阅读说明：本技术 一种可光控金属离子递送颗粒及其制备方法与应用 (Light-controllable metal ion delivery particle and preparation method and application thereof ) 是由 林静 唐祁南 黄鹏 贺婷 于 2021-08-31 设计创作，主要内容包括：本发明公开了一种可光控金属离子递送颗粒及其制备方法与应用,其中,所述可光控金属离子递送颗粒包括有机小分子配体和通过配位作用结合在所述有机小分子配体上的金属离子,所述有机小分子配体的化学结构式为：其中R为甲基、乙基和苄基中的一种；所述金属离子为铜离子或亚铜离子。本发明中的有机小分子配体可以保持金属离子价态稳定,并通过纳米自组装技术将金属离子递送到肿瘤部位；此外,有机小分子配体还兼具光敏剂的功能,可以实现先光动力治疗再化学动力学治疗的目的,因此可实现肿瘤部位的精准光控释放离子,减少全身毒性；这种新型递送药物的方式为肿瘤协同治疗提供了新的策略。(The invention discloses a light-controllable metal ion delivery particle and a preparation method and application thereof, wherein the light-controllable metal ion delivery particle comprises an organic micromolecule ligand and metal ions combined on the organic micromolecule ligand through coordination, and the chemical structural formula of the organic micromolecule ligand is as follows: whereinR is one of methyl, ethyl and benzyl; the metal ions are copper ions or cuprous ions. The organic small molecule ligand can keep the valence state of metal ions stable, and the metal ions are delivered to the tumor part by a nano self-assembly technology; in addition, the organic micromolecule ligand also has the function of a photosensitizer, and can realize the purpose of photodynamic therapy and then chemokinetic therapy, so that the accurate light control of tumor parts can be realized to release ions, and the toxicity of the whole body is reduced; this novel drug delivery approach provides a new strategy for tumor co-therapy.)

1. A light-controllable metal ion delivery particle comprising an organic small molecule ligand and a metal ion bound to the organic small molecule ligand by coordination, wherein the organic small molecule ligand has the chemical formula:wherein R is one of methyl, ethyl and benzyl; the metal ions are copper ions or cuprous ions.

2. The light-controllable metal ion delivery particle as recited in claim 1, wherein the hydrated particle size of the light-controllable metal ion delivery particle is 100-200 nm.

3. A method of making light-controllable metal ion delivery particles as defined in any of claims 1-2, comprising the steps of:

dissolving an organic small molecular ligand in an organic phase, adding metal ions, uniformly mixing, adding an amphiphilic polyethylene glycol compound, and carrying out ultrasonic treatment for first preset time to obtain a reaction product;

adding ultrapure water into the reaction product, carrying out ultrasonic treatment for a second preset time, and then sequentially carrying out rotary evaporation, membrane passing, ultrafiltration centrifugation and water washing treatment to obtain the light-controlled metal ion delivery particle.

4. A method of making light-controllable metal ion delivery particles according to claim 3, wherein the organic phase is one or more of dichloromethane, chloroform and tetrahydrofuran.

5. A method of making light-controllable metal ion delivery particles as claimed in claim 3 wherein the mass of added metal ions is 8-12 times the mass of the small organic molecule ligand.

6. A method of making light-controllable metal ion delivery particles according to claim 3, wherein the first predetermined time is 20-35 s; the second preset time is 4-6 min.

7. The method of claim 3, wherein the amphiphilic polyethylene glycol compound is DSPE-PEG₂₀₀₀。

8. Use of a light-controllable metal ion delivery particle as defined in any one of claims 1-2, wherein the light-controllable metal ion delivery particle is used for the manufacture of a medicament for the diagnosis and/or treatment of a tumour.

9. Use of the light-controllable metal ion delivery particles according to claim 8, wherein the agent for diagnosing tumors is a fluorescent imaging agent or a photoacoustic imaging agent.

10. Use of a light-controllable metal ion delivery particle according to claim 8, wherein the agent for the treatment of tumors is a combination of photodynamic therapy and chemodynamics.

Technical Field

The invention relates to the technical field of biomedical materials, in particular to a light-controllable metal ion delivery particle and a preparation method and application thereof.

Background

Malignant tumors have become an important threat to the health of people, and the number of attack and death cases is increasing every year. However, since the treatment of malignant tumors is limited and drug resistance is likely to occur, development of new therapeutic approaches is urgently needed. In recent years, chemokinetic therapy (CDT) has attracted considerable attention as an emerging modality for tumor therapy. The CDT utilizes metal ions such as iron and copper to catalyze hydrogen peroxide in a tumor microenvironment to generate highly toxic hydroxyl free radicals (. OH) so as to kill tumor cells. Among the numerous metal ions, ferrous ion (Fe)²⁺) The activity is highest, but the reaction needs to be carried out under the condition of strong acidity with the pH value of 2-4 to achieve the maximum efficiency. Cuprous ion (Cu)⁺) The catalytic efficiency under weak acidic and neutral conditions is 160 times higher than that of ferrous ion catalytic reaction under the same conditions. Compared with a ferrous ion delivery strategy, the cuprous ion anti-tumor treatment has larger application potential. However, Cu²⁺/Cu⁺(0.16V) very low redox potential, Cu⁺Is very easily oxidized into Cu²⁺And loses catalytic activity. In particular in aqueous solution, Cu⁺Disproportionation reaction to produce Cu²⁺And elemental copper, which cannot exist stably. To directly deliver Cu²⁺For CDT treatment, the reduction is necessary to generate Fenton catalytic activity, which has certain effect on tumors with high reduction level, but Cu is used for tumors with low reduction level²⁺The antitumor effect is very limited. Therefore how to deliver highly active Cu at the living body level with high efficiency⁺Achieving a tumor CDT effect is a significant challenge.

Accordingly, the prior art is yet to be improved and developed.

Disclosure of Invention

In view of the above-mentioned shortcomings of the prior art, the present invention aims to provide a light-controllable metal ion delivery particle, and a preparation method and application thereof, aiming to solve the problem of poor stability of cuprous ions for tumor chemokinetic treatment.

In a first aspect of the present invention, a light-controllable metal ion delivery particle is provided, which includes an organic small molecule ligand and a metal ion bound to the organic small molecule ligand through coordination, wherein the organic small molecule ligand has a chemical structural formula:wherein R is one of methyl, ethyl and benzyl; the metal ions are copper ions or cuprous ions.

Optionally, the hydrated particle size of the light-controllable metal ion delivery particle is 100-200 nm.

In a second aspect of the present invention, there is provided a method for preparing a light-controllable metal ion delivery particle as described above, comprising the steps of: dissolving an organic small molecular ligand in an organic phase, adding metal ions, uniformly mixing, adding an amphiphilic polyethylene glycol compound, and carrying out ultrasonic treatment for first preset time to obtain a reaction product;

adding ultrapure water into the reaction product, carrying out ultrasonic treatment for a second preset time, and then sequentially carrying out rotary evaporation, membrane passing, ultrafiltration centrifugation and water washing treatment to obtain the light-controlled metal ion delivery particle.

Optionally, the organic phase is one or more of dichloromethane, chloroform, and tetrahydrofuran.

Optionally, the added mass of the metal ion is 8-12 times of the mass of the organic small molecule ligand.

Optionally, the first predetermined time is 20-35 s; the second preset time is 4-6 min.

Optionally, the amphiphilic polyethylene glycol compound is DSPE-PEG₂₀₀₀。

In a third aspect of the invention there is provided the use of a light-controllable metal ion delivery particle as described above in the manufacture of a medicament for the diagnosis and/or treatment of a tumour.

Optionally, the agent that diagnoses the tumor is a fluorescence imaging agent or a photoacoustic imaging agent.

Optionally, the agent for treating a tumor is a combination of photodynamic therapy and chemodynamics.

Optionally, the dosage form of the medicament is capsule, tablet, oral preparation, injection, suppository, spray or ointment.

Has the advantages that: the light-controllable metal ion delivery particle provided by the invention comprises an organic small molecule ligand and metal ions combined on the organic small molecule ligand through coordination, wherein the chemical structural formula of the organic small molecule ligand is as follows:wherein R is one of methyl, ethyl and benzyl; the metal ions are copper ions or cuprous ions. The organic small molecule ligand can keep the valence state of metal ions stable, and the metal ions are delivered to the tumor part by a nano self-assembly technology; in addition, the organic micromolecule ligand also has the function of a photosensitizer, and can realize the purpose of photodynamic therapy and then chemokinetic therapy, so that the accurate light control of tumor parts can be realized to release ions, and the toxicity of the whole body is reduced; this novel drug delivery approach provides a new strategy for tumor co-therapy. The synthesis method of the light-controllable metal ion delivery particle is simple, the synthesis conditions are not harsh, the operation is convenient, and the light-controllable metal ion delivery particle can be used for large-scale production.

Drawings

Fig. 1 is a flow chart of a method for making a light-controllable metal ion delivery particle of the present invention.

Fig. 2a is a transmission electron micrograph of the self-assembly of a delivery system incorporating cuprous ions to form nanoparticles (LC1) and the corresponding hydrated particle size plot.

Fig. 2b is a transmission electron micrograph of the self-assembly of the delivery system bound copper ions to form nanoparticles (LC2) and the corresponding hydrated particle size plot.

Fig. 3a is a graph of the change of the ultraviolet absorption spectrum before and after the ion delivery system combines with cuprous ions to self-assemble to form the nano-particles.

FIG. 3b is a graph showing the UV absorption spectrum change before and after the ion delivery system combines with copper ion self-assembly to form nanoparticles.

FIG. 4 is an X-ray photoelectron spectrum of an ion delivery system incorporating copper ions of two different valence states, wherein a is the X-ray photoelectron spectrum of the incorporated cuprous ion; b is an X-ray photoelectron spectrum of the bound copper ion; c is a comparison graph of the X-ray photoelectron spectra of two nanoparticles at local magnification.

Fig. 5 is a graph showing the evaluation of the photodynamic effect of a delivery system combining copper ions of different valences.

FIG. 6a is a graph of the efficiency of two valence states of a copper ion delivery system in generating hydroxyl radicals.

FIG. 6b is a graph of the efficiency of LC1 in generating hydroxyl radicals under 660nm laser irradiation at different powers.

Fig. 6c is a graph of the efficiency of various concentrations of LC1 in generating hydroxyl radicals.

FIG. 7 shows the electron paramagnetic resonance spectroscopy for detecting hydroxyl radicals and singlet oxygen generated by LC1 and LC2

Fig. 8 is a graph showing changes in cell viability after incubation of LC1 and LC2 with 4T1 cells, respectively.

FIGS. 9 a-b are graphs of the fluorescence imaging of LC1 and LC2 in tumor-bearing mice as a function of time; and c-d in FIG. 9 are graphs of photoacoustic imaging of LC1 and LC2 in tumor-bearing mice along with time.

In FIG. 10, a is a graph for evaluating the treatment effect of LC1 and LC2 on a 4T1 tumor-bearing mouse model; b is a statistical graph of the tumor weight of the mice after the treatment is finished; and c is a graph of the change in body weight of each treatment group of mice during the treatment period.

Detailed Description

The invention provides a light-controllable metal ion delivery particle, and a preparation method and application thereof, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Researches find that after the nitrogen-containing organic ligand and copper ions form a stable complex, the stable valence state of the complex can be protected, and Cu is expected to be realized⁺Stability during delivery. In addition, accurate diagnosis and treatment integration is often required to be realized by means of imaging diagnosis in tumor curative effect monitoring, and the organic molecular structure is variable, so that the multifunctional tumor therapeutic apparatus is expected to be multifunctional. For example, delivery of Fe can be achieved by combining a cyanine parent molecule with optical imaging functionality with a terpyridine ligand²⁺While having the capability of both fluorescence and photoacoustic imaging. The high sensitivity and selectivity of fluorescence imaging are utilized, and the high resolution and deep tissue penetration of photoacoustic imaging are combined, so that the diagnosis and treatment integration of tumor treatment is realized.

Based on the above, the present invention provides a light-controllable metal ion delivery particle, which comprises an organic small molecule ligand and a metal ion bound to the organic small molecule ligand through coordination, wherein the organic small molecule ligand has a chemical structural formula as follows:wherein R is one of methyl, ethyl and benzyl; the metal ions are copper ions or cuprous ions.

In this embodiment, the organic small molecule ligand is prepared by combining an N, N-bipyridyl methyl diamine group with a cyanine parent molecular structure, and N on the organic small molecule ligand can be combined with a copper ion or a cuprous ion through coordination. Specifically, the N in pyridine on the organic small molecule ligand and the N connecting two pyridines can be coordinately bound with the cupric ion or cuprous ion, and the specific binding mode is as follows:

in this embodiment, the organic small molecule ligand can keep the valence state of the metal ion stable, and deliver the metal ion to the tumor site by the nano self-assembly technology; in addition, the organic micromolecule ligand also has the function of a photosensitizer, and can realize the purpose of photodynamic therapy and then chemokinetic therapy, so that the accurate light control of tumor parts can be realized to release ions, and the toxicity of the whole body is reduced; this novel drug delivery approach provides a new strategy for tumor co-therapy. Therefore, the light-controllable metal ion delivery particle provided by the embodiment can realize accurate delivery of cuprous ions and copper ions and tumor treatment under the guidance of fluorescence/photoacoustic imaging.

In some embodiments, the hydrated particle size of the light-controllable metal ion delivery particle is 100-200 nm.

In some embodiments, there is also provided a method of making the light-controllable metal ion delivery particle, as shown in fig. 1, comprising the steps of:

s10, dissolving an organic small molecular ligand in an organic phase, adding metal ions, mixing uniformly, adding an amphiphilic polyethylene glycol compound, and carrying out ultrasonic treatment for first preset time to obtain a reaction product;

and S20, adding ultrapure water into the reaction product, carrying out ultrasonic treatment for a second preset time, and then sequentially carrying out rotary evaporation, membrane passing, ultrafiltration centrifugation and water washing treatment to obtain the light-controllable metal ion delivery particle.

In this embodiment, the organic phase is a volatile organic solvent, and by way of example, the organic phase may be one or more of dichloromethane, chloroform and tetrahydrofuran, but is not limited thereto; the amphiphilic polyethylene glycol compound is DSPE-PEG2000, but is not limited thereto.

In this embodiment, in order to ensure that all the metal ions can be bound to the organic small molecule ligand, the mass of the added metal ions is 8-12 times of the mass of the organic small molecule ligand.

In this embodiment, the first predetermined time is 20-35 s; the second preset time is 4-6 min.

In this embodiment, the pore diameter of the PES membrane used in the membrane treatment is 220 μm, the reaction product is transferred to a 30kD ultrafiltration tube for centrifugation under 3000-4000 rpm for 15 minutes, and the resulting light-controllable metal ion delivery particle is washed with water after centrifugation, and then stored away from light at 4 ℃.

The preparation method of the light-controllable metal ion delivery particle provided by the embodiment is simple to synthesize, has mild synthesis conditions, is convenient to operate, and can be used for large-scale production.

In some embodiments, there is also provided a use of the above light-controllable metal ion delivery particle for the preparation of a medicament for the diagnosis and/or treatment of a tumor.

In this embodiment, the agent for diagnosing tumor is a fluorescence imaging agent or a photoacoustic imaging agent, but is not limited thereto; the medicament for treating the tumor is a combined medicament of photodynamic therapy and chemokinetics. The organic small molecule ligand in the embodiment can keep the valence state of the metal ion stable, and the metal ion is delivered to the tumor site through the nano self-assembly technology. In addition, the ligand molecule also has the function of a photosensitizer, and can realize the purposes of photodynamic therapy and chemical kinetic therapy, so that the accurate light control of tumor parts can be realized to release ions, and the toxicity of the whole body is reduced; this novel drug delivery approach provides a new strategy for tumor co-therapy.

Preferably, the dosage form of the medicament is capsule, tablet, oral preparation, injection, suppository, spray or ointment.

The technical solution of the present invention is further illustrated by the following specific examples.

Example 1: preparation of nanoparticles of copper ion delivery systems of different valence states

Dissolving 1mg ligand molecule in 1mL dichloromethane, adding 100 μ L cuprous ion (20mM), mixing by ultrasonic, adding DSPE-PEG2000(10mg) with different amount, ultrasonic for 30s, adding the above liquid into 5mL ultrapure water, ultrasonic for 5min, removing dichloromethane by rotary evaporation, passing 220 μm PES membrane, transferring into 30kD ultrafilter tube, centrifuging for 3500 rpm, 15 min, 4 deg.C. LC1 was obtained and washed twice with water and stored at 4 ℃ in the dark for further use.

And (3) replacing the cuprous ions with equivalent copper ions, keeping the subsequent operation steps unchanged to obtain LC2, and storing at 4 ℃ in a dark place for later use.

Fig. 2a is a transmission electron micrograph and corresponding hydrated particle size plot of the nanoparticles (LC1) formed in conjunction with the cuprous ion delivery system produced; FIG. 2b is a transmission electron micrograph and corresponding hydrated particle size plot of nanoparticles (LC2) formed from the prepared copper ion-binding ion delivery system; as can be seen from fig. 2a and 2b, the nanoparticles LC1 and LC2 are spherical and have uniform size and uniform dispersion.

FIG. 3a shows the change of UV absorption spectra before and after chelation with copper ions and after self-assembly with small organic molecule ligand, as can be seen from the figure, the probe generates red shift after binding with ions, the UV absorption peak is about 710nm, and the UV absorption blue shifts to 680nm after self-assembly; FIG. 3b shows that the fluorescence signal decreases after the organic small molecule ligand chelates copper ions, and the fluorescence intensity further decreases after self-assembly.

FIG. 4 shows X-ray photoelectron spectra of LC1 and LC2, and the fitting result of a in FIG. 4 shows that LC1 mainly contains cuprous ions; the fitting result of b in fig. 4 shows that LC2 contains mainly copper ions; in fig. 4, c is a partially enlarged comparative diagram.

Example 2: evaluation of photodynamic Effect of different valence copper ion delivery systems

Irradiating the nano-particle solution added with DPBF by adopting a 660nm laser with the irradiation power of 0.2W/cm²The duration of each irradiation was 10 seconds.

FIG. 5 shows the DPBF absorption change of LC2 under the same light power irradiation at the same concentration (20 μ M) of LC 1. DPBF can be used for detecting singlet oxygen (¹O₂) The faster the absorption at 415nm dropped, indicating the more singlet oxygen produced. The results in fig. 5 show that LC1 produces a more intense photodynamic effect than LC 2.

Example 3: evaluation of chemical kinetics effects of different valence copper ion delivery systems

The hydroxyl free radical generating effect of the copper ion delivery system with different valence states under the irradiation of different concentrations and different optical powers is respectively compared. Under specific conditions such asThe following: mu.L of 30% hydrogen peroxide solution was added to 6mM Terephthalic Acid (TA) solution, and then LC1 or LC2, 5. mu.M each, were added, and the change in fluorescence intensity of TA at 315nm was monitored by a fluorescence spectrophotometer under irradiation with different optical powers. And LC1 of different concentrations at 660nm laser 0.2W/cm²The change of the fluorescence intensity of TA at 315nm during power irradiation; the change of the fluorescence intensity of TA at 315nm under the laser irradiation of different laser power at the same concentration.

FIG. 6a shows a comparison of the efficiency of different valency copper ion delivery systems for generating hydroxyl radicals under non-light, light conditions. The results show that only LC1 caused a significant increase in the fluorescence intensity of TA after laser irradiation, while LC2 had little effect. This may result in the absence of a reducing agent in the solution environment, which may prevent the reduction of copper ions to cuprous ions and thus the fenton reaction. Fig. 6b shows the fluorescence intensity change of TA under the same laser irradiation condition, and the result shows that the cuprous ion concentration in the solution is proportional to the effect of fenton reaction. FIG. 6c shows that LC1 (5. mu.M) is at 0.5W/cm for a fixed concentration²The fluorescence intensity of TA is also increased under 660nm laser irradiation, so that the CDT effect of the copper ion delivery nanoprobe is dependent on the concentration and the laser dose range.

Fig. 7 is an electron paramagnetic resonance spectrum of a copper ion delivery system of different valence states, and the results more directly demonstrate that LC1 generates two reactive oxygen species, namely (a) singlet oxygen and (b) hydroxyl radical, after laser irradiation.

Example 4: evaluation of therapeutic Effect at cellular level of different valence copper ion delivery systems

The effect of chemokinetic/photodynamic therapy co-therapy on 4T1 cell viability was assessed using standard MTT methods. Mouse mammary cancer cell 4T1 cell 5X 10 per well³Inoculating into 96-well plate at a density of 37 deg.C and 5% CO₂Incubate for 24h under conditions. Next, the old medium in the 96-well plate was aspirated and medium solutions containing 0, 2.5, 5, 10, 20 μ M LC2 or LC1 were added, respectively. After further incubation for 24h, the old medium in the 96-well plate was aspirated, and 100. mu.L of a medium solution containing 10% MTT (0.5 mg/mL) was added to each well) The cultivation was continued for 4 h. The residual medium in the 96-well plate was aspirated, 150. mu.L of DMSO solution was added to each well, and after gentle shaking, the OD value (detection wavelength: 490nm) of each well was measured on a Synergy H1-type microplate reader, and the cell viability was calculated by the following equation. Cell viability (percent) (%) (OD 490 value of sample/blank OD490 value) × 100%. And the light group was cultured for 4 hours after adding the solution containing the nanoparticles, and then the culture was continued with a 660nm laser at 0.2W/cm²The wells were irradiated with light for 5 minutes, and then the incubation was continued for 20 hours, following the same procedure as in the non-irradiated group.

FIG. 8 shows the cell survival rate of the tumor cells (4T1) on LC1 and LC 2. The cell dark toxicity of the nanoparticles is low, but the survival rate of tumor cells is reduced to below 20% after the concentration of the light group reaches 10 mu M, which shows that the copper ion delivery system can effectively kill the tumor cells, and the effect of delivering the copper ions in a cell line with low GSH content is obviously lower than that of cuprous ions.

Example 5: evaluation of distribution change of copper ion delivery systems with different valence states in tumor-bearing mice

A breast cancer model of the mouse was constructed. Female athymic nude mice (six weeks, 20-25g) were purchased and injected subcutaneously in the right hind leg of nude mice with 150 million 4T1 tumor cells. When the tumor volume reaches 80mm³When the fluorescent light is used, LC1 or LC2 is injected into a mouse body by tail vein injection according to the dosage of 5mg/kg, and the change of the fluorescent light signal and the photoacoustic signal of a tumor area along with time is detected by using an IVIS fluorescence imaging system and a small animal photoacoustic imaging system.

As shown in a-b in FIG. 9, after nanoparticles are injected into tumor-bearing mice for 12h through tail vein, the fluorescence intensity of mouse tumors reaches the strongest. Meanwhile, as shown in c-d in fig. 9, the signal intensity of photoacoustic imaging also reaches a peak 12h after nanoparticle injection. The imaging result shows that the two copper ion delivery systems with different valence states can be effectively enriched to the tumor site.

Example 6: evaluation of in vivo therapeutic Effect of different valence copper ion delivery systems

Construction of a Breast cancer model in mice. Female athymic nude mice (six weeks, 20-25g) were purchased and injected subcutaneously in the right hind leg of nude mice with 150 million 4T1 tumor cells. When the tumor volume reaches 80mm³At the time, tumor-bearing mice were randomly divided into 5 groups, which were: (1) blank group; (2) group LC 2; (3) group LC 1; (4) LC2+ laser group; (5) LC1+ laser group. The LC1 and LC2 solutions were injected into mice via tail vein injection at a dose of 5mg/kg, and a 660 laser was used 12 hours after injection to irradiate the group with laser light at a dose of 0.2W/cm²20 minutes each. Tumor volume was measured every other day from the time of administration using a vernier caliper and according to the formula V ═ AB²The tumor volume was calculated where A is the major diameter of the tumor and B is the minor diameter (mm) of the tumor. Each measurement was normalized by the initial tumor volume before treatment and the change in body weight of each group of mice was observed. The results of the experiment are shown in FIG. 10.

In FIG. 10, a is the change of tumor volume with time in different treatment groups. The LC1+ laser group and the LC2+ laser group can obviously inhibit the growth of tumors, wherein the LC1 has better treatment effect than the LC 2. B in fig. 10 shows that the tumor weight in LC1 group was significantly less after the end of treatment than the other groups, further indicating that the strategy for cuprous ion delivery was significantly superior to copper ions in the 4T1 mouse model. In fig. 10 c shows no significant change in body weight of the mice during the treatment, indicating that due to its light controlled release profile, systemic toxicity is avoided and that the copper ion delivery system is biologically safe.

In summary, the light-controllable metal ion delivery particle (copper ion delivery system) provided by the invention can achieve the purpose of delivering copper ions with different valence states, and the light-controllable metal ion delivery particle obtained by the preparation method provided by the invention can achieve photodynamic combined chemical kinetics tumor therapy guided by fluorescence imaging and photoacoustic imaging. The light-controllable metal ion delivery particle provided by the invention can deliver cuprous ions and copper ions and generate chemokinetic treatment at a tumor part; the organic micromolecule ligand releases ions when initiating photodynamic therapy under near infrared light irradiation, subsequent chemical kinetic therapy is induced, and the combination of the two treatment modes can effectively inhibit tumor growth and overcome the problems of tumor drug resistance and the like.

It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.