. After shaking for 3 min, the absorbance at 570 nm was measured using a microplate reader to obtain the corresponding viability. The relationship between drug concentration and cell viability is as follows: Figure 9 As shown.

[0091] Figure 9 This refers to the cytotoxicity results of cisplatin, [H8TMPP]-Pt-PEG, and [H8TMPP]-Pt-PEG+PDT. Experimental results show that, without laser irradiation, cisplatin alone or [H8TMPP]-Pt-PEG (ICP-PDT) exhibits cytotoxicity. 50 The [H8TMPP]-Pt-PEG concentration (11.6 μg / mL) showed low toxicity to B16F10 cells, but compared to cisplatin, [H8TMPP]-Pt-PEG exhibited better tumor-suppressing effects, possibly due to the longer blood circulation time of the PEGylated porphyrin. When [H8TMPP]-Pt-PEG was combined with a laser (650 nm, 25 mW cm⁻¹), [H8TMPP]-Pt-PEG showed better tumor suppression. -2 After treatment (2 minutes), the killing effect on cancer cells was significantly enhanced. Figure 9 a) its IC 50 The value was only about 2 μg / mL, which is approximately the IC50 value of the cisplatin group. 50 At a concentration of 0.45 μg / mL, [H8TMPP]-Pt-PEG, which is 1 / 18th the effective value, can kill more than 90% of B16F10 cells, fully demonstrating the synergistic anti-cancer efficacy of chemotherapy and photodynamic therapy. Figure 9 b).

[0092] 2. Cell uptake experiment

[0093] B16F10 cells were incubated with [H8TMPP]-Pt-PEG at a concentration of 30 μg / mL porphyrin, and the uptake of [H8TMPP]-Pt-PEG by the cells was observed under an inverted fluorescence microscope. The results are as follows: Figure 10 The study showed that porphyrin exhibited red fluorescence within the cells, and co-localization of blue and red revealed that [H8TMPP]-Pt-PEG was successfully taken up into the cytoplasm. Figure 12The flow cytometry results of a further confirmed that [H8TMPP]-Pt-PEG was successfully taken up by the cells.

[0094] 3. Detection of intracellular ROS levels

[0095] The production of intracellular ROS in B16F10 cells under light irradiation was determined using 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA). Figure 11 As can be seen, compared with the control group, the cells treated with [H8TMPP]-Pt-PEG showed green fluorescence of DCF, indicating the generation of ROS within the cells. Figure 12 This was further confirmed by the flow cytometry results of b.

[0096] 4. Hemolysis test

[0097] Blood was collected from mice after enucleation to assess the blood compatibility of [H8TMPP]-Pt-PEG via a hemolysis test. After co-incubation with erythrocytes at 37°C for 4 hours, the hemolysis rate of [H8TMPP]-Pt-PEG was less than 2% within the concentration range of 0.025-0.5 mg / mL. Figure 13 This indicates that [H8TMPP]-Pt-PEG has good biocompatibility and is suitable for biological applications.

[0098] Example 3: Zoological Experiments with [H8TMPP]-Pt-PEG

[0099] 1. Establishment of animal tumor models

[0100] Under aseptic conditions, a suspension of B16F10 cells (100 μL, 2 × 10⁻⁶ cells) was subcutaneously injected into the right lateral region of BALB / c nude mice. 6 (number of tumors), until the average tumor volume reaches 90mm. 3 At that time, group experiments were conducted, and this day was set as day 0.

[0101] 2. The in vivo antitumor efficacy of photochemotherapy was evaluated using BALB / c tumor-bearing nude mice.

[0102] Nude mice with similar tumor sizes were randomly divided into four groups: PBS, cisplatin, [H8TMPP]-Pt-PEG, and [H8TMPP]-Pt-PEG+L, with five mice in each group. Mice received PBS, cisplatin (3.0 mg Pt / kg), and [H8TMPP]-Pt-PEG (3.00 mg Pt / kg) via tail vein injection twice weekly. For the [H8TMPP]-Pt-PEG+L group, laser therapy (650 nm, 100 mW cm⁻¹) was administered for 8 minutes four hours after each administration. -2The mice were irradiated every 10 seconds for 4 minutes, for a total of 3 weeks of drug and laser treatment. During the treatment period, the mice were weighed every three days, and the tumor size was measured. The tumor volume was calculated using the formula: (length) × (width). 2 / 2.

[0103] like Figure 14 As shown, this invention records relevant data such as tumor volume and mouse weight in mice during different treatments in each group. Figure 14 b shows that there was no significant change in the body weight of mice in each group before and after treatment, indicating that the intervention did not affect the normal physiological metabolic activities of the mice. From Figure 14 a's tumor growth inhibition curve and Figure 14 As shown in the tumor weight map (d), compared to the control group injected with PBS, tumor growth in mice receiving single chemotherapy (cisplatin and [H8TMPP]-Pt-PEG) was inhibited to some extent. Furthermore, due to the EPR effect of the nanoparticles, the uptake of the drug by cancer cells increased, resulting in a slightly better tumor-inhibiting effect of [H8TMPP]-Pt-PEG nanoparticles than cisplatin, and a higher survival rate in the mice. Figure 14 c). From Figure 14 Figures a, d, and e show that [H8TMPP]-Pt-PEG, when combined with laser therapy, can completely inhibit tumor growth, and the survival rate of mice during treatment is 100%. However, due to the limited penetration of the laser, the penetrated cancer cells are far from the epidermis, and photodynamic therapy alone is almost insufficient to completely remove the primary tumor.

[0104] 3. In vivo drug distribution study

[0105] Taking advantage of the red emission property of porphyrin, nude mice injected with [H8TMPP]-Pt-PEG (3.00 mg Pt / kg, n=5) via tail vein were sacrificed at 2 and 8 hours. Heart, liver, spleen, lung, kidney, and tumors were harvested, and the distribution of the material in each organ and tumor was observed and photographed using a small animal in vivo fluorescence imaging system (M-MSI-EX, CRI). Furthermore, to quantitatively compare the distribution of the material in vivo at different times and in different organs, the collected organs and tumors were ground, homogenized, centrifuged, and a certain amount of the supernatant was lysed with nitric acid. The lysate was analyzed by ICP-MS to determine the platinum ion content in each organ and tumor at 2 and 8 hours. Simultaneously, mice in the cisplatin group (3 mg Pt / kg) were treated under the same conditions to determine the distribution of cisplatin in various organs and tumors at 2 and 8 hours.

[0106] Biodistribution of cisplatin and [H8TMPP]-Pt-PEG in tumors and other organs, such as Figure 15As shown in the figure. According to the ICP-MS results, due to rapid clearance, cisplatin accumulation in the tumor was insufficient, only 0.69 μg / g, while it accumulated more in the liver, lungs, kidneys, and spleen, causing significant toxic side effects. In contrast, due to the prolonged circulation time of [H8TMPP]-Pt-PEG in vivo, the accumulation of porphyrins in the tumor was considerable, and the concentration increased with time. Eight hours after [H8TMPP]-Pt-PEG injection, the platinum concentration in the tumor was 2.55 μg / g, which was approximately 3.7 times higher than that of cisplatin. The prolonged blood circulation time and increased tumor accumulation resulted in the better antitumor effect of [H8TMPP]-Pt-PEG.

[0107] 4. Pharmacokinetic Study of [H8TMPP]-Pt-PEG

[0108] Blood circulation time of cisplatin and [H8TMPP]-Pt-PEG was assessed by enucleation of mice at different time points following tail vein injection of cisplatin (3 mg Pt / kg) or [H8TMPP]-Pt-PEG (3 mg Pt / kg). Plasma platinum concentration was measured using ICP-MS. Figure 16 As shown, within the first 5 hours after cisplatin injection, platinum concentration decreased rapidly, and by 12 hours, cisplatin had been almost completely cleared from the blood. In contrast, after [H8TMPP]-Pt-PEG injection, plasma platinum concentration decreased more slowly, with a high platinum concentration remaining even after 26 hours, and blood circulation time was significantly prolonged. Furthermore, Figure 16 The curve also showed that the total area under the [H8TMPP]-Pt-PEG curve was greater than that under cisplatin, indicating that the cycling behavior of porphyrin was improved. This is attributed to the formation of stable nanoparticles by the bilayer encapsulation of porphyrin by lipids and polyethylene glycol.

[0109] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A polyethylene glycol-modified nanoparticle based on pyridylporphyrin, characterized in that, The nanoparticles are spherical nanoparticles with a core-shell structure; the shell is a lipid-polyethylene glycol bilayer structure; and the core is a platinum ion compound based on pyridylporphyrin. The platinum ion-type compound based on pyridylporphyrin was prepared by mixing pyridyl alcohol ligands with PtCl2(PhCN)2; The pyridine ligands are selected from... meso -5,10,15,20-tetra(6-methyl-3-pyridine)porphyrin, meso -5,10,15,20-tetra(6-ethyl-3-pyridine)porphyrin, meso -5,10,15,20-tetra(6-isopropyl-3-pyridine)porphyrin, meso -5,10,15,20-tetra(6-tert-butyl-3-pyridine)porphyrin and meso One or more of -5,10,15,20-tetra(6-phenyl-3-pyridine)porphyrin; The lipid-polyethylene glycol bilayer structure was prepared from lipids, stabilizers, and distearate phosphatidylethanolamine.

2. The nanoparticles according to claim 1, characterized in that, The lipid is selected from 1,2-dioleoyl-glycerol-3-phosphocholine.

3. The nanoparticles according to claim 1, characterized in that, The stabilizer is selected from one or more of cholesterol, stigmasterol, and β-sitosterol.

4. The nanoparticles according to claim 1, characterized in that, The polyethylene glycol in the distearate phosphatidylethanolamine has a molecular weight of 500 Da-5000 Da.

5. The method for preparing polyethylene glycol-based nanoparticles according to any one of claims 1-4, characterized in that, Includes the following steps: Pyridine alcohol ligands were mixed with PtCl2(PhCN)2 and acetic acid, benzonitrile was added, and the mixture was heated to obtain a platinum ion compound based on pyridylporphyrin. The lipid and stabilizer are mixed in an organic solvent, and an alcoholic solution of the platinum ion compound based on pyridylporphyrin obtained in step (1) is added and mixed with distearate phosphatidylethanolamine to obtain PEGylated nanoparticles based on pyridylporphyrin.

6. The use of pyridylporphyrin-based polyethylene glycol-modified nanoparticles according to any one of claims 1-4 in the preparation of antitumor drugs.

7. The application according to claim 6, characterized in that, The drug in question is a combination therapy for photodynamic therapy and chemotherapy.

8. The application according to claim 6, characterized in that, The tumor is selected from one or more of melanoma, glioma, colon cancer, lung cancer, breast cancer, liver cancer, and ovarian cancer.

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