An acoustically powered targeting nanomaterial and a preparation method and application thereof

Abstract

The application discloses a kind of acoustically powered targeted nanomaterials and its preparation method and application, belong to medical technology field.The nanomaterial includes chemotherapeutic drug, heat-producing sound sensitizer, metal organic framework that the chemotherapeutic drug and the heat-producing sound sensitizer are loaded, liposome membrane that the metal organic framework is coated, tumor marker that is loaded on the surface of the liposome membrane.The nanomaterial enters human body, can target combination tumor cell, through the acoustically powered excitation sound sensitizer in nanomaterial and the release of chemotherapeutic drug (such as paclitaxel) heat production, to simulate the heat chemotherapy process in tumor peritoneal metastasis treatment, combine heat therapy and chemotherapy, obtain a new tumor peritoneal metastasis treatment scheme;The treatment scheme improves chemotherapy effect while reducing the side reaction of patient's whole body, improves the treatment effect of patient, prolongs the life cycle of patient.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a sonodynamic targeted nanomaterial, its preparation method, and its application. Background Technology

[0002] The information disclosed in the background section of this invention is intended only to enhance the understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Distant metastasis of tumors is the leading cause of death in cancer patients, including lung, liver, brain, and bone metastases. Peritoneal metastasis is a frequently overlooked pattern of tumor metastasis. For malignant tumors prone to peritoneal metastasis (such as ovarian cancer, colorectal cancer, gastric cancer, and bile duct cancer), peritoneal metastasis is often the most important prognostic factor, leading to low surgical radicality, insensitivity to chemotherapy, and a high recurrence rate, significantly reducing the survival time and quality of life of cancer patients.

[0004] Early 20th-century studies found that early chemotherapy and palliative debulking surgery could temporarily improve symptoms in patients with peritoneal metastases, but were insufficient to sustain tumor progression or prolong prognosis. However, with advancements in systemic treatments, optimization of debulking surgery techniques, and their combination with local therapies (especially hyperthermic intraperitoneal chemotherapy), patients with peritoneal metastases have gained access to more effective multimodal treatment options. Hyperthermic intraperitoneal chemotherapy (HIPEC) involves filling the peritoneal cavity with a chemotherapy-containing solution, precisely maintaining a constant temperature and rate, and circulating the solution for a specific time. This combines intraperitoneal chemotherapy with hyperthermia, utilizing the direct tumor-killing effect of high temperature, the synergistic effect of high temperature and chemotherapy drugs, and mechanical flushing to eliminate free cancer cells, subclinical lesions, and micrometastases in the peritoneal cavity. This approach aims to prevent and treat peritoneal metastases of cancer cells.

[0005] However, for patients with advanced cancer, the existing intraperitoneal hyperthermic perfusion therapy has poor clinical efficacy due to poor tolerance and numerous complications. Sonodynamic therapy (SDT) for tumors is a treatment method developed based on photodynamic therapy. This method involves absorbing a sonosensitive agent (chemical) into the tumor, followed by irradiation with ultrasound waves of a certain intensity (physical). The sonosensitive agent undergoes a sonochemical reaction to produce cytotoxic reactive oxygen species (singlet oxygen O2, free radicals, etc.), causing irreversible damage to tumor cells, leading to tumor cell death and achieving non-surgical localization of the tumor.

[0006] Therefore, a new technological solution is needed to synergistically improve the efficacy of chemotherapy while reducing systemic side effects, ultimately aiming to improve the treatment outcomes of peritoneal metastases, enhance patient outcomes, and prolong lifespan. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a sonodynamic targeted nanomaterial. After entering the human body, this nanomaterial generates heat and releases chemotherapy drugs through sonodynamic stimulation, combining thermotherapy and chemotherapy to synergistically improve the effect of chemotherapy while reducing systemic side effects.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] A sonodynamically targeted nanomaterial includes a chemotherapeutic drug, a thermogenic sonosensitive agent, a metal-organic framework encapsulating the chemotherapeutic drug and the thermogenic sonosensitive agent, a liposome membrane encapsulating the metal-organic framework, and a tumor marker loaded on the surface of the liposome membrane. After entering the human body, this nanomaterial can target and bind to tumor cells. Sonodynamic stimulation of the sonosensitive agent in the nanomaterial generates heat and releases the chemotherapeutic drug (such as paclitaxel), mimicking the thermochemotherapy process in the treatment of peritoneal metastases.

[0010] Preferably, the chemotherapy drug is any one of paclitaxel, docetaxel, camptothecin, 5-fluorouracil, cisplatin, oxaliplatin, irinotecan, doxorubicin, mitomycin, epirubicin, docetaxel, oxaliplatin, or irinotecan.

[0011] More preferably, the chemotherapy drug is paclitaxel, a commonly used chemotherapy drug for peritoneal transfer intraperitoneal perfusion chemotherapy.

[0012] Preferably, the metal-organic framework is ZIF-8. ZIF-8 has excellent properties such as high specific surface area, regular pore size, thermal stability, water stability, and low toxicity. It is also pH sensitive and is more easily released in the slightly acidic tumor microenvironment, so it can be used as a tumor drug carrier.

[0013] Preferably, the heat-generating acoustic sensor is Ce6.

[0014] Preferably, the tumor marker is selected from any one of carcinoembryonic antigen markers, enzyme markers, hormone markers, glycoprotein markers, and oncogene markers.

[0015] More preferably, the tumor marker is an EpCAM antibody.

[0016] This invention also provides a method for preparing acoustic-dynamic targeted nanomaterials, comprising the following steps: mixing a metal-organic framework, a chemotherapeutic drug, and a thermogenic acoustic sensitizer in an organic solvent, reacting fully to obtain a precipitate, separating and purifying the precipitate to obtain a metal cluster base; dispersing and dissolving the metal cluster base and a liposome membrane loaded with tumor markers in PBS, and ultrasonically emulsifying under ice bath to obtain acoustic-dynamic targeted nanomaterials.

[0017] Furthermore, the liposome membrane loaded with tumor markers is prepared by thin-film dispersion.

[0018] Another object of the present invention is to provide the application of the acoustic dynamic targeting nanomaterials described above in the preparation of a hyperthermic system for tumor peritoneal metastasis, the hyperthermic system comprising:

[0019] An injection module, comprising a reservoir unit and an intraperitoneal injection unit, wherein the reservoir unit stores a thermotherapy solution prepared from the aforementioned acoustic-dynamic targeted nanomaterials;

[0020] Ultrasound module;

[0021] The observation module includes an abdominal infrared imaging unit and a display unit.

[0022] The beneficial effects of this invention are as follows:

[0023] This invention provides a sonodynamically targeted nanomaterial and its application. After entering the human body, the nanomaterial can target and bind to tumor cells. Through sonodynamic stimulation, the sonosensitive agent in the nanomaterial generates heat and releases chemotherapeutic drugs (such as paclitaxel), simulating the thermochemotherapy process in the treatment of peritoneal metastasis of tumors. By combining thermotherapy and chemotherapy, a new treatment plan for peritoneal metastasis of tumors is obtained. This treatment plan not only synergistically improves the effect of chemotherapy, but also reduces the systemic side effects of patients, improves the treatment effect, and prolongs the life of patients.

[0024] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, the preferred embodiments of the present invention are described in detail below with reference to the accompanying drawings. Attached Figure Description

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

[0026] Figure 1Characterization of PCM@LIP-Ep: A. TEM image of ZIF-8; B. TEM image of PTX / Ce6-MOF@LIP-EP (PCM@LIP-Ep); C. SEM image of PTX / Ce6-MOF and elemental mapping (scale bar = 100nm);

[0027] Figure 2 Results of using PCM@LIP-Ep to treat peritoneal metastases of tumors in mice. Detailed Implementation

[0028] To better describe the present invention, specific embodiments are provided below for further explanation. Unless otherwise specified, the methods in the following embodiments are conventional methods.

[0029] Unless otherwise specified, the technical solutions described in this invention are all conventional solutions in the field; unless otherwise specified, the reagents or materials described are all from commercial sources.

[0030] The following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental conditions not specifically stated in the examples are generally performed under conventional conditions or as recommended by the reagent company; reagents, consumables, etc., used in the following examples are commercially available unless otherwise specified.

[0031] The abbreviations used in the following examples are as follows:

[0032] Example 1: Preparation of nanomaterial PCM@LIP-Ep

[0033] 1) Preparation of PTX-Ce6-MOF (PCM): At room temperature, under magnetic stirring, 30 mmol of Zn(NO3)2·6H2O and 200 mmol of 2-IMM were dissolved in 300 mL and 200 mL of methanol, respectively, and 50 mg of Ce6 and 50 mg of PTX (dissolved in DMSO) were added. The mixture was stirred at room temperature for 12 hours. The precipitate was centrifuged and washed three times with methanol to remove residual precursors, and then freeze-dried to obtain PCM.

[0034] 2) Liposomes were prepared by thin-film dispersion method. 100 mg of dioleoyl lecithin (DOPC), 5 mg of dioleoyl phosphatidylethanolamine (DOPE), 5 mg of DSPE-mPEG2000-EpCAM antibody, and 30 mg of cholesterol were weighed into a round-bottom flask and dissolved thoroughly in 10 mL of chloroform. The round-bottom flask was connected to a rotary evaporator, and the parameters were adjusted as follows: rotation speed 60 rpm, heating temperature 40℃, and running time 15 min. After a liposome film appeared at the bottom of the round-bottom flask, the vacuum was stopped, the film was resuspended in 4 mL of PBS, and dispersed by ultrasonication to obtain a relatively homogeneous liposome-PBS dispersion system.

[0035] 3) Weigh an appropriate amount of PCM, wash it several times with PBS, and then redisperse it with fresh PBS. Add the dispersed metal cluster-based MOF and liposomes to a 10 mL centrifuge tube and sonicate under ice bath. Relevant parameters: sonication time 2 s, interval time 2 s, sonication power 325 W, sonication time 3 min. Store the MOF@NPs-modified nanoparticles obtained after sonication at 4 °C.

[0036] Physicochemical properties of PCM@LIP-Ep nanomaterials:

[0037] Please see Figure 1 According to transmission electron microscopy (TEM) Figure 1 A) The results showed that ZnMOF (ZIF-8) has a uniform structure. After encapsulating Ce6-PTX and covering the liposome membrane, PTX-Ce6@ZnMOF@LIP-EpCAM (PCM@LIP-Ep) was constructed with a particle size of approximately 200 nm, and the outer membrane structure was identifiable under a microscope. Figure 1 B). TEM elemental analysis indicates that C, N, Zn, and O are uniformly distributed in the material. Figure 1 C).

[0038] Example 2: The thermochemotherapy effect of the nanomaterial PCM@LIP-Ep in the peritoneal cavity obtained in Example 1.

[0039] 2.1 Experimental animals: 6-8 week old male nude mice, weighing 18-25g. Provided by Lingchang Company, and acclimatized for one week before the experiment.

[0040] 2.2 Experimental Drugs

[0041] Example 1 yielded PCM@LIP-Ep nanoparticles (redispersed in 0.9% NaCl injection solution, physical stability > 8 hours); Ce6 nanoparticles (redispersed in 0.9% NaCl injection solution, physical stability > 8 hours); and PBS solution.

[0042] 2.3 Experimental Procedure:

[0043] Mice in the experimental group were injected intraperitoneally with PCM@LIP-Ep (10 μg / 1g mouse body weight); mice in control group 1 were injected intraperitoneally with Ce6 (5 μg / 1g mouse body weight); mice in control group 2 were injected intraperitoneally with PBS solution.

[0044] Twelve hours after intraperitoneal injection, each group of mice was subjected to ultrasound treatment for 5 minutes.

[0045] 2.4 Experimental Results:

[0046] Please see Figure 2 During the ultrasound treatment, infrared imaging results showed that the temperature of the peritoneal cavity of mice injected with PCM@LIP-EP during the ultrasound treatment was significantly increased, reaching 46℃, and the temperature rise was concentrated in the tumor site, proving that it played a role in thermochemotherapy in the peritoneal cavity.

[0047] In summary, this invention provides a sonodynamically targeted nanomaterial and its application. After entering the human body, this nanomaterial can target and bind to tumor cells. Through sonodynamic stimulation, the sonosensitive agent in the nanomaterial generates heat and releases chemotherapeutic drugs (such as paclitaxel), simulating the thermochemotherapy process in the treatment of peritoneal metastasis of tumors. By combining thermotherapy with chemotherapy, a new treatment plan for peritoneal metastasis of tumors is obtained. This treatment plan not only synergistically improves the effect of chemotherapy, but also reduces the systemic side effects of patients, improves the treatment effect, and prolongs the patient's life.

[0048] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0049] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. The application of a sonodynamically targeted nanomaterial in the preparation of a tumor peritoneal metastasis hyperthermia system, characterized in that, The hyperthermia system includes: An injection module, comprising a reservoir unit and an intraperitoneal injection unit, wherein the reservoir unit stores a thermotherapy solution configured with acoustic dynamic targeting nanomaterials, wherein the acoustic dynamic targeting nanomaterials include a chemotherapy drug, a thermogenic acoustic sensitizer, a metal-organic framework encapsulating the chemotherapy drug and the thermogenic acoustic sensitizer, a liposome membrane encapsulating the metal-organic framework, and a tumor marker loaded on the surface of the liposome membrane. Ultrasound module; The observation module includes an abdominal infrared imaging unit and a display unit; The heat-generating acoustic sensitizer is dihydroporphyrin e6 (Ce6), and the metal-organic framework is ZIF-8.

2. The application as described in claim 1, characterized in that, The chemotherapy drugs include any one of paclitaxel, docetaxel, camptothecin, 5-fluorouracil, cisplatin, oxaliplatin, irinotecan, doxorubicin, mitomycin, and epirubicin.

3. The application as described in claim 2, characterized in that, The chemotherapy drug is paclitaxel.

4. The application as described in claim 1, characterized in that, The tumor markers are selected from any one of carcinoembryonic antigen markers, enzyme markers, hormone markers, glycoprotein markers, and oncogene markers.

5. The application as described in claim 1, characterized in that, The tumor marker is EpCAM antibody.

6. The application as described in claim 1, characterized in that, The sonodynamic targeted nanomaterial is prepared by the following steps: a metal-organic framework, a chemotherapeutic drug, and a thermogenic sonosensitive agent are mixed in an organic solvent and reacted fully to obtain a precipitate. The precipitate is then separated and purified to obtain a metal cluster base. The metal cluster base and a liposome membrane loaded with tumor markers are dispersed and dissolved in PBS and ultrasonically emulsified under ice bath to obtain the sonodynamic targeted nanomaterial.

7. The application as described in claim 6, characterized in that, The liposome membrane loaded with tumor markers was prepared by thin-film dispersion.

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