Mitochondrial targeting anti-tumor preparation based on self-assembled nanoparticles

Abstract

The invention belongs to the technical field of pharmaceutical preparations and delivery, and particularly relates to a mitochondrial targeting anti-tumor preparation based on self-assembled nanoparticles, the mitochondrial targeting anti-tumor preparation comprises a core self-assembly body and a metal-organic framework shell, the core self-assembly body is formed by self-assembly of a small-molecule inhibitor, a ligand containing triphenylphosphine and ferrous ions, and the metal-organic framework shell is formed by self-assembly of the small-molecule inhibitor, the ligand containing triphenylphosphine and the ferrous ions. The metal-organic framework shell wraps the core self-assembly body and is composed of divalent zinc ions and imidazole ligands. According to the invention, functional molecules and metal ions are self-assembled through intermolecular force to form nanoparticles; the shell is a metal-organic framework protective layer which can be decomposed under specific conditions, and the multi-stage response mechanism ensures that the medicine is only released at correct time and place; the MOF shell provides a protection measure for the core self-assembly body, so that the core self-assembly body can be effectively prevented from being degraded or removed too early in blood circulation, the circulation time and the stability of the medicine in the body are greatly improved, and the non-specific attack on normal tissues is reduced.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations and delivery technology, and particularly relates to a mitochondria-targeting anti-tumor preparation based on self-assembled nanoparticles. BACKGROUND

[0002] The targeting anti-tumor preparation refers to a drug or delivery system that precisely acts on tumor cells or microenvironment through a specific mechanism, and reduces damage to normal tissues. The core lies in the use of molecular markers, metabolic characteristics or signal pathways specific to tumor cells to achieve selective killing.

[0003] In the prior art, traditional nanometer delivery systems, such as liposomes and polymer micelles, generally have the core defects of insufficient targeting accuracy and poor release control.

[0004] These systems often rely on a single passive targeting, such as the EPR effect, or a single stimulus-responsive mechanism, such as only responding to pH, resulting in their inability to achieve precise spatiotemporal controlled release of drugs in complex in vivo environments. After being taken up by cells, they are easily trapped in lysosomes and degraded, so that the drugs cannot reach the subcellular organelle targets in the cytoplasm, and the therapeutic effect is greatly reduced.

[0005] On the other hand, they are also prone to premature leakage of drugs in the blood circulation or non-target tissues, not only reducing the effective drug concentration at the tumor site, but also producing significant toxic side effects on normal tissues. In addition, traditional drug loading methods are difficult to coordinate the synergistic delivery and synchronous release of different properties of therapeutic components, such as hydrophilic and hydrophobic drugs, small molecules and metal ions, and cannot achieve efficient multi-modal synergistic therapy. SUMMARY

[0006] To solve the above problems in the prior art, the present application provides a mitochondria-targeting anti-tumor preparation based on self-assembled nanoparticles, which aims to solve the technical problems in the prior art that precise spatiotemporal controlled release of drugs cannot be achieved in complex in vivo environments, and traditional drug loading methods are difficult to coordinate different properties of therapeutic components.

[0007] To achieve the above purpose, the present application provides the following technical scheme: a mitochondria-targeting anti-tumor preparation based on self-assembled nanoparticles, comprising a core self-assembly and a metal-organic framework shell, the core self-assembly is formed by self-assembly of a small molecule inhibitor, a triphenylphosphine-containing ligand and a divalent iron ion, and the metal-organic framework shell wraps the core self-assembly and is composed of divalent zinc ions and imidazole ligands.

[0008] Further, the small molecule inhibitor is IMT1.

[0009] Further, the triphenylphosphine-containing ligand is triphenylphosphine-grafted gallic acid.

[0010] Further, the imidazole ligand is 2-methylimidazole.

[0011] Further, the molar ratio of the small molecule inhibitor, the triphenylphosphine-containing ligand and the divalent iron ion in the core self-assembly is 1: (0.8-1.2): (0.8-1.2).

[0012] Further, the molar ratio of the divalent zinc ion and the imidazole ligand in the metal-organic framework shell is 1: (3-5).

[0013] Further, the self-assembled nanoparticle has a hydrodynamic diameter of 50-200 nm and a Zeta potential of -10 mV to +10 mV.

[0014] Further, the core self-assembly is formed by stirring reaction in a solvent, and the solvent comprises dimethyl sulfoxide and water.

[0015] Further, the metal-organic framework shell is formed by reacting the core self-assembly with divalent zinc ions and imidazole ligands in a solution, and the reaction time is 30-90 minutes.

[0016] A pharmaceutical preparation comprising the self-assembled nanoparticle and a pharmaceutically acceptable carrier.

[0017] Compared with the prior art, the present application has the following beneficial effects:

[0018] 1、In the present application, the nanoparticle is self-assembled by functional molecules and metal ions through intermolecular forces; the shell is a metal-organic framework protective layer that is decomposed only under specific conditions, which is not a simple physical mixing or wrapping, but a precise structure achieved through a controllable chemical preparation process; the MOF shell is first dissolved in the acidic microenvironment of the tumor to realize lysosome escape and deliver the core into the cytoplasm. Subsequently, the core is further dissociated under the action of high concentrations of ATP and H2O2 in the cytoplasm, and finally all active ingredients are released at the target site mitochondria. This multi-level response mechanism ensures that the drug is released only at the right time and place; the MOF shell provides a protective measure for the unstable core self-assembly, which can effectively prevent it from being degraded or removed too early in the blood circulation, greatly improving the circulation time and stability of the drug in the body. Since the drug is effectively stored and protected before reaching the tumor site, non-specific attacks on normal tissues are reduced, thereby significantly reducing the systemic toxicity and side effects of traditional chemotherapy or metal ion therapy;

[0019] 2、In the application, it is used as one of the basic structural units for constructing the core of nanoparticles. IMT1 directly participates in the formation of the skeleton of nanoparticles through self-assembly. Since the drug molecules themselves are part of the nanomaterials, rather than "guests" carried, the drug loading rate can theoretically far exceed that of traditional nanocarriers, solving the bottleneck problem of insufficient drug loading when multiple drugs are co-loaded; IMT1 can specifically inhibit mitochondrial RNA polymerase, block the transcription of mitochondrial DNA, and cut off the replication ability of mitochondria of tumor cells, which perfectly complements the strategy of only destroying the function of existing mitochondria, and the synergistic effect can effectively solve the problem of treatment resistance caused by rapid regeneration of mitochondria. IMT1 inhibits energy production, and the Fenton reaction triggered by Fe2+ consumes a large amount of energy metabolism substrates and damages the structure of mitochondria. Both throttling and opening source from two dimensions together create an energy crisis for tumor cells, achieving a synergistic anti-tumor effect;

[0020] 3、In the application, three components with different functions are integrated into a single and stable nanostructure core through one-step self-assembly. Gallic acid serves as a ligand for Fe2+ and a grafting platform for TPP targeting molecules in this application. A nanoparticle has both chemical kinetics therapy and mitochondrial gene therapy. This multi-mechanism attack makes it difficult for tumor cells to survive through a single escape path, greatly reducing the risk of drug resistance and improving treatment efficiency; Traditional multiple drug delivery may not be consistent in distribution and release behavior in the body. However, the design chemically integrates components with different functions into the same nano core, ensuring that they can be delivered to the same cell, even the same organelle, to achieve synergistic effect; Triphenylphosphine is a classic mitochondrial targeting group. Integrating it into the self-assembled core through covalent connection enables the entire nanoparticle to naturally have the ability to enrich mitochondria, greatly increasing the local concentration of drugs in the mitochondrial region, enhancing the therapeutic effect and further reducing off-target effects. BRIEF DESCRIPTION OF DRAWINGS

[0021] The accompanying drawings are included to provide a further understanding of the application, and constitute a part of the specification, illustrate embodiments of the application, and are used to explain the application, and do not constitute a limitation on the application. In the drawings:

[0022] Fig. 1 Flow chart for preparation and in vivo delivery of the nano-preparation in the application;

[0023] Fig. 2 Flow chart for intracellular triggering and synergistic therapy in the application. DETAILED DESCRIPTION

[0024] With reference to the drawings of the embodiments of the present application, the technical solutions in the embodiments of the present application will be described clearly and completely. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art without creative effort belong to the scope of the present application.

[0025] Embodiment 1:

[0026] Please refer to Figs. 1-2 The present embodiment provides the following technical solutions: a mitochondrion-targeting anti-tumor preparation based on self-assembled nanoparticles, comprising a core self-assembly and a metal-organic framework shell, the core self-assembly is formed by self-assembly of a small molecule inhibitor, a triphenylphosphine-containing ligand and a divalent iron ion, and the metal-organic framework shell wraps the core self-assembly and is composed of divalent zinc ions and imidazole ligands.

[0027] Specifically, it comprises: a core self-assembly formed by self-assembly of a mitochondrial RNA polymerase small molecule inhibitor, a triphenylphosphine-functionalized gallic acid ligand and a ferrous ion through intermolecular interaction;

[0028] a metal-organic framework shell wrapping the core self-assembly, the shell is formed by coordination of zinc ions and 2-methylimidazole;

[0029] and, optionally, a targeting aptamer connected to the surface of the metal-organic framework shell;

[0030] Wherein, the metal-organic framework shell can be degraded in the micro-acidic environment of the tumor to realize lysosome escape; the core self-assembly can be disassembled under the trigger of high-concentration ATP and hydrogen peroxide in the cytoplasm of the tumor cell to release the small molecule inhibitor and start the Fenton reaction;

[0031] Through the core-shell structure comprising the core self-assembly and the metal-organic framework shell, programmed intelligent release and efficient protection of the drug are realized. The metal-organic framework shell degrades in the micro-acidic environment of the tumor to promote lysosome escape; after entering the cytoplasm, the core self-assembly responds to high-concentration ATP and hydrogen peroxide to further dissociate, accurately releasing the active components, thereby significantly improving the targeting and reducing the systemic toxic side effects.

[0032] The small molecule inhibitor is IMT1.

[0033] Specifically, the mitochondrial RNA polymerase small molecule inhibitor is IMT1.

[0034] By limiting the small molecule inhibitor to IMT1, specific inhibition of mitochondrial DNA transcription is achieved. This directly blocks mitochondrial regeneration at the genetic level, and synergizes with other treatment modalities that disrupt mitochondrial function, effectively overcoming the problem of therapy resistance caused by mitochondrial metabolic reprogramming.

[0035] The triphenylphosphine-containing ligand is triphenylphosphine-grafted gallic acid.

[0036] Specifically, the triphenylphosphine-functionalized gallic acid ligand is formed by covalently linking a triphenylphosphine group to a gallic acid molecule;

[0037] By limiting the triphenylphosphine-containing ligand to triphenylphosphine-grafted gallic acid, the entire nanoparticle is provided with intrinsic mitochondrial targeting ability. The triphenylphosphine group can drive the nanoparticle to efficiently enrich in mitochondria, significantly increasing the local concentration of the drug at the organelle action site, thereby enhancing the therapeutic effect and reducing off-target effects.

[0038] The imidazole ligand is 2-methylimidazole.

[0039] Specifically, the metal-organic framework shell is ZIF-8;

[0040] By limiting the imidazole ligand to 2-methylimidazole, a ZIF-8 metal-organic framework shell with acid-responsive properties is constructed with zinc ions. The shell is stable in normal physiological environment and can protect the core drug; it rapidly degrades in the weakly acidic environment of tumors, enabling the initiation of specific drug release in response to the tumor microenvironment.

[0041] The molar ratio of the small molecule inhibitor, the triphenylphosphine-containing ligand, and the divalent iron ion in the core self-assembly is 1:(0.8-1.2):(0.8-1.2).

[0042] The molar ratio of the divalent zinc ion and the imidazole ligand in the metal-organic framework shell is 1:(3-5).

[0043] Specifically, in the core self-assembly, the molar feed ratio of the small molecule inhibitor, the triphenylphosphine-functionalized gallic acid ligand, and the ferrous ion is 1:(0.8-1.2):(0.8-1.2); when forming the metal-organic framework shell, the molar feed ratio of the zinc ion and the 2-methylimidazole is 1:(3-5).

[0044] By limiting the specific molar ratios of the components in the core self-assembly and the metal-organic framework shell, the repeatability of the nanoparticle preparation process and the uniformity and stability of the product are ensured. This precise ratio is the key to forming a nanoparticle structure with ideal size, morphology, and high drug loading capacity, laying the foundation for the industrial production and quality control of the drug.

[0045] The self-assembled nanoparticles have a hydrodynamic diameter of 50-200 nm and a Zeta potential of -10 mV to +10 mV.

[0046] Specifically, the nanoparticles have a hydrodynamic diameter of 50-200 nm and a Zeta potential of -10 mV to +10 mV.

[0047] By limiting the hydrodynamic diameter and Zeta potential of the self-assembled nanoparticles within a specific range, the pharmacokinetic behavior thereof in vivo is optimized. The appropriate size is conducive to enrichment in tumor tissues through enhanced permeability and retention effect; and the appropriate surface potential reduces non-specific interaction with blood components, prolongs blood circulation time and improves biocompatibility.

[0048] The core self-assembly is formed by stirring reaction in a solvent, which includes dimethyl sulfoxide and water.

[0049] The metal-organic framework shell is formed by reacting the core self-assembly with divalent zinc ions and imidazole ligands in a solution, and the reaction time is 30-90 minutes.

[0050] Specifically, the preparation method of the core self-assembly includes: dissolving the small molecule inhibitor in dimethyl sulfoxide, mixing with an aqueous solution of triphenylphosphine functionalized gallic acid ligand, stirring for 0.5-1.5 hours; then slowly adding a ferrous ion solution, continuing to stir for 1-3 hours under light-proof conditions, and finally purifying by dialysis; the encapsulation method of the metal-organic framework shell includes: mixing the purified core self-assembly with a zinc nitrate solution and stirring for 20-40 minutes, then adding a 2-methylimidazole solution and continuing to react for 40-80 minutes, and obtaining the final product after centrifugal washing;

[0051] By limiting the preparation method and reaction conditions of the core self-assembly and the metal-organic framework shell, an explicit, controllable and scalable synthesis route is provided. This method does not require complex equipment, and the steps are simple, which is conducive to the transformation of the nanometer preparation from laboratory research to large-scale production.

[0052] A pharmaceutical preparation comprising the self-assembled nanoparticles and a pharmaceutically acceptable carrier.

[0053] Specifically, a pharmaceutical composition comprises the antitumor preparation according to any one of claims 1-9, and a pharmaceutically acceptable carrier.

[0054] By claiming a pharmaceutical preparation comprising self-assembled nanoparticles, the aforementioned advantages are integrated into a directly applicable medical product. The preparation inherits all the smart responses, high efficiency targeting and synergistic treatment advantages of nanoparticles, and provides a new and efficient solution for clinical antitumor treatment.

[0055] Example 2:

[0056] See Figs. 1-2 In this embodiment, the workers use the nude mouse transplanted tumor model of human liver cancer cell HepG2 as the research object according to the technology disclosed in the present application;

[0057] Verify the actual operation process and curative effect of the mitochondrion-targeting antitumor preparation. At the beginning of the experiment, first, the target nano-preparation MFGI NPs is prepared. 5.0 milligrams of IMT1 inhibitor is accurately weighed and dissolved in 0.5 milliliters of dimethyl sulfoxide as A liquid. 10.0 milligrams of triphenylphosphine grafted gallic acid TPP-GA is dissolved in 10 milliliters of ultrapure water as B liquid. On a magnetic stirrer, A liquid is slowly added to B liquid, and the reaction is stirred at a speed of 500 revolutions per minute at room temperature for 1 hour. Subsequently, 2.0 milliliters of ferrous sulfate aqueous solution with a concentration of 10 millimoles per liter is slowly added at a speed of 0.1 milliliters per minute using a micro-injection pump, and the whole system continues to be stirred under the condition of avoiding light for 2 hours. After the reaction is completed, the mixed solution is transferred to a dialysis bag with a molecular weight cut-off of 3500, and is dialyzed against ultrapure water for 24 hours to remove unreacted impurities and organic solvents, and finally the purified core self-assembly FG I NPs aqueous dispersion is obtained and is stored in a 4-degree Celsius refrigerator for standby use.

[0058] Next, the wrapping of the metal-organic framework shell is carried out. 5 milliliters of the above-mentioned FG I NPs solution with a core effective component concentration of about 0.5 milligrams per milliliter is taken and is mixed with 10 milliliters of zinc nitrate aqueous solution with a concentration of 40 millimoles per liter, and is stirred at room temperature for 30 minutes. Then, 10 milliliters of 2-methylimidazole aqueous solution with a concentration of 160 millimoles per liter is quickly added, and the reaction continues to be stirred for 60 minutes. After the reaction is completed, the mixed solution is centrifuged in a high-speed centrifuge at a speed of 10,000 revolutions per minute for 10 minutes, and the supernatant is discarded, and the precipitate is collected. The precipitate is repeatedly washed by centrifugation with ultrapure water for three times, and finally is re-dispersed in 5 milliliters of ultrapure water, and thus the final product MFGI NPs is obtained and is stored at 4 degrees Celsius for standby use.

[0059] The prepared MFGI NPs is systematically characterized. The hydration kinetic diameter is measured using a Malvern nanoparticle size analyzer Zetasizer Nano ZS90, and the result shows that it is 125.3 nanometers, and the polydispersity index PDI is 0.15. The Zeta potential is measured to be negative 2.5 millivolts. The morphology is observed using a Hitachi HT7800 transmission electron microscope, and it can be seen that the nanoparticles are regular spherical or spherical, have obvious core-shell structure, and have uniform size distribution.

[0060] After the characterization, in vitro cell experiments were performed. Human liver cancer cells HepG2 were seeded in 96-well plates at a density of 5000 cells per well and cultured in a cell incubator at 37 degrees Celsius with 5% carbon dioxide for 24 hours. Then, fresh culture medium containing different concentration gradients of zero micrograms per milliliter, twenty-five micrograms per milliliter, fifty micrograms per milliliter, and one hundred micrograms per milliliter of MFGI NPs was replaced, and the cells were cultured for another 24 hours and 48 hours. At the time point, 10 microliters of CCK8 solution was added to each well, and after 2 hours of incubation, the absorbance value of each well was detected using a Bio-Rad iMark microplate reader at a wavelength of 450 nanometers. The cell survival rate was calculated, and the results showed that at a concentration of one hundred micrograms per milliliter for 48 hours, the cell survival rate decreased to twenty-eight and a half percent, indicating that the preparation had significant cytotoxicity.

[0061] In the laser confocal microscope experiment, we used Cy5 fluorescent molecules labeled MFGI NPs for treatment. HepG2 cells were seeded in confocal culture dishes and cultured for 24 hours, then fifty micrograms per milliliter of Cy5 labeled MFGI NPs were added for co-culture for 4 hours. Then, the cells were gently washed with PBS three times, and MitoTracker Green mitochondrial green fluorescent probe and Hoechst 33342 cell nucleus blue fluorescent probe were added for staining. Through the observation of Zeiss LSM 880 laser confocal microscope, it can be clearly seen that the red Cy5 fluorescent signal and the green mitochondrial fluorescent signal are highly overlapped, with a colocalization coefficient as high as zero point nine one, strongly proving that the nanoparticles successfully target to mitochondria.

[0062] Finally, the in vivo anti-tumor effect evaluation was performed. Six-week-old healthy BALB / c nude mice were selected, and one hundred microliters of PBS suspension containing five times ten to the sixth power of HepG2 cells were injected subcutaneously on the right hind leg of the mice to construct a tumor xenograft model. When the tumor volume grew to about fifty cubic millimeters, the nude mice were randomly divided into two groups, five in each group. The experimental group was injected with one hundred and fifty microliters of PBS solution of MFGI NPs at a concentration of five milligrams per milliliter, and the control group was injected with the same volume of normal saline, once every two days, a total of five times.

[0063] The long diameter and short diameter of the tumor were measured every two days during the period using a digital caliper, and the tumor volume was calculated according to the formula equal to one-half times the long diameter times the square of the short diameter. At the end of the experiment, the tumor volume of the control group increased to 452 cubic millimeters, while the tumor volume of the MFGI NP treatment group was significantly inhibited to about 125 cubic millimeters, with a tumor inhibition rate of 72.4%, and no significant decrease in the body weight of the mice during the experiment, showing good biological safety. After the mice were sacrificed, the main organs such as the heart, liver, spleen, lung and kidney were taken for H&E staining section observation, and no obvious pathological damage was found, further confirming the safety of the nano preparation.

[0064] This embodiment fully demonstrates the whole process from the preparation, characterization to the in vitro cell internalization mechanism research of the nano preparation, and then to the in vivo drug efficacy and safety evaluation, which fully verifies the great potential of the nano preparation as a new strategy for efficient and low-toxic tumor treatment.

[0065] The working principle of the present application is as follows:

[0066] First step: After intravenous injection, the nano preparation circulates in the blood circulation. Due to its size controlled at the nanometer level and the protection of the MOF shell, it has high stability and is not easily cleared by the body. It can be passively enriched in the tumor tissue interstitial space by taking advantage of the high permeability and retention effect unique to solid tumor tissues.

[0067] Second step: After enrichment in the tumor tissue, the nano particles are phagocytosed by tumor cells through endocytosis and enter the vesicle named endosome. The endosome will then fuse with the lysosome to form a strong acid and enzyme-rich chamber, which aims to degrade foreign substances. At this time, the ZIF-8 metal-organic framework shell of the nano particle is unstable in this acidic environment and rapidly decomposes into non-toxic zinc ions and 2-methylimidazole. This process, on the one hand, destroys the integrity of the lysosome, achieves lysosome escape, and successfully releases the core of the nano particle into the cytoplasm; on the other hand, the decomposition of the shell also removes the protective layer, exposing the internal core self-assembly body, which is ready for the subsequent response.

[0068] Third step: After successfully escaping to the cytoplasm, the core self-assembly body faces two key signal molecules, adenosine triphosphate and hydrogen peroxide, which are abnormally high in concentration in the cytoplasm of tumor cells.

[0069] ATP can competitively bind to the gallic acid-iron coordination structure in the core self-assembly body, destroying its assembly stability. H2O2, as a substrate for the Fenton reaction, will consume the ferrous ions in the system, also destroying the coordination bond that maintains the self-assembly structure.

[0070] Under the joint action of the two molecules, the core self-assembly structure is disintegrated, realizing the final disassembly, so as to carry out site-specific release of the "payload" carried by it, namely the IMT1 inhibitor and ferrous ions, near the target mitochondria.

[0071] The fourth step: the released components can be quickly guided to the mitochondria and enriched due to the mitochondrial targeting modification by triphenylphosphine when the core self-assembly is constructed. Subsequently, they launch a coordinated attack on the mitochondria of tumor cells from two different dimensions;

[0072] The released Fe²⁺ reacts with the abundant H2O2 in the mitochondria to generate hydroxyl radicals with extremely high cytotoxicity. These radicals will immediately oxidize and damage the lipids, proteins and DNA of the mitochondria, leading to dysfunction and membrane potential collapse, and triggering strong oxidative stress. The released IMT1 inhibitor specifically invades the interior of the mitochondria and inhibits the activity of the RNA polymerase of the mitochondria. This will block the transcription process of the mitochondrial DNA, so that the mitochondria cannot synthesize the key proteins and RNA for maintaining their own function and regeneration, and fundamentally cuts off the regeneration and energy supply of the mitochondria.

[0073] The fifth step: the acute oxidative damage caused by the Fenton reaction and the energy regeneration blockage caused by IMT1 intensify the functional disorder of the mitochondria, and the energy regeneration blockage makes the cell lose the ability to repair damage and proliferate. This multiple attack finally efficiently induces the cell death program such as the apoptosis of the mitochondrial pathway, thereby realizing a significant anti-tumor effect.

[0074] Finally, it should be noted that the above only describes the preferred embodiments of the present application and is not intended to limit the present application. Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions recorded in the foregoing embodiments or make equivalent replacements to some technical features. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A mitochondria-targeting antitumor preparation based on self-assembled nanoparticles, characterized in that: A core self-assembly formed by a small molecule inhibitor, a triphenylphosphine-containing ligand and a divalent iron ion through self-assembly, and a metal-organic framework shell encapsulating the core self-assembly and composed of divalent zinc ions and imidazole ligands.

2. The self-assembled nanoparticle-based mitochondrial-targeting antitumor preparation according to claim 1, characterized in that: The small molecule inhibitor is IMT1.

3. The self-assembled nanoparticle-based mitochondrial-targeting antitumor formulation according to claim 1, characterized in that: The triphenylphosphine-containing ligand is triphenylphosphine-grafted gallic acid.

4. The self-assembled nanoparticle-based mitochondrial-targeting antitumor preparation according to claim 1, characterized in that: The imidazole ligand is 2-methylimidazole.

5. The self-assembled nanoparticle-based, mitochondria-targeted antitumor formulation according to claim 1, characterized in that: The molar ratio of the small molecule inhibitor, the triphenylphosphine-containing ligand and the divalent iron ion in the core self-assembly is 1:(0.8-1.2):(0.8-1.2).

6. The self-assembled nanoparticle-based, mitochondria-targeted antitumor formulation according to claim 1, characterized in that: The molar ratio of the divalent zinc ion and the imidazole ligand in the metal-organic framework shell is 1:(3-5).

7. The self-assembled nanoparticle-based, mitochondria-targeted antitumor formulation according to claim 1, characterized in that: The self-assembly nanoparticle has a hydrodynamic diameter of 50-200 nm and a Zeta potential of -10 mV to +10 mV.

8. The self-assembled nanoparticle-based, mitochondria-targeted antitumor formulation according to claim 1, characterized by: The core self-assembly is formed by stirring reaction in a solvent comprising dimethyl sulfoxide and water.

9. The self-assembled nanoparticle-based, mitochondria-targeted antitumor formulation according to claim 1, characterized in that: The metal-organic framework shell is formed by reacting the core self-assembly with divalent zinc ions and imidazole ligands in solution for 30-90 minutes.

10. A pharmaceutical preparation comprising the self-assembly nanoparticle of any one of claims 1-9 and a pharmaceutically acceptable carrier.

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