Use of iron-loaded carbon nanoparticle suspension injection for combined administration

Abstract

The present invention belongs to the field of medicine and relates to use of an iron-loaded carbon nanoparticle suspension injection for combined administration. The iron-loaded carbon nanoparticle suspension injection is administered in combination with an anticancer drug to inhibit tumor growth. In the combined administration, the anticancer drug is administered orally or intravenously, and the iron-loaded carbon nanoparticle suspension injection is administered via intratumoral injection. After the iron-loaded carbon nanoparticle suspension injection is injected into a tumor, it is found that the anticancer drug administered orally or intravenously is enriched in the tumor, thereby increasing the concentration of the anticancer drug in the tumor, enabling the anticancer drug to more accurately act on the tumor site, and reducing the dose of the anticancer drug and its toxic side effects on normal cells and tissues. The combined administration of the iron-loaded carbon nanoparticle suspension injection and the anticancer drug has a synergistic effect.

Description

Use of a nano-carbon iron suspension injection for combined drug delivery

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese application No. 2024118733636, filed on December 18, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application belongs to the pharmaceutical field, and in particular relates to the use of a nano-carbon iron suspension injection for combined administration. Background Technology

[0004] Ferroptosis is an iron-dependent, novel form of programmed cell death distinct from apoptosis, necrosis, and autophagy. Its essence lies in the depletion of glutathione (GSH), leading to a decrease in glutathione peroxidase (GPX4) activity. Lipid oxides cannot be metabolized by GPX4-catalyzed glutathione reductase, resulting in the oxidation of lipids by divalent iron ions, producing reactive oxygen species (ROS), thus promoting ferroptosis. The main mechanisms of ferroptosis include inhibition of the cysteine-glutamate transporter receptor (system XC-), inhibition of glutathione peroxidase 4 (GPX4), ROS generation, inhibition of glutathione-independent ferroptosis inhibitory protein 1 (FSP1), and inhibition of dihydroorotate dehydrogenase (DHODH).

[0005] Nano-carbon iron suspension injection (CNSI-Fe) is an innovative anticancer drug using nano-carbon as a carrier and ferrous ions as the active ingredient. It exerts its anticancer effect through the ferroptosis pathway and is used to treat pancreatic cancer, lung cancer, gastric cancer, colorectal cancer, breast cancer, cervical cancer, liver cancer, thyroid cancer, ovarian cancer, and sarcoma. Its mechanism of action is as follows: After local injection into cancerous tissue, the nano-carbon iron enters the cancer cells through overexpressed iron channels on the cancer cell membrane. Excess iron ions enter the hydrogen peroxide (H2O2)-rich cancer cells and undergo a Fenton reaction with H2O2, producing a large number of hydroxyl radicals (·OH). ·OH has extremely strong oxidizing properties and reacts with unsaturated polyfatty acids (UPFAs) within the cell to produce large amounts of highly destructive lipid hydrogen peroxide (L-OH), also known as lipid reactive oxygen species (Lipid-ROS). Lipid-ROS can destroy organelles, leading to cell damage and inducing ferroptosis.

[0006] Chemotherapy is the most common treatment for cancer, its mechanism being the indiscriminate attack on both normal and tumor cells, often causing severe toxic side effects. With advancements in science and technology, targeted therapy has been found to be effective in some patients with fewer side effects. However, targeted therapy is only suitable for a subset of patients selected through clinical trials. Sorafenib is an oral targeted therapy drug whose main function is to inhibit multiple kinases, block tumor angiogenesis, inhibit tumor cell proliferation, and induce tumor cell apoptosis. Clinical trials and practical experience have shown that sorafenib has certain anti-cancer effects in the treatment of some cancers, especially advanced liver cancer and renal cell carcinoma. Sorafenib can prolong patient survival, slow disease progression, and alleviate symptoms and improve quality of life in some patients. There are also reports that sorafenib can exert its cancer-killing effect by inducing a new cell death pathway—ferroptosis. Sorafenib is not effective for all patients; its efficacy varies from person to person, and long-term use can easily lead to drug resistance, reducing treatment effectiveness. Meanwhile, sorafenib may cause some adverse reactions, including hand-foot syndrome, rash, hypertension, diarrhea, etc. These side effects may affect the patient's quality of life and require timely monitoring and treatment.

[0007] Currently, high doses are required when using chemotherapy drugs alone, or when using sorafenib or nano-carbon iron suspension injection. Summary of the Invention

[0008] The purpose of this application is to provide the use of nano-carbon iron suspension injection for combined administration, in order to solve the problem of high doses required when using chemotherapy drugs alone or sorafenib or nano-carbon iron suspension injection in the prior art.

[0009] To address the aforementioned technical problems, according to some embodiments, this application provides a use of a nano-carbon iron suspension injection for combined administration, wherein the nano-carbon iron suspension injection and an anticancer drug are administered in combination to inhibit tumor growth, wherein the anticancer drug is administered orally or intravenously, and the nano-carbon iron suspension injection is administered via intratumoral injection.

[0010] Furthermore, the anticancer drug is one or more of sorafenib, doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel, and hydroxycamptothecin.

[0011] Furthermore, the nano-carbon iron suspension injection, when administered in combination with anticancer drugs, is used to treat pancreatic cancer, lung cancer, gastric cancer, colorectal cancer, breast cancer, cervical cancer, liver cancer, thyroid cancer, ovarian cancer, and sarcoma.

[0012] Furthermore, the nano-carbon iron suspension injection is prepared by mixing nano-carbon suspension injection and ferrous sulfate for injection; wherein the concentration of the nano-carbon suspension injection is 20-100 mg / mL, and the concentration of ferrous ions in the nano-carbon iron suspension injection is 0.1-60 mg / mL.

[0013] Furthermore, the concentration of nano-carbon in the nano-carbon suspension injection is 50 mg / mL, and the concentration of ferrous ions in the nano-carbon iron suspension injection is 7.0–60 mg / mL.

[0014] Furthermore, the concentration of ferrous ions in the nano-carbon iron suspension injection is 30 mg / mL or 60 mg / mL.

[0015] Furthermore, the nano-carbon iron suspension injection has a particle size of 90–250 nm and a pH value of 2.0–6.0.

[0016] Furthermore, the combined use of nano-carbon iron suspension injection and anticancer drugs is for 1-6 cycles; wherein, within the combined use cycle, the ratio is:

[0017] The nano-carbon iron suspension injection is administered once every 14 days, with each injection containing 30mg-150mg of ferrous ions.

[0018] The proportions of the anticancer drugs include:

[0019] Sorafenib is administered twice daily, 0.2g-0.4g each time; or,

[0020] Doxorubicin is administered every three weeks at a dose of 1.2–2.4 mg / kg or 30–75 mg / m². 2 ;or,

[0021] Cisplatin, 50–120 mg / m² every four weeks. 2 Or once daily for five days, 15-20 mg / m² each time. 2 ;or,

[0022] Paclitaxel once a week, 80 mg / m² each time. 2 Or once every three to four weeks, 135–175 mg / m² each time. 2 ;or,

[0023] Gemcitabine once a week, 1000-1250 mg / m² each time. 2 ;or,

[0024] Docetaxel once every three weeks, 75 mg / m² each time. 2 ;or,

[0025] Hydroxycamptothecin, 4-6 mg once daily.

[0026] The above-described technical solution of the present invention has at least the following beneficial technical effects:

[0027] (1) After being injected into the tumor, the nano-carbon iron suspension injection can enrich the tumor with oral or intravenous sorafenib, doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel and hydroxycamptothecin, thereby increasing the concentration of sorafenib, doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel and hydroxycamptothecin in the tumor, and making sorafenib, doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel and hydroxycamptothecin act more precisely on the tumor site, thereby relatively reducing the dosage and toxic side effects on normal cells and tissues.

[0028] (2) Sorafenib inhibits tumor proliferation by inhibiting receptor tyrosine kinase activity. Doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel, and hydroxycamptothecin inhibit tumor proliferation by inhibiting cell DNA or microtubule protein. Nano-carbon iron suspension injection effectively promotes ferroptosis of cancer cells by generating excessive ROS. Drugs with different mechanisms of action have a synergistic effect when administered in combination, resulting in better anti-cancer efficacy.

[0029] (3) After administration of nano-carbon iron suspension (CNSI-Fe), intracellular iron content increases, triggering the Fenton reaction, generating hydroxyl radicals, consuming intracellular GSH and GPX4, producing lipid peroxides, and causing ferroptosis. Administering sorafenib or cisplatin concurrently with CNSI-Fe can enhance the cytotoxicity of nano-carbon iron, consuming more GSH, and generating more hydroxyl radicals and lipid peroxides. Attached Figure Description

[0030] To more clearly illustrate the technical solutions in the embodiments of this application or in the conventional technology, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0031] Figure 1 shows the in vitro isothermal adsorption curves of sorafenib by nano-carbon iron suspension injections with ferrous ion concentrations of 15, 30, and 60 mg / mL in one embodiment of this application.

[0032] Figure 2 shows the in vitro isothermal adsorption curves of doxorubicin adsorbed by nano-carbon iron suspension injections with ferrous ion concentrations of 15, 30, and 60 mg / mL in one embodiment of this application.

[0033] Figure 3 is a comparison of intracellular iron content in the untreated control group, CNSI-Fe treatment group, SRF treatment group, and CNSI-Fe+SRF treatment group in an in vitro cell experiment according to one embodiment of this application.

[0034] Figure 4 is a comparison of hydroxyl radical detection in cells of the untreated control group, CNSI-Fe treatment group, SRF treatment group, and CNSI-Fe+SRF treatment group in an in vitro cell experiment according to one embodiment of this application.

[0035] Figure 5 is a comparison of the oxidative stress detection results of cells in the untreated control group, CNSI-Fe treatment group, SRF treatment group and CNSI-Fe+SRF treatment group in an in vitro cell experiment according to one embodiment of this application.

[0036] Figure 6 is a comparison of GPX4 levels in cells of the untreated control group, CNSI-Fe treatment group, SRF treatment group, and CNSI-Fe+SRF treatment group in an in vitro cell experiment according to one embodiment of this application.

[0037] Figure 7 is a comparison of tumor volume in mice in an in vivo experiment of the 4T1 breast cancer model, H22 liver cancer model, and AsPC-1 pancreatic cancer model, including the negative control group, CNSI control group, CDDP control group, CNSI-Fe administration group, SRF administration group, and CNSI-Fe+SRF administration group.

[0038] Figure 8 is a comparison of hydroxyl radicals in mouse tumors in an in vivo experiment in one embodiment of this application, in the negative control group, CNSI-Fe administration group, SRF administration group, and CNSI-Fe+SRF administration group.

[0039] Figure 9 is a comparison of SRF content in mouse tumor tissues in the SRF-treated group and the CNSI-Fe+SRF-treated group of the 4T1 breast cancer model, H22 liver cancer model and AsPC-1 pancreatic cancer in vivo experiments in one embodiment of this application.

[0040] Figure 10 is a comparison of the SRF content in mouse tumor cells in an in vivo experiment in one embodiment of this application between the SRF-treated group and the CNSI-Fe+SRF-treated group.

[0041] Figure 11 is a comparison of tumor volume changes in the in vivo experimental negative control group, CNSI-Fe group, DOX group, and CNSI-Fe+DOX group treated with CT26.WT colon cancer subcutaneous tumor and HT1080 fibrosarcoma subcutaneous tumor in one embodiment of this application.

[0042] Figure 12 shows the concentration of DOX in the tumor tissues of CT26.WT colon cancer subcutaneous tumor and HT1080 fibrosarcoma subcutaneous tumor in an in vivo experiment according to one embodiment of this application.

[0043] Figure 13 is a graph showing the tumor volume changes of the negative control group, CNSI-Fe group, CDDP group, and CNSI-Fe+CDDP group treated with subcutaneous hepatocellular carcinoma in one embodiment of this application.

[0044] Figure 14 shows the concentration of CDDP in the subcutaneous tumor tissue of liver cancer in the CDDP group and CNSI-Fe+CDDP group in an in vivo experiment according to one embodiment of this application.

[0045] Figure 15 is a graph showing the tumor volume changes of the negative control group, CNSI-Fe group, PTX group, and CNSI-Fe+PTX group in an in vivo experiment of one embodiment of this application.

[0046] Figure 16 shows the concentration of PTX in the subcutaneous tumor tissue of breast cancer in the PTX group and CNSI-Fe+PTX group in an in vivo experiment according to one embodiment of this application.

[0047] Figure 17 is a comparison of tumor volume changes in the in vivo negative control group, CNSI-Fe group, GEM group, and CNSI-Fe+GEM group treated with subcutaneous pancreatic cancer in one embodiment of this application.

[0048] Figure 18 shows the concentration of GEM in pancreatic cancer subcutaneous tumor tissue in the GEM group and CNSI-Fe+GEM group in an in vivo experiment according to one embodiment of this application.

[0049] Figure 19 is a graph showing the tumor volume changes of the negative control group, CNSI-Fe group, DTX group, and CNSI-Fe+DTX group in an in vivo experiment of one embodiment of this application.

[0050] Figure 20 shows the concentration of DTX in the subcutaneous tumor tissue of breast cancer in the DTX group and CNSI-Fe+DTX group in an in vivo experiment according to one embodiment of this application.

[0051] Figure 21 is a graph showing the tumor volume changes of the negative control group, CNSI-Fe group, HCPT group, and CNSI-Fe+HCPT group treated with subcutaneous colorectal cancer in an embodiment of this application.

[0052] Figure 22 shows the concentration of HCPT in the subcutaneous tumor tissue of colon cancer in the HCPT group and the CNSI-Fe+HCPT group in an in vivo experiment according to one embodiment of this application.

[0053] Figure 23 is a graph showing the tumor volume changes of pancreatic cancer subcutaneous tumors in the negative control group, CNSI-Fe group, PTX+GEM group, and CNSI-Fe+PTX+GEM group in an embodiment of this application. Detailed Implementation

[0054] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the various embodiments of this application will be described in detail below with reference to the accompanying drawings. However, those skilled in the art will understand that many technical details are presented in the various embodiments of this application to facilitate a better understanding of the application. However, the technical solutions claimed in this application can be implemented even without these technical details and various variations and modifications based on the following embodiments. The division of the various embodiments below is for ease of description and should not constitute any limitation on the specific implementation of this application. The various embodiments can be combined with and referenced by each other without contradiction.

[0055] Currently, existing technologies suffer from the problem of requiring high dosages when using either anticancer drugs or nano-carbon iron suspension injections alone.

[0056] To address the aforementioned issues, one embodiment of this application provides the use of a nano-carbon iron suspension injection for combined administration. The nano-carbon iron suspension injection, when combined with one or more of sorafenib (SRF), doxorubicin (DOX), cisplatin (CDDP), paclitaxel (PTX), gemcitabine (GEM), docetaxel (DTX), and hydroxycamptothecin (HCPT), can be used to treat cancer, primarily pancreatic cancer, lung cancer, gastric cancer, colorectal cancer, breast cancer, cervical cancer, liver cancer, thyroid cancer, ovarian cancer, and sarcoma. Sorafenib is administered orally, while doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel, and hydroxycamptothecin are administered intravenously. The nano-carbon iron suspension injection is administered via intratumoral injection. The nano-carbon iron suspension injection is prepared by mixing nano-carbon suspension injection and ferrous sulfate for injection.

[0057] Combination therapy is a common strategy in clinical cancer treatment. Using combination drugs is more likely to improve treatment efficacy, reduce the risk of drug resistance, and lessen the side effects experienced by patients. The advantage of this comprehensive treatment lies in its ability to utilize the complementary effects of different drugs or treatment modalities, simultaneously targeting multiple pathways of tumor growth and development, thereby more comprehensively inhibiting tumor growth and spread and improving the overall treatment effect.

[0058] This application has found that, after intratumoral injection, the nano-carbon iron suspension injection can increase the concentration of orally administered or intravenously administered sorafenib, doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel, and hydroxycamptothecin within the tumor, thereby increasing the concentration of these drugs within the tumor. This allows sorafenib, doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel, and hydroxycamptothecin to act more precisely on the tumor site, relatively reducing the dosage and toxic side effects on normal cells and tissues.

[0059] Furthermore, the nano-carbon iron suspension injection itself has anti-cancer effects, exerting its anti-cancer effect through the ferroptosis pathway. It is a nano-suspension anti-cancer drug using nano-carbon as a carrier and ferrous ions as the active ingredient, administered directly to the tumor via intratumoral injection. 2+ Targeted ferroptosis can effectively inhibit tumor growth (CNSI-Fe) 2++H2O2→ROS(·OH)→L-ROS→Ferroptosis). Sorafenib is an oral multi-kinase inhibitor that directly inhibits tumor growth by inhibiting the Raf / MEK / ERK signaling pathway. It also indirectly inhibits tumor growth by inhibiting the activity of tyrosine kinase receptors related to angiogenesis and tumor growth, blocking tumor angiogenesis. Furthermore, it inhibits tumor growth by inhibiting the cysteine / glutamate antitransporter (system xc-), depleting GSH, and causing iron-dependent accumulation of lipid ROS, leading to ferroptosis. Doxorubicin is a broad-spectrum anticancer drug that primarily exerts its effects by inserting into cellular DNA and triggering topoisomerase II to disrupt the tertiary structure of DNA. Cisplatin mainly inhibits cell proliferation by binding to DNA to form Pt / DNA adducts, disrupting DNA structure. It can also induce ferroptosis through mechanisms such as GSH depletion, GPX inactivation, iron metabolism disruption, ROS production, and lipid peroxidation promotion. Paclitaxel primarily acts on tubulin, stabilizing and enhancing its polymerization, thereby preventing depolymerization and disrupting the normal dynamic balance between polymerization and depolymerization. This prevents the formation of spindle fibers and fusiform structures during mitosis, inhibiting cell division and proliferation, and thus exerting its anti-tumor effect. Gemcitabine, a pyrimidine nucleotide analog, primarily acts during DNA synthesis (S phase). Activated by deoxycytosine kinase, it forms gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP), which inhibit DNA synthesis, leading to apoptosis. Docetaxel, a paclitaxel-based antitumor drug, binds to free tubulin, promoting its assembly into stable microtubules while inhibiting depolymerization. This results in the formation of dysfunctional microtubule bundles and microtubule fixation, thereby inhibiting cell mitosis. Hydroxycamptothecin is a DNA synthesis inhibitor that primarily acts during the DNA synthesis phase (S phase), inhibiting DNA topoisomerase I and exhibiting a significant inhibitory effect on nucleic acid synthesis, especially DNA. Combining these drugs with different mechanisms of action with nano-carbon iron suspension injection can block different signaling pathways, alter the tumor microenvironment, overcome tumor heterogeneity, and demonstrate a synergistic effect, resulting in better anti-cancer efficacy. It may also reduce drug resistance.

[0060] Furthermore, administration of nano-carbon iron suspension increases intracellular iron levels, triggering the Fenton reaction, generating hydroxyl radicals, consuming intracellular GSH and GPX4, producing lipid peroxides, and leading to ferroptosis. Administering sorafenib or cisplatin concurrently with nano-carbon iron can enhance its cytotoxicity, consuming even more GSH and generating more hydroxyl radicals and lipid peroxides.

[0061] In one embodiment of this application, during combined drug administration, sorafenib is first administered orally or directly by gavage, followed by intratumoral injection of nano-carbon iron suspension, or nano-carbon iron suspension is first injected into the tumor, followed by intravenous injection of chemotherapy drugs. The optional process is as follows:

[0062] The nano-carbon iron suspension injection is administered once every 14 days, with each injection containing 30mg-150mg of ferrous ions.

[0063] The proportion of anticancer drugs includes: sorafenib, administered twice daily, 0.2g-0.4g each time;

[0064] Alternatively, doxorubicin can be administered every three weeks at a dose of 1.2–2.4 mg / kg or 30–75 mg / m². 2 ;or,

[0065] Cisplatin, 50–120 mg / m² every four weeks. 2 Or once daily for five days, 15-20 mg / m² each time. 2 ;or,

[0066] Paclitaxel once a week, 80 mg / m² each time. 2 Or once every three to four weeks, 135–175 mg / m² each time. 2 ;or,

[0067] Gemcitabine once a week, 1000-1250 mg / m²; or,

[0068] Docetaxel once every three weeks, 75 mg / m² each time. 2 ;or,

[0069] Hydroxycamptothecin, 4-6 mg once daily.

[0070] The above units of measurement include mg / m 2 The expression indicates drug weight / body surface area; mg / kg indicates drug weight / body weight. In one embodiment of this application, the nano-carbon iron suspension injection is composed of a mixture of nano-carbon suspension injection and ferrous sulfate for injection.

[0071] During storage, the nano-carbon suspension injection and ferrous sulfate for injection are stored separately. For clinical use, the ferrous sulfate for injection is dissolved in the nano-carbon suspension injection to form a nano-carbon iron suspension injection. The concentration of nano-carbon in the nano-carbon suspension injection is 20–100 mg / mL, and the concentration of ferrous ions in the nano-carbon iron suspension injection is 0.1–60 mg / mL. Preferably, the concentration of the nano-carbon suspension injection is 50 mg / mL, and the concentration of ferrous ions in the nano-carbon iron suspension injection is 7.0–60 mg / mL. More preferably, the concentration of ferrous ions in the nano-carbon iron suspension injection is 30 mg / mL or 60 mg / mL.

[0072] In one embodiment of this application, the nano-carbon iron has a particle size of 90-250 nm and a pH value of 2.0-6.0. The nano-carbon iron enters the cell through iron import channels overexpressed on the cancer cell membrane or through phagocytosis, and is enriched with sorafenib, doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel or hydroxycamptothecin.

[0073] In one embodiment of this application, the preparation method of the nano-carbon suspension injection is as follows:

[0074] Weigh out 60 mg of sodium citrate and 400 mg of poloxamer, dissolve them in 20 mL of physiological saline, then add 1000 mg of nano-carbon raw material. Homogenize for 5-10 minutes (7000 rpm). After homogenization, transfer to a homogenizer and homogenize three times (homogenization pressure 20000 psi) to obtain the nano-carbon suspension injection. Optionally, the nano-carbon raw material is carbon black (C4). 40 ).

[0075] The preparation method of ferrous sulfate for injection is as follows:

[0076] 1490 mg of ferrous sulfate heptahydrate raw material was dissolved in 20 mL of water for injection. After complete dissolution, the pH of the solution was adjusted to 2.8 with sulfuric acid.

[0077] Then, it is dispensed, freeze-dried, backfilled with nitrogen, and capped to obtain ferrous sulfate for injection.

[0078] When needed, the preparation method of the nano-carbon iron suspension injection is as follows: extract the nano-carbon suspension injection, add it to ferrous sulfate for injection (bottled) under air-isolated conditions, and mix well.

[0079] The preparation methods for nano-carbon iron suspension injections with different ferrous ion concentrations are as follows:

[0080] When the ferrous ion concentration is 60 mg / mL: Take 0.5 mL of nano-carbon suspension injection solution with a syringe, pass it through the rubber stopper of the ferrous sulfate injection bottle under air-isolated conditions, and inject it into the ferrous sulfate injection bottle for mixing. Shake well; after mixing for 5 minutes, shake well again to obtain the solution.

[0081] When the ferrous ion concentration is 30 mg / mL: Take 1 mL of nano-carbon suspension injection solution with a syringe, pass it through the rubber stopper of the ferrous sulfate injection bottle under air-isolated conditions, and inject it into the ferrous sulfate injection bottle. Mix well and shake well. After mixing for 5 minutes, shake well again to obtain the solution.

[0082] When the ferrous ion concentration is 15 mg / mL: Take 2 mL of nano-carbon suspension injection solution with a syringe, pass it through the rubber stopper of the ferrous sulfate injection bottle under air-isolated conditions, and inject it into the ferrous sulfate injection bottle. Mix well and shake well. After mixing for 5 minutes, shake well again to obtain the solution.

[0083] When the ferrous ion concentration is 7.5 mg / mL: Take 4 mL of nano-carbon suspension injection solution with a syringe, pass it through the rubber stopper of the ferrous sulfate injection bottle under air-isolated conditions, and inject it into the ferrous sulfate injection bottle. Mix well and shake well. After mixing for 5 minutes, shake well again to obtain the solution.

[0084] When the ferrous ion concentration is 3.75 mg / mL: Take 8 mL of nano-carbon suspension injection solution with a syringe, pass it through the rubber stopper of the ferrous sulfate injection bottle under air-isolated conditions, and inject it into the ferrous sulfate injection bottle. Mix well and shake well. After mixing for 5 minutes, shake well again to obtain the final product.

[0085] The following explanation is based on specific experiments, which are divided into in vitro isothermal adsorption experiments, in vitro cell experiments, and in vivo experiments:

[0086] The in vitro isothermal adsorption test is as follows:

[0087] Example 1

[0088] Prepare a series of sorafenib solutions of individual concentrations (mg / mL). Add 1 mL of nano-carbon iron suspension injection (nano-carbon suspension injection concentration of 50 mg / mL, ferrous ion concentrations of 15, 30, and 60 mg / mL, respectively), 2.8 mL of methanol, and 0.2 mL of sorafenib solution to a 10 mL centrifuge tube in sequence. After mixing, place the tube in a shaker at 37℃ and shake (110 r / min) for 1 h. Centrifuge at 8000 r / min for 10 min. Take 0.2 mL of the supernatant, add 1 mL of methanol and mix well. Detect the sorafenib concentration by membrane HPLC and calculate the adsorption capacity (Qe) according to the Langmuir model.

[0089] The test results showed that the maximum adsorption capacity of sorafenib by nano-carbon iron suspension injections with ferrous ion concentrations of 15 mg / mL, 30 mg / mL, and 60 mg / mL were not significantly different, at 42.36, 41.57, and 43.79 mg / g, respectively. The isothermal adsorption curves are shown in Figure 1: (a) is the isothermal adsorption curve of sorafenib by nano-carbon iron with a ferrous ion concentration of 15 mg / mL; (b) is the isothermal adsorption curve of sorafenib by nano-carbon iron with a ferrous ion concentration of 30 mg / mL; and (c) is the isothermal adsorption curve of sorafenib by nano-carbon iron with a ferrous ion concentration of 60 mg / mL.

[0090] Example 2

[0091] A series of doxorubicin solutions (mg / mL) at different concentrations were prepared, and isothermal adsorption experiments were conducted using the same method as in Example 1. The results showed that the maximum adsorption capacity of sorafenib by nano-carbon iron suspension injections with ferrous ion concentrations of 15 mg / mL, 30 mg / mL, and 60 mg / mL were not significantly different, at 134.57, 138.37, and 135.79 mg / g, respectively. The isothermal adsorption curves are shown in Figure 2. (a) is the isothermal adsorption curve of doxorubicin by nano-carbon iron with a ferrous ion concentration of 15 mg / mL, (b) is the isothermal adsorption curve of doxorubicin by nano-carbon iron with a ferrous ion concentration of 30 mg / mL, and (c) is the isothermal adsorption curve of doxorubicin by nano-carbon iron with a ferrous ion concentration of 60 mg / mL.

[0092] Example 3

[0093] A series of individual cisplatin solutions (mg / mL) were prepared and isothermal adsorption tests were conducted using the same method as in Example 1. The results showed that the maximum adsorption capacity of cisplatin by the nano-carbon iron suspension injection (ferrous ion concentration of 15 mg / mL) was 8.20 mg / g.

[0094] Example 4

[0095] A series of individual paclitaxel solutions (mg / mL) were prepared, and isothermal adsorption tests were conducted using the same method as in Example 1. The results showed that the maximum adsorption capacity of paclitaxel by the nano-carbon iron suspension injection (ferrous ion concentration of 15 mg / mL) was 35.98 mg / g.

[0096] Example 5

[0097] A series of gemcitabine solutions of different concentrations (mg / mL) were prepared and isothermal adsorption tests were conducted using the same method as in Example 1. The results showed that the maximum adsorption capacity of the nano-carbon iron suspension injection (ferrous ion concentration of 15 mg / mL) for gemcitabine was 19.23 mg / g.

[0098] Example 6

[0099] A series of docetaxel solutions of different concentrations (mg / mL) were prepared and isothermal adsorption tests were conducted using the same method as in Example 1. The results showed that the maximum adsorption capacity of the nano-carbon iron suspension injection (ferrous ion concentration of 15 mg / mL) for docetaxel was 46.77 mg / g.

[0100] Example 7

[0101] A series of individual hydroxycamptothecin solutions (mg / mL) were prepared, and isothermal adsorption tests were conducted using the same method as in Example 1. The results showed that the maximum adsorption capacity of hydroxycamptothecin by the nano-carbon iron suspension injection (ferrous ion concentration of 15 mg / mL) was 12.41 mg / g.

[0102] The in vitro cell experiments are as follows:

[0103] Example 8

[0104] Experimental materials: RPMI-1640 medium, DMEM medium, fetal bovine serum (FBS), cell digestion solution with trypsin, penicillin-streptomycin mixture, phosphate-buffered saline (PBS, pH 7.4), nano-carbon suspension injection, nano-carbon iron suspension injection (nano-carbon-ferrous sulfate, CNSI-Fe, concentration expressed as ferrous ions), sorafenib (SRF), doxorubicin (DOX), cisplatin (CDDP), paclitaxel (PTX), gemcitabine (GEM), docetaxel (DTX), hydroxycamptothecin (HCPT).

[0105] Cell lines: murine 4T1 triple-negative breast cancer cells, murine CT26.WT colon cancer cells, murine H22 liver cancer cells, human AsPC-1 pancreatic cancer cells, and human HT1080 fibrosarcoma cells.

[0106] Experimental methods: Cancer cells in the logarithmic growth phase were collected, the cell suspension concentration was adjusted, and they were cultured in 12-well plates and incubated at 37°C for 24 h with 5% CO2. The experiment was divided into 5 groups: control group without drug treatment, nano-carbon control group (CNSI), CNSI-Fe treatment group, series concentration of anticancer drug treatment group, and CNSI-Fe + series concentration of anticancer drug treatment group. Each group / each drug concentration had 3 replicates.

[0107] Among them, (1) a complete culture medium containing a series of concentrations of anticancer drugs was added to the series of concentrations of anticancer drugs administration groups.

[0108] (2) The CNSI-Fe+ series concentration anticancer drug administration group was first added with complete culture medium containing a series concentration of anticancer drugs. After culturing for 6 hours, CNSI-Fe solution was added to make the final Fe ion concentration 100 μg / mL.

[0109] (3) Add complete culture medium containing 333 μg / mL of nano-carbon to the nano-carbon control group.

[0110] (4) Add complete culture medium containing 100 μg / mL of iron ions to the CNSI-Fe drug administration group.

[0111] (5) The control group without medication received no medication.

[0112] Then, the above groups (1)-(5) were placed in 5% CO2 and incubated at 37°C for 48 hours.

[0113] Discard the culture medium, collect the cells, count the number of cells under a light microscope, calculate the inhibition rate, and calculate q = E based on the co-occurrence effect (q) using the formula. A+B / (E A +E B -E A ×E B Calculate the value of q, where E A E represents the effect of drug A when administered alone. B E represents the effect of drug B when administered alone. A+B This represents the combined effect of drugs A and B, and is the expected value of the combined effect. If the actual combined effect equals the expected value, i.e., q = 1, it is additive; q > 1, it is synergistic; and q < 1, it is antagonistic. The test results are recorded in Tables 1-7.

[0114] 1. In vitro drug administration of combined nano-carbon iron suspension injection (CNSI-Fe) and sorafenib (SRF):

[0115] Table 1: Inhibition rates (%) and q values ​​of CNSI, CNSI-Fe, SRF, and CNSI-Fe+SRF on 4T1 triple-negative breast cancer in in vitro cell experiments.

[0116] The test results in Table 1 show that:

[0117] Nano-carbon administration alone had no effect on cancer cell growth, with an inhibition rate of 3.55 ± 2.88%.

[0118] Nano-carbon iron alone significantly inhibited cell growth, with an inhibition rate of 46.34 ± 1.94%.

[0119] When nano-carbon iron was combined with different concentrations of sorafenib, the q value was >1 when the sorafenib concentration was ≤2μg / mL, indicating a synergistic effect on cell growth inhibition (Table 1). This suggests that the combined administration of nano-carbon iron and sorafenib can enhance the cytotoxicity of nano-carbon iron.

[0120] 2. In vitro drug administration of combined nano-carbon iron suspension injection (CNSI-Fe) and doxorubicin (DOX):

[0121] Table 2: Inhibition rates (%) and q values ​​of CNSI, CNSI-Fe, DOX, and CNSI-Fe+DOX against CT26.WT colon cancer in in vitro cell experiments.

[0122] The test results in Table 2 show that:

[0123] Nano-carbon administration alone had no effect on cancer cell growth, with an inhibition rate of 4.67 ± 2.38%.

[0124] Nano-carbon iron alone significantly inhibited cell growth, with an inhibition rate of 53.47 ± 2.09%.

[0125] When nano-carbon iron was co-administered with different concentrations of doxorubicin, the q value was >1 when the doxorubicin concentration was ≤2μg / mL, indicating a synergistic effect on cell growth inhibition (Table 2). This suggests that co-administration of nano-carbon iron with doxorubicin can enhance the cytotoxicity of nano-carbon iron.

[0126] 3. In vitro drug administration of nano-carbon iron suspension injection (CNSI-Fe) in combination with cisplatin (CDDP):

[0127] Table 3: Inhibition rates (%) and q values ​​of CNSI, CNSI-Fe, CDDP, and CNSI-Fe+CDDP against H22 hepatocellular carcinoma in in vitro cell experiments.

[0128] The test results in Table 3 show that:

[0129] Nano-carbon alone had no effect on cancer cell growth, with an inhibition rate of 5.18 ± 3.42%.

[0130] Nano-carbon iron alone significantly inhibited cell growth, with an inhibition rate of 55.34 ± 3.79%.

[0131] When nano-carbon iron was co-administered with different concentrations of cisplatin, the q value was >1 when the cisplatin concentration was ≤20μg / mL, indicating a synergistic effect on cell growth inhibition (Table 3). This suggests that co-administration of nano-carbon iron with cisplatin can enhance the cytotoxicity of nano-carbon iron.

[0132] 4. In vitro drug administration of combined nano-carbon iron suspension injection (CNSI-Fe) and paclitaxel (PTX):

[0133] Table 4: Inhibition rates (%) and q values ​​of CNSI, CNSI-Fe, PTX, and CNSI-Fe+PTX against 4T1 breast cancer in in vitro cell experiments.

[0134] The test results in Table 4 show that:

[0135] Nano-carbon administration alone had no effect on cancer cell growth, with an inhibition rate of 3.05 ± 1.69%.

[0136] Nano-carbon iron alone significantly inhibited cell growth, with an inhibition rate of 54.39 ± 1.29%.

[0137] When nano-carbon iron was co-administered with different concentrations of paclitaxel, the q value was greater than 1 when the paclitaxel concentration was ≤1 μg / mL, indicating a synergistic effect on cell growth inhibition (Table 4). This suggests that co-administration of nano-carbon iron with paclitaxel can enhance the cytotoxicity of nano-carbon iron.

[0138] 5. In vitro drug administration of combined nano-carbon iron suspension injection (CNSI-Fe) and gemcitabine (GEM):

[0139] Table 5: Inhibition rates (%) and q values ​​of CNSI, CNSI-Fe, GEM, and CNSI-Fe+GEM against AsPC-1 pancreatic cancer in in vitro cell experiments.

[0140] The test results in Table 5 show that:

[0141] Nano-carbon administration alone had no effect on cancer cell growth, with an inhibition rate of 3.77 ± 2.55%.

[0142] Nano-carbon iron alone significantly inhibited cell growth, with an inhibition rate of 50.74 ± 2.97%.

[0143] When nano-carbon iron was combined with different concentrations of gemcitabine, the q value was >1 when the gemcitabine concentration was ≤0.08μg / mL, indicating a synergistic effect on cell growth inhibition (Table 5). This suggests that the combined administration of nano-carbon iron and gemcitabine can enhance the cytotoxicity of nano-carbon iron.

[0144] 6. In vitro administration of nano-carbon iron suspension injection (CNSI-Fe) in combination with docetaxel (DTX):

[0145] Table 6: Inhibition rates (%) and q values ​​of CNSI, CNSI-Fe, DTX, and CNSI-Fe+DTX on 4T1 breast cancer in in vitro cell experiments.

[0146] The test results in Table 6 show that:

[0147] Nano-carbon administration alone had no effect on cancer cell growth, with an inhibition rate of 5.35 ± 3.14%.

[0148] Nano-carbon iron alone significantly inhibited cell growth, with an inhibition rate of 49.87±2.97%.

[0149] When nano-carbon iron was combined with different concentrations of docetaxel, the q value was greater than 1 when the docetaxel concentration was ≤1 μg / mL, which showed a synergistic effect on cell growth inhibition (Table 6). This indicates that the combined administration of nano-carbon iron and docetaxel can enhance the cytotoxicity of nano-carbon iron.

[0150] 7. In vitro drug administration of combined nano-carbon iron suspension injection (CNSI-Fe) and hydroxycamptothecin (HCPT):

[0151] Table 7: Inhibition rates (%) and q values ​​of CNSI, CNSI-Fe, HCPT, and CNSI-Fe+HCPT against CT26.WT colon cancer in in vitro cell experiments.

[0152] The test results in Table 7 show that:

[0153] Nano-carbon administration alone had no effect on cancer cell growth, with an inhibition rate of 4.02 ± 1.42%.

[0154] Nano-carbon iron alone significantly inhibited cell growth, with an inhibition rate of 51.74 ± 1.09%.

[0155] When nano-carbon iron was administered in combination with different concentrations of hydroxycamptothecin, the q value was greater than 1 when the concentration of hydroxycamptothecin was ≤4 μg / mL, indicating a synergistic effect on cell growth inhibition (Table 7). This suggests that the combined administration of nano-carbon iron and hydroxycamptothecin can enhance the cytotoxicity of nano-carbon iron.

[0156] 4T1 triple-negative breast cancer cells were cultured using the same drug administration method as in Example 1. The drugs were grouped as negative control, CNSI-Fe (100 μg / mL), SRF (2 μg / mL), and CNSI-Fe (100 μg / mL) + SRF (2 μg / mL). Cells were collected and the following assays were performed. The antitumor mechanism of CNSI-Fe + SRF on cells is as follows:

[0157] (1) The collected cells were digested by microwave digestion and the iron content of the cells was detected by inductively coupled plasma mass spectrometry (ICP-MS).

[0158] The test results are shown in Figure 3. The intracellular iron content in the CNSI-Fe group and the CNSI-Fe+SRF group was significantly increased, indicating that a large amount of Fe ions entered the cells.

[0159] (2) Prepare cell lysis buffer, add lysis buffer to each group, and add 5,5-dimethyl-1-pyrrolline-n-oxide (DMPO). Then, detect hydroxyl radicals using electron spin resonance spectroscopy (ESR).

[0160] The test results are shown in Figure 4. The characteristic peaks of intracellular hydroxyl radicals in the CNSI-Fe group and the SRF group were significantly increased, and the characteristic peaks of intracellular hydroxyl radicals in the CNSI-Fe+SRF group were higher than those in the CNSI-Fe group and the SRF group.

[0161] (3) Detect the cellular oxidative stress indicators hydrogen peroxide (H2O2), peroxidase (POD), glutathione (GSH), and malondialdehyde (MDA) according to the instructions of the hydrogen peroxide, peroxidase, glutathione and malondialdehyde detection kit.

[0162] Figure 5 compares the oxidative stress results of cells in the untreated control group, CNSI-Fe treatment group, SRF treatment group, and CNSI-Fe+SRF treatment group in the in vitro cell experiments of this embodiment. As shown in Figure 5, after CNSI-Fe administration, POD and GSH were significantly reduced; after SRF administration, H2O2 increased compensatorily, and GSH decreased; after CNSI-Fe+SRF administration, H2O2 increased compensatorily, POD and GSH were significantly reduced, and MDA was significantly increased. GSH is a substrate of GPX4, and MDA is a marker product of lipid peroxidation. The results indicate that the combined administration of CNSI-Fe and SRF further reduced intracellular GSH, the substrate of GPX4, and produced more MDA, a lipid peroxidation product.

[0163] (4) The level of GPX4 was detected by Western blot.

[0164] Figure 6 shows a comparison of GPX4 levels in cells from the untreated control group, CNSI-Fe treatment group, SRF treatment group, and CNSI-Fe+SRF treatment group in the in vitro cell experiments of this example. The detection results are shown in Figure 6, with GPX4 levels detected by Western blotting (WB). GPX4 has the function of scavenging lipid peroxides and can be used as one of the indicators for assessing ferroptosis. GPX4 levels decreased significantly after CNSI-Fe and CNSI-Fe+SRF administration, indicating that ferroptosis occurred in the cells.

[0165] The in vivo tests are as follows:

[0166] Experimental materials: murine 4T1 triple-negative breast cancer cells, murine CT26.WT colon cancer cells, murine H22 liver cancer cells, human AsPC-1 pancreatic cancer cells, RPMI-1640 medium, fetal bovine serum (FBS), cell digestion solution with trypsin, penicillin-streptomycin mixture, phosphate-buffered saline (PBS, pH 7.4), nano-carbon suspension injection, nano-carbon iron suspension injection (nano-carbon-ferrous sulfate, CNSI-Fe, concentration expressed as ferrous ions), sorafenib (SRF), doxorubicin (DOX), cisplatin (CDDP), paclitaxel (PTX), gemcitabine (GEM), docetaxel (DTX), and hydroxycamptothecin (HCPT).

[0167] Experimental animals: SPF-grade Balb / c mice, female, 4-6 weeks old, weighing 20±2g. BalB / c-nu mice, female, 5-7 weeks old, weighing 20±2g. Free access to water and food was provided throughout the experiment. 12 hours of light per day was provided. Five mice were housed in individually ventilated, isolated cages.

[0168] Test method:

[0169] Example 9

[0170] In vivo administration of nano-carbon iron suspension (CNSI-Fe) in combination with sorafenib (SRF):

[0171] Collect 4T1 cells in the logarithmic growth phase and adjust the cell suspension concentration to 3 × 10⁻⁶. 7 0.1 mL of the solution was injected into the right upper limb of Balb / c mice. After 7 days, the tumor volume reached 100-150 mm. 3 The mice were divided into 6 groups, with 7 mice in each group.

[0172] The six groups were: negative control group, CNSI group, CDDP 5mg / kg group, CNSI-Fe 0.75mg / mouse group, SRF 30mg / kg group, and CNSI-Fe 0.75mg / mouse + SRF 30mg / kg group.

[0173] Among them, (1) 50 μL of physiological saline was injected into the tumor of mice in the negative control group once a week for a total of 2 times.

[0174] (2) 50 μL of CNSI was injected into the tumor of mice in the CNSI group. The dosage of nanocarbon was 2.5 mg / mouse. Once a week for a total of 2 weeks.

[0175] (3) Mice in the CDDP 5mg / kg group were injected intraperitoneally with CDDP at a dose of 5mg / kg; twice a week for a total of 2 weeks.

[0176] (4) 50 μL of CNSI-Fe was injected into the tumor of mice in the CNSI-Fe 0.75 mg / mouse group. The iron ion concentration in CNSI-Fe was 15 mg / mL. This was done once a week for a total of 2 weeks.

[0177] (5) Mice in the SRF 30mg / kg group were administered SRF by gavage at a dose of 30mg / kg once a day for 14 days.

[0178] (6) In the group of mice receiving CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg, inject 50 μL of CNSI-Fe (Fe ion concentration 15 mg / mL) into the tumor, once a week for a total of 2 times; one day before the injection of CNSI-Fe, administer sorafenib at a dose of 30 mg / kg by gavage for 14 consecutive days.

[0179] The same method was used to establish an H22 hepatocellular carcinoma model and administer the drugs. Mice were divided into 7 groups of 7 mice each: negative control group, CNSI-Fe 0.375 mg / mouse group, SRF 15 mg / kg group, SRF 30 mg / kg group, CNSI-Fe 0.375 mg / mouse + SRF 15 mg / kg group, CNSI-Fe 0.375 mg / mouse + SRF 30 mg / kg group, and CNSI-Fe 0.75 mg / mouse group.

[0180] The AsPC-1 pancreatic cancer model was established and administered the drug using the same method. Mice were divided into 4 groups of 7 mice each: negative control group, CNSI-Fe 0.75 mg / mouse group, SRF 30 mg / kg group, and CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg group.

[0181] Group testing was conducted, and multiple indicators of mice and tumors were detected:

[0182] (1) Measure tumor volume 3 times a week. Tumor volume = length * width 2 / 2. Calculate the tumor growth inhibition rate and q-value.

[0183] Figure 7(a) shows a comparison of tumor volume in mice of the negative control group, CNSI control group, CDDP control group, CNSI-Fe treatment group, SRF treatment group, and CNSI-Fe+SRF treatment group in the in vivo 4T1 breast cancer model in this embodiment. As shown in Figure 7(a), compared with the negative control group, CDDP 5 mg / kg, CNSI-Fe 0.75 mg / mouse, SRF 30 mg / kg, and CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg all showed significant differences and significantly inhibited tumor growth.

[0184] Compared with CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg, the difference was statistically significant (p < 0.01).

[0185] The tumor volume inhibition rate at day 15 was calculated. CNSI-Fe 0.75 mg / mouse had an inhibition rate of 59.75%, SRF 30 mg / kg had an inhibition rate of 50.27%, and CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg had the highest inhibition rate of 82.95%. The calculated q value was 1.04, indicating a synergistic effect.

[0186] Figure 7(b) shows a comparison of tumor volume in mice of the negative control group, CNSI-Fe group, SRF group, and CNSI-Fe+SRF group in the H22 hepatocellular carcinoma model in this embodiment. The results are shown in Figure 7(b). On day 15, the tumor volume inhibition rates were: 53.84% for CNSI-Fe 0.375 mg / mouse, 50.59% for SRF 15 mg / kg, 76.16% for SRF 30 mg / kg, 84.25% for CNSI-Fe 0.375 mg / mouse + SRF 15 mg / kg, 90.91% for CNSI-Fe 0.375 mg / mouse + SRF 30 mg / kg, and 73.40% for CNSI-Fe 0.75 mg / mouse. All these rates showed significant differences compared to the negative control group, indicating a significant inhibition of tumor growth. The concentrations of CNSI-Fe 0.375 mg / mouse + SRF 15 mg / kg showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and SRF 15 mg / kg. Similarly, the concentrations of CNSI-Fe 0.375 mg / mouse + SRF 30 mg / kg also showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and SRF 30 mg / kg. The q-values ​​were 1.09 for CNSI-Fe 0.375 mg / mouse + SRF 15 mg / kg and 1.02 for CNSI-Fe 0.375 mg / mouse + SRF 30 mg / kg, indicating a synergistic effect.

[0187] Figure 7(c) shows a comparison of tumor volume in mice of the AsPC-1 pancreatic cancer model in vivo, including the negative control group, CNSI-Fe group, SRF group, and CNSI-Fe+SRF group. The results, as shown in Figure 7(c), indicate that the tumor volume inhibition rates on day 15 were: 51.21% for CNSI-Fe 0.75 mg / mouse, 40.68% for SRF 30 mg / kg, and 72.37% for CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg. These rates were significantly different from the negative control group, demonstrating significant inhibition of tumor growth. CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg showed a significant difference compared to CNSI-Fe 0.75 mg / mouse and SRF 30 mg / kg alone. The q-value for CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg was 1.02, indicating a synergistic effect.

[0188] (2) Detect hydroxyl radicals in tumor tissue.

[0189] Figure 8 is a comparison of hydroxyl radicals in mouse tumors in the negative control group, CNSI-Fe group, SRF group, and CNSI-Fe+SRF group of the 4T1 breast cancer model in this embodiment. Figure 8(a) shows the intensity of hydroxyl radicals in the tumor of the negative control group, Figure 8(b) shows the intensity of hydroxyl radicals in the tumor of the CNSI-Fe group, Figure 8(c) shows the intensity of hydroxyl radicals in the tumor of the SRF group, and Figure 8(d) shows the intensity of hydroxyl radicals in the tumor of the CNSI-Fe+SRF group.

[0190] The test results are shown in Figure 8(a), (b), (c), and (d). The characteristic peak of hydroxyl radicals in the tumors of mice in the CNSI-Fe group and SRF group was significantly increased, and the characteristic peak of hydroxyl radicals in the tumors of mice in the CNSI-Fe+SRF group was significantly higher than that in the CNSI-Fe group and SRF group.

[0191] (3) HPLC method was used to detect the concentration of sorafenib in tumor tissues and tumor cells.

[0192] Figure 9(a) is a comparison of SRF content in tumor tissue in the SRF-treated group and the CNSI-Fe+SRF-treated group of the 4T1 breast cancer model in this embodiment. The results of detecting sorafenib concentration in tumor tissue are shown in Figure 9(a). The SRF concentration in the tumor of the SRF 30 mg / kg group was 3.53 ± 0.47 μg / g; the SRF concentration in the tumor of the CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg group was 6.19 ± 1.17 μg / g, which was significantly higher than that of SRF alone, and 1.75 times that of SRF alone, indicating that nano-carbon iron can enrich SRF in tumors.

[0193] Figure 9(b) is a comparison of SRF content in tumor tissue in the SRF-treated group and the CNSI-Fe+SRF-treated group of the H22 liver cancer model in vivo in this embodiment. The results of detecting sorafenib concentration in tumor tissue are shown in Figure 9(b). The tumor SRF concentration in the SRF 15 mg / kg group was 1.31 ± 0.09 μg / g, and the tumor SRF concentration in the CNSI-Fe 0.375 mg / mouse + SRF 15 mg / kg group was 6.65 ± 0.32 μg / g, which were significantly higher than those of SRF alone, and were 5.09 times higher than those of SRF alone. The tumor SRF concentration in the SRF 30 mg / kg group was 1.78 ± 0.08 μg / g, and the tumor SRF concentration in the CNSI-Fe 0.375 mg / mouse + SRF 30 mg / kg group was 9.35 ± 0.37 μg / g, which were significantly higher than those of SRF alone, and were 5.26 times higher than those of SRF alone. This indicates that nano-carbon iron can enrich SRF in tumors.

[0194] Figure 9(c) is a comparison of SRF content in tumor tissue in the AsPC-1 pancreatic cancer model in vivo experiment of this embodiment, between the SRF administration group and the CNSI-Fe+SRF administration group. The results of sorafenib concentration detection in tumor tissue are shown in Figure 9(c). The SRF concentration in the tumor of the SRF 30 mg / kg group was 1.95 ± 0.10 μg / g, and the SRF concentration in the CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg group was 9.86 ± 1.21 μg / g, significantly higher than that of SRF alone, and 5.06 times higher than that of SRF alone, indicating that nano-carbon iron can enrich SRF within the tumor.

[0195] Figure 10 is a comparison of SRF levels in mouse tumor cells in the SRF-treated group and the CNSI-Fe+SRF-treated group in the in vivo 4T1 breast cancer model of this embodiment. As shown in Figure 10, the SRF content in tumor cells of the SRF 30 mg / kg group (per 10 4 The SRF concentration in tumor cells (per 10 cells) was 0.0447 ± 0.0048 ng / mL. In the CNSI-Fe 0.75 mg / mouse + SRF 30 mg / kg group, the intracellular SRF concentration in tumor cells (per 10 cells) was... 4 The SRF concentration in individual cells was 0.1233±0.0241 ng / mL, which was significantly higher than that of SRF alone, by 2.76 times, indicating that nano-carbon iron can enrich SRF and increase SRF in tumor cells.

[0196] In summary, CNSI-Fe and SRF administration induce intracellular hydroxyl radicals, leading to ferroptosis and significantly inhibiting tumor growth. Pre-administration of sorafenib before CNSI-Fe generates even more hydroxyl radicals, enriching the sorafenib concentration within the tumor and enhancing the anticancer effects of nano-carbon iron and sorafenib, demonstrating a synergistic effect.

[0197] Example 10

[0198] In vivo administration of nano-carbon iron suspension (CNSI-Fe) in combination with doxorubicin (DOX):

[0199] CT26.WT colon cancer cells in the logarithmic growth phase were collected, and the cell suspension concentration was adjusted to 3 × 10⁻⁶. 7 0.1 mL of the solution was injected into the right upper limb of Balb / c mice. After 7 days, the tumor volume reached 100-150 mm. 3 The mice were divided into 7 groups, with 7 mice in each group.

[0200] The seven groups were: negative control group, CNSI-Fe 0.375 mg / mouse group, DOX 2.5 mg / kg group, DOX 5 mg / kg group, CNSI-Fe 0.375 mg / mouse + DOX 2.5 mg / kg group, CNSI-Fe 0.375 mg / mouse + DOX 5 mg / kg group, and CNSI-Fe 0.75 mg / mouse group.

[0201] Among them, (1) 50 μL of physiological saline was injected into the tumor of mice in the negative control group once a week for a total of 2 times.

[0202] (2) 50 μL of CNSI-Fe was injected into the tumor of mice in the CNSI-Fe group. The iron ion concentrations in CNSI-Fe were 7.5 mg / mL and 15 mg / mL, respectively. The injection was given once a week for a total of 2 weeks.

[0203] (3) DOX was administered intravenously to mice in the DOX group at doses of 2.5 mg / kg and 5 mg / kg, twice a week for a total of 4 times.

[0204] (4) In the CNSI-Fe 0.375mg / mouse + DOX group, 50μL of CNSI-Fe (Fe ion concentration 7.5mg / mL) was injected into the tumor of mice once a week for a total of 2 times. DOX was administered after CNSI-Fe injection at doses of 2.5mg / kg and 5mg / kg, respectively, intravenously twice a week for a total of 4 times.

[0205] The same method was used to establish an HT1080 fibrosarcoma model and administer the drugs. Mice were divided into 4 groups of 7 mice each: negative control group, CNSI-Fe 0.75 mg / mouse group, DOX 2.5 mg / kg group, and CNSI-Fe 0.75 mg / mouse + DOX 2.5 mg / kg group.

[0206] Measure tumor volume 2-3 times per week. Tumor volume = length * width 2 / 2. Calculate the tumor growth inhibition rate and q-value; take tumor tissue and detect the DOX concentration in the tumor tissue by HPLC.

[0207] Figure 11(a) shows the tumor volume changes in the negative control group, CNSI-Fe group, DOX group, and CNSI-Fe+DOX group of the CT26.WT colon cancer model in this embodiment. Based on Figure 11(a), the tumor volume inhibition rate on day 14 was calculated as follows: CNSI-Fe 0.375 mg / mouse: 44.29%; DOX 2.5 mg / kg: 36.50%; DOX 5 mg / kg: 47.15%; CNSI-Fe 0.375 mg / mouse + DOX 2.5 mg / kg: 66.81%; CNSI-Fe 0.375 mg / mouse + DOX 5 mg / kg: 77.43%; CNSI-Fe 0.75 mg / mouse: 69.04%. All these rates showed significant differences compared to the negative control group, indicating a significant inhibition of tumor growth. The concentrations of CNSI-Fe 0.375 mg / mouse + DOX 2.5 mg / kg showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and DOX 2.5 mg / kg. Similarly, the concentrations of CNSI-Fe 0.375 mg / mouse + DOX 5 mg / kg also showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and DOX 5 mg / kg. The q-values ​​were 1.03 for CNSI-Fe 0.375 mg / mouse + DOX 2.5 mg / kg and 1.10 for CNSI-Fe 0.375 mg / mouse + DOX 5 mg / kg, indicating a synergistic effect.

[0208] Figure 11(b) shows the tumor volume changes in the negative control group, CNSI-Fe group, DOX group, and CNSI-Fe+DOX group of the HT1080 fibrosarcoma model treated with fibrosarcoma subcutaneous tumors in this embodiment. Based on Figure 11(b), the tumor volume inhibition rate at day 14 was calculated as follows: CNSI-Fe 0.75 mg / mouse was 43.80%, DOX 2.5 mg / kg was 38.01%, and CNSI-Fe 0.75 mg / mouse + DOX 2.5 mg / kg was 67.38%. All these rates showed significant differences compared to the negative control group, indicating significant inhibition of tumor growth. The CNSI-Fe 0.75 mg / mouse + DOX 2.5 mg / kg rate also showed significant differences compared to CNSI-Fe 0.75 mg / mouse and DOX 2.5 mg / kg alone. The q-value was calculated to be 1.03 for CNSI-Fe 0.75 mg / mouse + DOX 2.5 mg / kg, indicating a synergistic effect.

[0209] Figure 12(a) shows the concentration of DOX in the CT26.WT subcutaneous colorectal cancer tumor tissue of the DOX group and the CNSI-Fe+DOX group in this embodiment. As shown in Figure 12(a), on day 14, the tumor DOX concentration of 2.5 mg / kg DOX was 1.34±0.21 μg / g, and the tumor DOX concentration of 0.375 mg / mouse CNSI-Fe+2.5 mg / kg DOX was 2.76±0.30 μg / g, which was significantly higher than that of DOX alone, and 2.06 times that of DOX alone; the tumor DOX concentration of 5 mg / kg DOX was 2.31±0.28 μg / g, and the tumor DOX concentration of 0.375 mg / mouse CNSI-Fe+5 mg / kg DOX was 5.09±0.35 μg / g, which was significantly higher than that of DOX alone, and 2.20 times that of DOX alone, indicating that nano-carbon iron can enrich DOX in the tumor.

[0210] Figure 12(b) shows the concentration of DOX in the subcutaneous tumor tissue of HT1080 fibrosarcoma in the DOX group and the CNSI-Fe+DOX group in this embodiment. As shown in Figure 12(b), on day 14, the tumor DOX concentration of 2.5 mg / kg DOX was 1.72 ± 0.21 μg / g, and the tumor DOX concentration of 0.75 mg / mouse CNSI-Fe + 2.5 mg / kg DOX was 4.53 ± 0.52 μg / g, which was significantly higher than that of DOX alone, and 2.63 times that of DOX alone, indicating that nano-carbon iron can enrich DOX in the tumor.

[0211] Example 11

[0212] In vivo administration of nano-carbon iron suspension (CNSI-Fe) in combination with cisplatin (CDDP):

[0213] An H22 hepatocellular carcinoma model was established and administered the drugs using the same method as in Example 10. Mice were divided into 7 groups of 7 mice each: negative control group, CNSI-Fe 0.35 mg / mouse group, CDDP 2.5 mg / kg group, CDDP 5 mg / kg group, CNSI-Fe 0.35 mg / mouse + CDDP 2.5 mg / kg group, CNSI-Fe 0.35 mg / mouse + CDDP 5 mg / kg group, and CNSI-Fe 0.75 mg / mouse group. Tumor volume was measured, inhibition rate and q-value were calculated, and CDDP concentration in tumor tissue was detected.

[0214] Figure 13 shows the tumor volume changes of subcutaneous hepatocellular carcinoma in the negative control group, CNSI-Fe group, CDDP group, and CNSI-Fe+CDDP group in this embodiment. The detection results are shown in Figure 13. The tumor volume inhibition rate at day 14 was calculated as follows: CNSI-Fe 0.35 mg / mouse: 52.14%; CDDP 2.5 mg / kg: 35.50%; CDDP 5 mg / kg: 67.62%; CNSI-Fe 0.35 mg / mouse + CDDP 2.5 mg / kg: 81.97%; CNSI-Fe 0.35 mg / mouse + CDDP 5 mg / kg: 88.17%; CNSI-Fe 0.75 mg / mouse: 73.88%. All these results showed significant differences compared to the negative control group, indicating a significant inhibition of tumor growth. The concentrations of CNSI-Fe 0.35 mg / mouse + CDDP 2.5 mg / kg and CNSI-Fe 0.35 mg / mouse + CDDP 2.5 mg / kg showed significant differences compared to both. Similarly, the concentrations of CNSI-Fe 0.35 mg / mouse + CDDP 5 mg / kg and CNSI-Fe 0.35 mg / mouse + CDDP 5 mg / kg also showed significant differences compared to both. The q-values ​​were 1.18 for CNSI-Fe 0.35 mg / mouse + CDDP 2.5 mg / kg and 1.04 for CNSI-Fe 0.35 mg / mouse + CDDP 5 mg / kg, both indicating a synergistic effect.

[0215] Figure 14 shows the concentration of CDDP in the subcutaneous tumor tissue of liver cancer in the CDDP group and the CNSI-Fe+CDDP group in this embodiment. The detection results are shown in Figure 14. The tumor CDDP concentration at 2.5 mg / kg was 0.33 ± 0.04 μg / g, and the tumor CDDP concentration at 0.35 mg / mouse of CNSI-Fe + 2.5 mg / kg was 0.41 ± 0.02 μg / g, significantly higher than that of CDDP alone, being 1.25 times higher. The tumor CDDP concentration at 5 mg / kg was 0.61 ± 0.06 μg / g, and the tumor CDDP concentration at 0.35 mg / mouse of CNSI-Fe + 5 mg / kg was 0.78 ± 0.05 μg / g, significantly higher than that of CDDP alone, being 1.28 times higher, indicating that nano-carbon iron can enrich CDDP within the tumor.

[0216] Example 12

[0217] In vivo administration of combined nano-carbon iron suspension (CNSI-Fe) and paclitaxel (PTX):

[0218] A 4T1 breast cancer model was established and administered the drug using the same method as in Example 10. Mice were divided into 7 groups of 7 mice each: negative control group, CNSI-Fe 0.375 mg / mouse group, PTX 5 mg / kg group, PTX 10 mg / kg group, CNSI-Fe 0.375 mg / mouse + PTX 5 mg / kg group, CNSI-Fe 0.375 mg / mouse + PTX 10 mg / kg group, and CNSI-Fe 0.75 mg / mouse group. Tumor volume was measured, inhibition rate and q-value were calculated, and PTX concentration in tumor tissue was detected.

[0219] Figure 15 shows the tumor volume changes in the negative control group, CNSI-Fe group, PTX group, and CNSI-Fe+PTX group treated with subcutaneous breast cancer in this embodiment. The tumor volume inhibition rate at day 14 was calculated as follows: CNSI-Fe 0.375 mg / mouse: 36.89%; PTX 5 mg / kg: 31.34%; PTX 10 mg / kg: 42.87%; CNSI-Fe 0.375 mg / mouse + PTX 5 mg / kg: 60.02%; CNSI-Fe 0.375 mg / mouse + PTX 10 mg / kg: 64.89%; CNSI-Fe 0.75 mg / mouse: 61.36%. All these rates showed significant differences compared to the negative control group, indicating a significant inhibition of tumor growth. The concentrations of CNSI-Fe 0.375 mg / mouse + PTX 5 mg / kg showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and PTX 5 mg / kg. Similarly, the concentrations of CNSI-Fe 0.375 mg / mouse + PTX 10 mg / kg also showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and PTX 10 mg / kg. The q-values ​​were calculated to be 1.06 for CNSI-Fe 0.375 mg / mouse + PTX 5 mg / kg and 1.01 for CNSI-Fe 0.375 mg / mouse + PTX 10 mg / kg, indicating a synergistic effect.

[0220] Figure 16 shows the concentration of PTX in the subcutaneous tumor tissue of breast cancer in the PTX group and the CNSI-Fe+PTX group in this embodiment. The detection results are shown in Figure 16. The tumor PTX concentration at 5 mg / kg was 0.53 ± 0.04 μg / g, and the tumor PTX concentration at 0.375 mg / mouse of CNSI-Fe + 5 mg / kg was 0.62 ± 0.04 μg / g, significantly higher than that of PTX alone, being 1.17 times higher than that of PTX alone. The tumor PTX concentration at 10 mg / kg was 1.01 ± 0.11 μg / g, and the tumor PTX concentration at 0.375 mg / mouse of CNSI-Fe + 10 mg / kg was 1.31 ± 0.06 μg / g, significantly higher than that of PTX alone, being 1.30 times higher than that of PTX alone, indicating that nano-carbon iron can enrich PTX within the tumor.

[0221] Example 13

[0222] In vivo administration of nano-carbon iron suspension (CNSI-Fe) in combination with gemcitabine (GEM):

[0223] An AsPC-1 pancreatic cancer model was established and administered the drug using the same method as in Example 10. Mice were divided into 5 groups of 7 mice each: negative control group, CNSI-Fe 0.375 mg / mouse group, GEM 120 mg / kg group, CNSI-Fe 0.375 mg / mouse + GEM 120 mg / kg group, and CNSI-Fe 0.75 mg / mouse group. Tumor volume was measured, inhibition rate and q value were calculated, and GEM concentration in tumor tissue was detected.

[0224] Figure 17 shows the tumor volume changes of subcutaneous pancreatic cancer lesions in the negative control group, CNSI-Fe group, GEM group, and CNSI-Fe+GEM group in this embodiment. The detection results are shown in Figure 17. The tumor volume inhibition rate at day 14 was calculated as follows: CNSI-Fe 0.375 mg / mouse was 34.42%, GEM 120 mg / kg was 40.29%, CNSI-Fe 0.375 mg / mouse + GEM 120 mg / kg was 66.08%, and CNSI-Fe 0.75 mg / mouse was 58.06%. All these rates showed significant differences compared to the negative control group, indicating significant inhibition of tumor growth. The CNSI-Fe 0.375 mg / mouse + GEM 120 mg / kg rate showed a significant difference compared to CNSI-Fe 0.375 mg / mouse and GEM 120 mg / kg alone. The q-value was calculated to be 1.09 for CNSI-Fe 0.375 mg / mouse + GEM 120 mg / kg, indicating a synergistic effect.

[0225] Figure 18 shows the concentration of GEM in the subcutaneous pancreatic tumor tissue of the GEM group and the CNSI-Fe+GEM group in this embodiment. The GEM detection results in the tumor tissue are shown in Figure 18. The tumor GEM concentration of 120 mg / kg GEM was 5.62 ± 0.26 μg / g, and the tumor GEM concentration of 0.375 mg / mouse CNSI-Fe + 120 mg / kg GEM was 6.19 ± 0.16 μg / g, significantly higher than that of GEM alone, and 1.10 times higher than that of GEM alone. This indicates that nano-carbon iron can enrich GEM within the tumor.

[0226] Example 14

[0227] In vivo administration of nano-carbon iron suspension (CNSI-Fe) in combination with docetaxel (DTX):

[0228] A 4T1 breast cancer model was established and administered the drug using the same method as in Example 10. Mice were divided into 7 groups of 7 mice each: negative control group, CNSI-Fe 0.375 mg / mouse group, DTX 5 mg / kg group, DTX 10 mg / kg group, CNSI-Fe 0.375 mg / mouse + DTX 5 mg / kg group, CNSI-Fe 0.375 mg / mouse + DTX 10 mg / kg group, and CNSI-Fe 0.75 mg / mouse group. Tumor volume was measured, inhibition rate and q-value were calculated, and DTX concentration in tumor tissue was detected.

[0229] Figure 19 shows the tumor volume changes in the negative control group, CNSI-Fe group, DTX group, and CNSI-Fe+DTX group treated with subcutaneous breast cancer in this embodiment. The test results are shown in Figure 19. The tumor volume inhibition rate at day 14 was calculated as follows: CNSI-Fe 0.375 mg / mouse: 41.74%; DTX 5 mg / kg: 31.07%; DTX 10 mg / kg: 39.75%; CNSI-Fe 0.375 mg / mouse + DTX 5 mg / kg: 61.75%; CNSI-Fe 0.375 mg / mouse + DTX 10 mg / kg: 65.32%; CNSI-Fe 0.75 mg / mouse: 57.51%. All these results showed significant differences compared to the negative control group, indicating a significant inhibition of tumor growth. The concentrations of CNSI-Fe 0.375 mg / mouse + DTX 5 mg / kg showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and DTX 5 mg / kg. Similarly, the concentrations of CNSI-Fe 0.375 mg / mouse + DTX 10 mg / kg also showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and DTX 10 mg / kg. The q-values ​​were calculated to be 1.03 for CNSI-Fe 0.375 mg / mouse + DTX 5 mg / kg and 1.01 for CNSI-Fe 0.375 mg / mouse + DTX 10 mg / kg, indicating a synergistic effect.

[0230] Figure 20 shows the concentration of DTX in subcutaneous breast cancer tumor tissue in the DTX group and the CNSI-Fe+DTX group. The results are shown in Figure 20. The tumor DTX concentration at 5 mg / kg was 0.54 ± 0.04 μg / g, and the tumor DTX concentration at 0.375 mg / mouse of CNSI-Fe + 5 mg / kg was 0.66 ± 0.04 μg / g, significantly higher than that of DTX alone, being 1.22 times higher. The tumor DTX concentration at 10 mg / kg was 1.07 ± 0.06 μg / g, and the tumor DTX concentration at 0.375 mg / mouse of CNSI-Fe + 10 mg / kg was 1.20 ± 0.05 μg / g, significantly higher than that of DTX alone, being 1.12 times higher. This indicates that nano-carbon iron can enrich DTX within the tumor.

[0231] Example 15

[0232] In vivo administration of nano-carbon iron suspension injection (CNSI-Fe) in combination with hydroxycamptothecin (HCPT):

[0233] A CT26.WT colon cancer model was established and administered the drug using the same method as in Example 10. Mice were divided into 7 groups of 7 mice each: negative control group, CNSI-Fe 0.375 mg / mouse group, HCPT 5 mg / kg group, HCPT 10 mg / kg group, CNSI-Fe 0.375 mg / mouse + HCPT 5 mg / kg group, CNSI-Fe 0.375 mg / mouse + HCPT 10 mg / kg group, and CNSI-Fe 0.75 mg / mouse group. Tumor volume was measured, inhibition rate and q-value were calculated, and HCPT concentration in tumor tissue was detected.

[0234] Figure 21 shows the tumor volume changes in the negative control group, CNSI-Fe group, HCPT group, and CNSI-Fe+HCPT group treated with subcutaneous colorectal cancer in this embodiment. The test results are shown in Figure 21. The tumor volume inhibition rate at day 14 was calculated as follows: CNSI-Fe 0.375 mg / mouse: 57.28%; HCPT 5 mg / kg: 38.72%; HCPT 10 mg / kg: 49.33%; CNSI-Fe 0.375 mg / mouse + HCPT 5 mg / kg: 80.44%; CNSI-Fe 0.375 mg / mouse + HCPT 10 mg / kg: 85.92%; and CNSI-Fe 0.75 mg / mouse: 75.31%. All these results showed significant differences compared to the negative control group, indicating a significant inhibition of tumor growth. The concentrations of CNSI-Fe 0.375 mg / mouse + HCPT 5 mg / kg showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and HCPT 5 mg / kg. Similarly, the concentrations of CNSI-Fe 0.375 mg / mouse + HCPT 10 mg / kg also showed significant differences compared to both CNSI-Fe 0.375 mg / mouse and HCPT 10 mg / kg. The q-values ​​were 1.09 for CNSI-Fe 0.375 mg / mouse + HCPT 5 mg / kg and 1.10 for CNSI-Fe 0.375 mg / mouse + HCPT 10 mg / kg, indicating a synergistic effect.

[0235] Figure 22 shows the concentration of HCPT in subcutaneous colorectal tumor tissue of the HCPT group and the CNSI-Fe+HCPT group. The results are shown in Figure 22. The tumor HCPT concentration at 5 mg / kg was 0.80±0.05 μg / g, and the tumor HCPT concentration at 0.375 mg / mouse + 5 mg / kg CNSI-Fe was 0.93±0.04 μg / g, significantly higher than that of HCPT alone, being 1.22 times higher. The tumor HCPT concentration at 10 mg / kg was 1.48±0.08 μg / g, and the tumor HCPT concentration at 0.375 mg / mouse + 10 mg / kg CNSI-Fe was 1.63±0.04 μg / g, significantly higher than that of HCPT alone, being 1.12 times higher. This indicates that nano-carbon iron can enrich HCPT within the tumor.

[0236] Example 16

[0237] Nano-carbon iron suspension injection (CNSI-Fe) combined with paclitaxel (PTX) and gemcitabine (GEM) for in vivo drug administration:

[0238] An AsPC-1 pancreatic cancer model was established and administered the drug using the same method as in Example 10. Mice were divided into 5 groups of 7 mice each: negative control group, CNSI-Fe 0.75 mg / mouse group, PTX 20 mg / kg + GEM 120 mg / kg group, and CNSI-Fe 0.75 mg / mouse + PTX 20 mg / kg + GEM 120 mg / kg group. Tumor volume was measured, and inhibition rate and q-value were calculated.

[0239] Figure 23 shows the tumor volume changes of subcutaneous pancreatic cancer lesions in the negative control group, CNSI-Fe group, PTX+GEM group, and CNSI-Fe+PTX+GEM group in this embodiment. The detection results are shown in Figure 23. The tumor volume inhibition rate at day 14 was calculated as follows: CNSI-Fe 0.75 mg / mouse was 52.71%, PTX 20 mg / kg + GEM 120 mg / kg was 47.30%, and CNSI-Fe 0.75 mg / mouse + PTX 20 mg / kg + GEM 120 mg / kg was 76.63%. These rates were significantly different from the negative control group, indicating significant inhibition of tumor growth. The CNSI-Fe 0.75 mg / mouse + PTX 20 mg / kg + GEM 120 mg / kg group showed a significant difference compared to CNSI-Fe 0.75 mg / mouse and PTX 20 mg / kg + GEM 120 mg / kg groups. The q-value was calculated to be 1.02 for CNSI-Fe 0.75 mg / mouse + PTX 20 mg / kg + GEM 120 mg / kg, indicating a synergistic effect.

[0240] It should be understood that the specific embodiments described above are merely illustrative or explanatory of the principles of this application and do not constitute a limitation thereof. Therefore, any modifications, equivalent substitutions, improvements, etc., made without departing from the spirit and scope of this application should be included within the protection scope of this application. Furthermore, the appended claims are intended to cover all variations and modifications falling within the scope and boundaries of the appended claims, or equivalent forms of such scope and boundaries.

Claims

1. Use of nano-carbon-iron suspension injection combined administration, characterized in that, The nano-carbon iron suspension injection and the anticancer drug are combined for inhibiting tumor growth, the anticancer drug is used in the form of oral administration or intravenous administration, and the nano-carbon iron suspension injection is used in the form of intratumoral injection.

2. The use of nano-carbon iron suspension injection combined administration according to claim 1, characterized in that, The anticancer drug is one or more of sorafenib, doxorubicin, cisplatin, paclitaxel, gemcitabine, docetaxel and hydroxycamptothecine.

3. The use of nano-carbon iron suspension injection combined administration according to claim 2, characterized in that, The nano-carbon iron suspension injection and the anticancer drug are combined for treating pancreatic cancer, lung cancer, gastric cancer, colorectal cancer, breast cancer, cervical cancer, liver cancer, thyroid cancer, ovarian cancer and sarcoma.

4. The use of nano-carbon-iron suspension injection combined administration according to any one of claims 1-3, characterized in that, The nano-carbon iron suspension injection is prepared by mixing a nano-carbon suspension injection and ferrous sulfate for injection; wherein the concentration of the nano-carbon suspension injection is 20-100 mg / mL, and the concentration of ferrous ions in the nano-carbon iron suspension injection is 0.1-60 mg / mL.

5. The use of nano-carbon iron suspension injection combined administration according to claim 4, characterized in that, The concentration of nano-carbon in the nano-carbon suspension injection is 50 mg / mL, and the concentration of ferrous ions in the nano-carbon iron suspension injection is 7.0-60 mg / mL.

6. The use of nano-carbon iron suspension injection combined administration according to claim 4, characterized in that, The concentration of ferrous ions in the nano-carbon iron suspension injection is 30 mg / mL or 60 mg / mL.

7. The use of nano-carbon iron suspension injection combined administration according to claim 5 or 6, characterized in that, The particle size of nano-carbon iron in the nano-carbon iron suspension injection is 90-250 nm, and the pH value is 2.0-6.

0.

8. Use of nano-carbon-iron suspension injection combined administration according to any one of claims 1-7, characterized in that, The combined use cycle of the nano-carbon iron suspension injection and the anticancer drug is 1-6 cycles; wherein the ratio in the combined use cycle is: The nano-carbon iron suspension injection is administered once every 14 days, and the ferrous ion for each injection is 30 mg-150 mg; The ratio of the anticancer drug includes: Sorafenib is administered twice a day, each time 0.2 g-0.4 g; or, Doxorubicin once every three weeks at 1.2-2.4 mg / kg or 30-75 mg / m 2 ; or, Cisplatin once every four weeks at 50-120 mg / m 2 or once daily for five days at 15-20 mg / m 2 ; or, Taxol 80 mg / m weekly 2 or 135-175 mg / m once every three to four weeks 2 or, Gemcitabine once weekly at 1000-1250 mg / m 2 ; or, Docetaxel every three weeks at 75 mg / m2 2 ; or, Hydroxycamptothecine is administered once a day, each time 4-6 mg.

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