Application of iodized oil emulsion as radiosensitizer or lymph node tracer

Abstract

The present invention relates to the field of radiotherapy technology, and in particular to the use of lipiodol emulsion as a radiotherapy sensitizer or lymph node tracer. The lipiodol emulsion comprises: an oil phase and an aqueous phase; the oil phase comprises lipiodol, and the volume percentage of the oil phase in the lipiodol emulsion is: 30-90%; the volume percentage of the lipiodol in the oil phase is above 30%. The present invention unexpectedly discovered during the research process that lipiodol has an excellent radiotherapy sensitization effect after being prepared into an emulsion state, and a single lipiodol emulsion can be used as a radiotherapy sensitizer, which can effectively improve the radiotherapy effect and improve the killing efficiency of X-rays on tumor cells. The use of the lipiodol emulsion provided by the present invention as a radiotherapy sensitizer is of great significance to the existing radiotherapy treatment field.

Description

Technical Field

[0001] The invention relates to the technical field of radiotherapy, and in particular to the application of iodized oil emulsion as a radiotherapy sensitizer or lymph node tracer. Background Art

[0002] Radiotherapy is a treatment method that uses radiation or radioactive substances to treat cancer and other diseases. It can directly destroy the DNA structure of cancer cells, thereby inhibiting their growth and division to achieve therapeutic effects. The treatment process is usually painless or low pain, and patients can live a normal life during treatment. However, it still has disadvantages such as high radiation dose, large side effects on healthy tissues, and especially strong radiation resistance of tumor cells.

[0003] At present, in order to address the problem of strong radioresistance of tumor cells, radiosensitizers are usually used to improve the effectiveness of radiotherapy. The commonly used radiosensitizers are irisin, sodium glycidazole and NBTXR3, and these drugs all have significant disadvantages. For example, irisin and sodium glycidazole are both administered intravenously or orally, which reduces the efficiency of drug use, and both have significant toxic side effects on the body. At the same time, they need to be taken during radiotherapy, which further increases the harm to the patient's body; the hafnium oxide in NBTXR3 cannot be metabolized or degraded in the body, and the long-term toxicity of heavy metals is unknown; and the price of NBTXR3 is relatively high. Summary of the invention

[0004] In order to solve the problems existing in the prior art, the present invention provides the use of iodized oil emulsion as a radiotherapy sensitizer or lymph node tracer.

[0005] Lipiodol is due to its excellent absorption for X-ray, and it is generally used as CT contrast agent in clinical practice. Also lipiodol is used for tumor treatment process, generally in transcatheter arterial chemoembolization (TACE) of liver cancer and chemotherapeutic drugs are used simultaneously, based on the characteristics of its natural targeted tumor, lipiodol mainly has the effect of drug carrier at this. The present invention unexpectedly found in the research process, although lipiodol itself does not possess the cell that kills tumor cells, does not possess the effect of radiosensitization, but when it is prepared into emulsion form, use lipiodol emulsion alone to play the effect of radiosensitization, can be used as radiosensitizer. This point is beyond the expectation of technicians completely.

[0006] The present invention has been found that, compared to radiosensitizers such as hafnium oxide, which is also based on high-Z elements, iodine has good clinical safety and metabolizability. Using iodized oil emulsion as a radiosensitizer can ensure clinical safety and improve the effect of radiotherapy; specifically, after adding iodized oil emulsion in radiotherapy, using the same dose of X-rays can cause stronger cell damage, reflecting the enhancement effect. After entering the body, iodized oil emulsion can be retained in, for example, liver cancer lesions for a long time, but will be quickly removed in normal liver tissue or cirrhosis liver tissue, so it has a very safe application prospect. And in the lesion, iodized oil emulsion can be evenly targeted to the tumor site, and stay for a long time (for example, more than 1 month), realizing the needs of clinical single or multiple radiotherapy, continuous or alternate day radiotherapy.

[0007] The radiotherapy sensitizer provided by the present invention, iodized oil emulsion, can be used in combination with different cancer treatment schemes. For example, it can be surgery, intervention, chemotherapy, or treatment including cytostatics, cytotoxic drugs, targeted therapy, immunotherapy, vaccines, radionuclides (especially immune radionuclides) and any other biological or inorganic products intended to treat cancer. At the same time, it can target lymph nodes and lymphatic vessels, and can be used as a lymph node and lymphatic vessel tracer to achieve radiotherapy clearance of lymph node and lymphatic vessel tumors.

[0008] In a first aspect, the present invention provides a radiotherapy sensitizer, which consists of an oil phase and an aqueous phase; the oil phase includes iodized oil, and the volume percentage of the oil phase in the iodized oil emulsion is: 30-90%; the volume percentage of the iodized oil in the oil phase is above 30%.

[0009] Furthermore, the volume percentage of the oil phase in the iodized oil emulsion is 50-85%, preferably 70-85%.

[0010] Furthermore, the volume percentage of iodized oil in the oil phase is above 50%.

[0011] Furthermore, the radiotherapy sensitizer consists of an oil phase, an aqueous phase and a surfactant; the oil phase includes iodized oil, and the volume percentage of the oil phase in the iodized oil emulsion is 30-90%.

[0012] The iodized oil of the present invention can be one or more of iodized oil, iodized oil soft capsule or iodized vegetable oil in iodized oil injection, and can be purchased commercially.

[0013] The iodized oil emulsion of the present invention can be a water-in-oil emulsion, an oil-in-water emulsion, a water-in-oil-in-water emulsion or an oil-in-water-in-oil emulsion.

[0014] The particle size of the dispersed phase of the iodized oil emulsion of the present invention is 1nm-50μm.

[0015] Furthermore, the oil phase also includes: one or more of vegetable oil, glycerol, octadecyl alcohol or stearic acid; and / or the aqueous phase includes: one or more of non-ionic contrast agent solution, sodium chloride solution, water, glucose aqueous solution, Ringer's solution, sodium lactate Ringer's solution, acetate Ringer's solution, compound sodium acetate Ringer's solution, sodium bicarbonate Ringer's solution, hydroxyethyl starch, succinylated gelatin, dextran or sugar saline.

[0016] The reagent used in the aqueous phase of the present invention can be a commonly used clinical liquid, which not only facilitates the preparation of the iodized oil emulsion, reduces the production cost of the iodized oil emulsion, but also makes the iodized oil emulsion suitable for clinical requirements.

[0017] Furthermore, the non-ionic contrast agent solution includes one or more of iohexol, iopromide or ioversol.

[0018] Furthermore, the surfactant comprises:

[0019] One or more of nonionic surfactants, anionic surfactants, cationic surfactants, natural surfactants, liposomes and polymers.

[0020] Further, the nonionic surfactant includes Tween and / or polyethylene glycol; the anionic surfactant includes sodium dioctyl succinyl sulfonate and / or sodium lauryl sulfate; the natural surfactant includes one or more of gum arabic, gelatin or shellac; the polymer includes one or more of polyethylene glycol, chitosan, polylactic acid-co-glycolic acid copolymer, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polymethyl methacrylate or hydroxypropyl methylcellulose acetate succinate. Macromolecules such as chitosan can help form Pickering emulsions and increase the dispersion and stability of emulsions.

[0021] In a second aspect, the present invention provides a radiotherapy drug preparation, the radiotherapy drug preparation comprising:

[0022] A drug or a prodrug thereof having a chemotherapeutic effect, and the radiosensitizer.

[0023] The radiotherapy sensitizer provided by the present invention can carry drugs with chemotherapy effects. If it is a hydrophilic drug, it can be dissolved in the water phase, and if it is a hydrophobic drug, it can be dispersed in iodized oil.

[0024] Furthermore, the drug having a chemotherapeutic effect includes any one or more of the following:

[0025] i) Compounds that affect tissue growth, cell growth or cell differentiation;

[0026] ii) compounds that induce biological effects;

[0027] iii) Nanomedicines with the ability to promote radiosensitization or induce cellular changes.

[0028] The biological effect described in the present invention is a biological effect that is beneficial to the effect of chemotherapy, such as immune response.

[0029] Nano medicine of the present invention can be granular nano material, and granular nano material can be used as surfactant to make pickering emulsion, and can also be used as medicine to play therapeutic effect. Granular nano material of the present invention can be hydrophilic or hydrophobic nano particle (particle diameter is 1-1000nm).Ice lipiodol emulsion and granular nano material can be mixed by ultrasonic method, obtain the iodized oil emulsion that comprises granular nano material.

[0030] In a preferred embodiment of the present invention, the drug included in the iodized oil emulsion may include one or more of an antibacterial agent and an antitumor agent. Further, the antibacterial agent may be an antibiotic, an antiviral agent, and an antifungal agent; the antitumor agent may be an anticancer chemotherapeutic agent (e.g., a cytostatic agent, a cytotoxic agent) and any other biological or inorganic product used to treat cancer, such as a therapeutic nucleic acid, in particular microRNA (miRNA), short hairpin RNA (shRNA), and small interfering RNA (siRNA).

[0031] In a preferred embodiment of the present invention, the drug in the iodized oil emulsion includes one or more of chemotherapeutic drugs, small molecule drugs, targeted drugs, protein / antibody drugs, photosensitizers or immune-related drugs.

[0032] In a preferred embodiment of the present invention, the drug in the iodized oil emulsion can be one or more of an anti-tumor vascular drug, an anti-tumor targeted drug or an anti-tumor nano drug.

[0033] Further, the chemotherapy drugs include nimustine, carmustine, lomustine, cyclophosphamide, ifosfamide, glyphosate mustard semustine, ilisimol, doxiflurane, fluorouracil, mercaptopurine, thioguanine, cytarabine, azacitidine, paris saponin VI, fluguanosine, tegafur, gemcitabine, carmofur, hydroxyurea, methotrexate, eufodine, ancitabine, decitabine, actinomycin D, doxorubicin, daunorubicin, epirubicin, mitomycin, pelocin, bleomycin, salinomycin, pirarubicin, irinotecan, Harringtonine, hydroxycamptothecin, vinorelbine, paclitaxel, taxotere, topotecan, vincristine, vindesine, vinblastine, teniposide, etoposide, atamestane, aminoglutethimide, letrozole, formestane, megestrol, tamoxifen, asparaginase, carboplatin, cisplatin, miplatin, dacarbazine, oxaliplatin, mitoxantrone, thioridazine, tirapazamine, motexafin gadolinium, procarbazine, boron carrier (small molecule boron drug of boron-10 or biological complex combined with boron) and one or more of the derivatives of the above drugs.

[0034] Further, protein drugs include pembrolizumab, necituzumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, ramucirumab, bevacizumab, lung cancer vaccine-CimaVax, Adotrastuzumab, anti-PD-L1, anti-CTLA-4, TNFerade, HSV-tk, G207, pertuzumab, trastuzumab, cetuximab, panitumumab, ipilimumab, emtansine ine, Lanreotideacetate, avelumab, Lu177dotatate, 25Sipueucel-T, recombinant human interleukin-2, atezolizumab, obinutuzumab, ofatumumab, rituximab, blinatumomab, ibritumomab tiuxetan, brentuximab daratumumab, cetuximab, elotuzumab, olaratumab, recombinant human endostatin.

[0035] Furthermore, the anti-tumor vascular drugs include one or more of tyrosine kinase inhibitors, sorafenib, apatinib, axitinib, sunitinib, lenvatinib, regorafenib, pazopanib, vandetanib, nintedanib, cabozantinib, cediranib, anlotinib, fruquintinib, tivozanib, mosatinib and derivatives of the above drugs.

[0036] Furthermore, targeted anti-tumor drugs include gefitinib, erlotinib, osimertinib, afatinib, ceritinib, Alunbrig, brigatinib, alectinib, crizotinib, trametinib, dalatinib, palbociclib, ribociclib, pomacicillin, neratinib, lapatinib, everolimus, veliparib, olaparib, salvicin, aflibercept, imatinib, sunitinib, niraparib, everolimus, temsirolimus, ponatinib, dasatinib, and bortezomib. Sutinib, Midostaurin, Ibrutinib, Idelalisib, Venetoclax, NU-7441, KU-55933, EZN-2968, CBL0137HCl, Belinostat, Panobinostat, Romidepsin, Vorinostat, Bortezomib, Carfismitrol, Ixazomib, Panostatin, Denosumab, Cobimetinib, Alitretinoin, Vismod, Sonidegi and one or more of the derivatives of the above drugs.

[0037] The radiosensitizer of the present invention can be locally administered through different interventional routes, especially superconducting percutaneous administration, puncture administration, endoscopic administration, direct tissue injection, intramuscular injection, lymphatic and lymphatic vessel injection, cervical canal administration, etc. Local administration can diffuse the radiosensitizer in the tumor site in a targeted manner and achieve long-term retention, providing a basis for clinical long-term multiple radiotherapy.

[0038] The preparation of the radiotherapy sensitizer of the present invention can be prepared by one or more of the medical three-way drug mixing method, ultrasonic method, microfluidic method, membrane high-pressure extrusion method, microfluid high-pressure reaction method, high-pressure homogenization method, supercritical fluid high-pressure method, high-pressure electrostatic spray method or subcritical fluid high-pressure method to achieve the emulsification of iodized oil. Further, if it is necessary to load drugs, the drugs can be dissolved or uniformly dispersed in the iodized oil emulsion under high pressure; the drugs can also be combined with iodized oil by a stable chemical bond through a chemical reaction method or connected through an intermediate connector.

[0039] In a third aspect, the present invention provides the use of iodized oil emulsion as a radiosensitizer or lymph node tracer (also including the use in the preparation of radiosensitizer or lymph node tracer);

[0040] The iodized oil emulsion comprises: an oil phase and an aqueous phase;

[0041] The oil phase comprises iodized oil, and the volume percentage of the oil phase in the iodized oil emulsion is 30-90%; the volume percentage of the iodized oil in the oil phase is above 30%.

[0042] Furthermore, the oil phase also includes: one or more of vegetable oil, glycerol, octadecyl alcohol or stearic acid; and / or, the aqueous phase includes: one or more of non-ionic contrast agent solution, sodium chloride solution, water, glucose aqueous solution, Ringer's solution, sodium lactate Ringer's solution, acetate Ringer's solution, compound sodium acetate Ringer's solution, sodium bicarbonate Ringer's solution, hydroxyethyl starch, succinylated gelatin, dextran, sugar saline, etc.

[0043] Furthermore, the iodized oil emulsion also includes a surfactant.

[0044] Furthermore, the surfactant comprises:

[0045] One or more of nonionic surfactants, anionic surfactants, cationic surfactants, natural surfactants, liposomes and polymers.

[0046] The radiotherapy described in the present invention is radiation radiotherapy, wherein radiation refers to ionizing radiation, including radiation caused by X-rays, α-rays, β-rays, γ-rays, electron beams, neutron beams, ion beams, radioisotopes, etc. X-rays are a particularly preferred excitation source; the radiation voltage is generally about 2keV to 25000keV, further about 2keV to 6000keV (linear accelerator source), and further about 2keV to 1500keV (for example, cobalt 60 source). The radiation dose of X-rays can be 1-80Gy.

[0047] The radiotherapy of the present invention is applicable to tumor radiotherapy of organisms, especially mammals, and the mammals may be humans or mice.

[0048] The radiotherapy of the present invention is applicable to the radiotherapy of various types of tumors, and has a good radiosensitization effect on different tumors, so that the tumor volume is significantly reduced. The tumor may include one or more of skin malignancies (skin cancer), central nervous system tumors, head and neck tumors, lung cancer, breast cancer, gastrointestinal tumors, male urogenital system tumors, gynecological tumors, adrenal and retroperitoneal tumors, bone and soft tissue sarcomas (regardless of their locations), lymphomas, myeloma, leukemia, and childhood tumors.

[0049] Furthermore, skin cancer includes AIDS-related malignancies and melanoma; central nervous system tumors include tumors related to the brain, brainstem, cerebellum, pituitary gland, spinal canal, eyes, and orbits; gastrointestinal tumors include liver cancer and hepatobiliary tract cancer, colon cancer, rectal cancer and anal cancer, gastric cancer, pancreatic cancer, and esophageal cancer; male genitourinary system tumors include prostate cancer, testicular cancer, penile cancer, and urethral cancer; gynecological tumors include cervical cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, vaginal cancer, and vulvar cancer, etc.; childhood tumors include Wilm's tumor, neuroblastoma, central nervous system tumors, or Ewing's sarcoma.

[0050] The radiotherapy described in the present invention is suitable for the treatment of primary tumors or secondary invasions, local or distant metastases, as well as in the context of prevention to avoid secondary malignant central nervous system damage, such as invasion (metastasis) from melanoma, lung cancer, kidney cancer, breast cancer, etc.

[0051] Furthermore, the radiosensitizer can be used at any time point during radiotherapy, for example, as a neoadjuvant (before cancer surgery) or as an adjuvant (after surgery), and can also be used for advanced tumors that cannot be removed by surgery.

[0052] The iodized oil emulsion of the present invention has high radiation absorption, high tumor targeting, high tumor diffusion and retention time, and good clinical safety. The iodized oil emulsion of one embodiment of the present invention is used as a radiotherapy sensitizer to cooperate with radiotherapy, which can reduce the volume of tumors and prolong the survival period of animals.

[0053] The present invention has the following beneficial effects:

[0054] The present invention unexpectedly discovered during the research process that although iodized oil itself does not have a radiotherapy sensitization effect, it can have an excellent radiotherapy sensitization effect after being prepared into an emulsion. Based on this, the present invention provides the use of iodized oil emulsion as a radiotherapy sensitizer.

[0055] The application of the iodized oil emulsion provided by the present invention has high radiation absorption, high tumor targeting, high tumor diffusion and retention time, and good clinical safety. Its effect of reducing the volume of tumors and prolonging the survival period of animals is even better than that of existing hafnium oxide radiotherapy sensitizers, and its safety factor is much higher than that of hafnium oxide, which is of great significance in the field of radiotherapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0057] Figure 1 It is a schematic diagram of the comparison results of the X-ray absorption capabilities of hafnium oxide (HfO2), iodized oil (IO), IG2:1 and IG4:1 provided in Example 2 of the present invention.

[0058] Figure 2 It is a schematic diagram comparing the DLS detection results of iodized oil, IW2:1, IW3:1, IW4:1, IG2:1, IG3:1 and IG4:1 provided in Example 2 of the present invention.

[0059] Figure 3 It is a schematic diagram of the radiosensitization effect of each group on liver cancer provided by Example 2 of the present invention, including the blank control, X-ray only, and X-ray combined with iodized oil (IO), hafnium oxide (HfO2), IG2:1, IW4:1 or IG4:1.

[0060] Figure 4 Schematic diagram of the radiosensitization effect of each group on breast cancer in the blank control, X-ray alone, X-ray combined with iodized oil (IO), IG2:1, IW4:1 or IG4:1 provided in Example 2 of the present invention

[0061] Figure 5 It is a schematic diagram of the sensitization effect of iodized oil emulsion IOG on radiotherapy of pancreatic cancer provided by Example 2 of the present invention.

[0062] Figure 6 It is a schematic diagram of the sensitization effect of iodized oil emulsion IOG on radiotherapy of breast cancer provided by Example 2 of the present invention.

[0063] Figure 7 This is a schematic diagram of the radiosensitization effect of the IW2:1 loaded cisplatin drug on mouse tumors provided in Example 2 of the present invention.

[0064] Figure 8 It is a schematic diagram of the radiosensitization effect of iodized oil provided in Example 2 of the present invention on different types of cancer cells.

[0065] Fig. 9 Schematic diagram of IO, IW4:1 and IG4:1 targeting and retention in lymph nodes provided in Example 2 of the present invention.

[0066] Fig.10 It is a schematic diagram of the radiosensitization effect of iodized oil emulsion IOG on lymph node size provided in Example 2 of the present invention.

[0067] Fig.11 It is a comparative schematic diagram of the distribution of the hafnium oxide group and the IG4:1 group in the tumor provided by Example 2 of the present invention.

[0068] Fig.12 It is a schematic diagram of the radiotherapy effects of the blank control, iodized oil (IO), X-ray group, IO+X-ray group, and iohexol+X-ray group provided in Example 2 of the present invention. DETAILED DESCRIPTION

[0069] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in conjunction with the drawings of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0070] Example 1

[0071] This embodiment provides different types of iodized oil emulsions, as follows:

[0072] 1. Mix iodized oil and iopromide solution by three-way method at a volume ratio of 2:1, 3:1 or 4:1 to prepare emulsions, which are named IW2:1, IW3:1 and IW4:1 respectively.

[0073] The iodized oil used in this embodiment is commercially available. Figure 1-4 , 6, 9, and 11 are Hengrui brands, and the iodized oil used in other figures is produced by Guerbet of France (the iodine concentration in the currently available iodized oil products is about 480 mg / ml).

[0074] 2. Mix iodized oil with 0.9% sodium chloride or 5% glucose solution in different volumes using a three-way method, wherein the emulsion obtained by mixing iodized oil and 5% glucose solution is abbreviated as IG. Specifically, mix with 5% glucose solution by a three-way method in a volume ratio of 2:1, 3:1, and 4:1, respectively, to obtain emulsions, which are named IG2:1, IG3:1, and IG4:1, respectively.

[0075] 3. Add surfactant to prepare iodized oil emulsion, which is as follows (% are all volume percentages):

[0076] (1) 80% oil phase (40% iodized oil + 60% soybean oil) + 20% water for injection + 5% emulsifier polyoxyethylene hydrogenated castor oil HCO-40;

[0077] (2) 60% iodized oil + 40% 5% glucose aqueous solution + 5% emulsifier (80% Tween 80 + 20% polyoxyethylene hydrogenated castor oil HCO-40);

[0078] (3) 50% iodized oil + 50% water for injection + 2% surfactant (80% Tween 80 + 20% polyoxyethylene hydrogenated castor oil HCO-40) + 1% chitosan.

[0079] Each emulsion was ultrasonically disrupted for 20 min and homogenized for 10 min.

[0080] Example 2

[0081] In this embodiment, the iodized oil emulsion involved in Example 1 is subjected to X-ray attenuation coefficient comparison and radiotherapy sensitization performance test, as follows:

[0082] 1. The X-ray absorption capacity of hafnium oxide (HfO2), iodized oil (IO), IG2:1 and IG4:1 was tested through CT value comparison test.

[0083] Among them, hafnium oxide (HfO2) is synthesized according to the method provided by NANOBIOTIX company patent (patent number WO2009147214).

[0084] The results are as follows Figure 1 As shown, the CT values ​​of iodized oil, IG2:1 and IG4:1 are significantly higher than those of hafnium oxide (HfO2).

[0085] 2. The particle sizes of IW2:1, IW3:1, IW4:1, IG2:1, IG3:1 and IG4:1 were tested by DLS particle size analyzer.

[0086] The results are as follows Figure 2 As shown, the particle sizes of iodized oil emulsion are different, but emulsions of different particle sizes all show good radiosensitization effect; in the figure, IW21, IW31, IW41, IG21, IG31 and IG41 correspond to IW2:1, IW3:1, IW4:1, IG2:1, IG3:1 and IG4:1 respectively, and the corresponding methods in other figures are the same.

[0087] 3. Radiotherapy sensitization experiment 1 (liver cancer)

[0088] C57BL / 6 mice, 6 weeks old; mouse subcutaneous hepatocellular carcinoma (hepa1-6) model; tumor volume 50-100 mm 3 At the beginning of treatment, 50 μL of different drugs were injected into each group. After the injection treatment, the tumor volume was measured every other day.

[0089] The groups used included blank control, X-ray alone, X-ray combined with hafnium oxide (HfO2), IO, IG2:1, IW4:1 or IG4:1.

[0090] The X-ray irradiation method was: 2 Gy once every other day starting from the 12th day, for a total of three times.

[0091] Related test results such as Figure 3As shown, the arrows below the abscissa represent that the experimental mice were irradiated with X-rays three times on the 12th day, the 14th day and the 16th day respectively. The results show that there is no statistically significant difference between the IO+X-ray group and the X-ray group alone. IG4:1, IW4:1 and IG2:1 have obvious sensitization effects on the radiotherapy of liver cancer, which are better than the hafnium oxide nano-radiotherapy sensitizer (about 50nm) used clinically. The higher the iodized oil content, the better the effect of radiotherapy sensitization.

[0092] 4. Radiotherapy sensitization experiment 2 (breast cancer)

[0093] BALB / c mice, 6 weeks old; mouse orthotopic breast cancer (4T1) model; tumor volume 50-100mm 3 At the beginning of treatment, 50 μL of different drugs were injected into each group. After the injection treatment, the tumor volume was measured every other day.

[0094] The groups used included blank control, X-ray alone, and X-ray combined with IO, IG2:1, IW4:1, or IG4:1.

[0095] The X-ray irradiation method was: 2 Gy once every other day starting from the 12th day, for a total of three times.

[0096] For relevant test results, see Figure 4 The arrows below the abscissa indicate that the experimental mice were irradiated with X-rays three times on days 12, 14, and 16. The results showed that there was no statistically significant difference between the IO+X-ray group and the X-ray group alone, and IG4:1 and IW4:1 had a significant sensitizing effect on radiotherapy of breast cancer.

[0097] 5. Radiotherapy sensitization experiment 3 (pancreatic cancer)

[0098] BALB / c mice, 6 weeks old; mouse subcutaneous pancreatic cancer model; tumor volume 50-100mm 3 At the beginning of treatment, each group received a single intratumoral injection of 25 μL of different drugs and a single X-ray irradiation of 6 Gy. After the injection treatment, the tumor volume was measured every other day.

[0099] For relevant test results, see Figure 5 , Figure 5 The horizontal axis represents time, and the vertical axis represents tumor size. Control represents the X-ray group, and Emulsion represents the lipiodol emulsion and the X-ray group, wherein the composition of the lipiodol emulsion is: 60% lipiodol, 40% 5% glucose aqueous solution and 5% emulsifier (80% tween80+20% polyoxyethylene hydrogenated castor oil (HCO-40)). It can be seen from the results that the lipiodol emulsion has a significant sensitization effect on the radiotherapy of pancreatic cancer.

[0100] 6. Radiotherapy sensitization experiment 4 (breast cancer)

[0101] BALB / c mice, 6 weeks old; mouse breast cancer footpad model; tumor volume 50-100mm 3 Treatment was started with a single injection of 25 μL of different drugs into the orthotopic tumor of each group; and a single X-ray irradiation of 6 Gy was performed (simultaneously irradiating the orthotopic tumor and lymph node metastasis, i.e., the foot pad and thigh root). After the injection treatment, the tumor volume was detected every two or four days (later period).

[0102] Related test results can be found in Figure 6 On the 8th day, the experimental mice were irradiated with X-rays once. The results showed that iodized oil emulsion IOG had a significant sensitizing effect on the radiotherapy of breast cancer. IOG: 20% injection water, 80% oil phase (including 40% iodized oil and 60% soybean oil) and 5% emulsifier polyoxyethylene hydrogenated castor oil HCO-40.

[0103] 7. Testing of radiosensitization and synergistic effects of loaded chemical drugs

[0104] C57 / L mice, 6 weeks old; subcutaneous liver cancer model; volume 50-100mm 3 Fractionated radiotherapy was started; a single dose of 50 μL was injected into the tumor. After the injection treatment, the tumor volume was measured every other day.

[0105] The groups used included blank control, X-ray only, and X-ray + IW2:1 loaded with cisplatin drug.

[0106] The X-ray irradiation method was: 2 Gy once starting from the 8th day, irradiated every other day, for a total of three times.

[0107] For relevant test results, see Figure 7 , Figure 7 The arrows below the horizontal axis indicate that the experimental mice were irradiated with X-rays three times on the 8th, 10th, and 12th days. Figure 7 It can be seen that iodized oil emulsion IW2:1 loaded with cisplatin has a significant inhibitory effect on mouse tumors.

[0108] 8. Testing of radiosensitization performance of different tumors

[0109] This example further adopts the following method to test the radiosensitization performance of different tumor cells, as follows:

[0110] Human tumor cell lines (including Hela, PANC-1, A549, HCT116, B16, 143B or U87) were seeded in 96-well plates (2-4×10 3cells). After 24 hours, the culture medium was replaced with a culture medium containing iodized oil (30ug / ml) for 12 hours. Then, the cells were treated with X-rays (4Gy for A549 and hct116, and 2Gy for other cells); after 3 days, the absorbance of the supernatant at 450nm was measured by the CCK method, and the result was that iodized oil enhanced cell radiation damage (cells in the group with iodized oil had a greater killing effect under X-ray irradiation).

[0111] The results are as follows Figure 8 As shown, iodized oil has a radiosensitizing effect on different types of cancer cells (from left to right A549 lung cancer, Hela cervical cancer, PANC1 pancreatic cancer, HCT116 colon cancer, U87 brain glioma, B16 melanoma, 143B osteosarcoma). The cell-level experiment may be due to the fact that iodized oil forms an emulsion (oil in water) after mixing with the culture medium, thus showing a significant radiosensitizing effect.

[0112] 9. Test of targeting lymph nodes with iodized oil and imaging

[0113] BALB / C mice, 6 weeks old; footpad breast cancer lymph node metastasis model; 25 μL of drug was injected after tumor lymph node metastasis (approximately 9 days).

[0114] The medication groups included: iodized oil only (IO), IW4:1, and IG4:1.

[0115] When the iodized oil emulsion was just injected into the foot pad tumor on day 0, the lymph node metastasis of the iodized oil emulsion could be observed under CT (the popliteal fossa pointed by the arrow is the lymph node location of the iodized oil imaging). After 7 days, the iodized oil emulsion still remained in the original tumor and lymph node metastasis. The test results are shown in Fig. 9 , Fig. 9 The results showed that both iodized oil and iodized oil emulsion have the ability to target lymph nodes and remain in the lymph nodes for a long time.

[0116] The present invention further verifies the radiosensitization effect of iodized oil emulsion on lymph node metastasis by detecting the volume of lymph nodes. Fig.10 The result is shown in the figure on the right.

[0117] The groups used included a blank control group, an X-ray only group, X-ray+IW4:1, and X-ray+IG4:1.

[0118] The drug injection and X-ray treatment method is as follows: after the tumor lymph node metastasis (approximately on the 9th day), 25 μL of drug is injected and a single 6 Gy X-ray irradiation is performed.

[0119] The present invention further uses IOG (IOG: 20% injection water, 80% oil phase (including 40% iodized oil and 60% soybean oil) and 5% emulsifier polyoxyethylene hydrogenated castor oil HCO-40) to conduct the same experiment and obtain the following Fig.10 The results are shown in the left figure. The results show that iodized oil emulsion has an inhibitory effect on the size of lymph node metastases and can improve the radiotherapy clearance of lymph node metastases. It can be seen from the figure that iodized oil emulsions including IOG, IW4:1 and IG4:1 all have the effect of radiotherapy clearance of lymph node metastases.

[0120] 11. Intratumoral distribution of iodized oil emulsion and hafnium oxide

[0121] This example further detects the intratumoral distribution of lipiodol emulsion and hafnium oxide, and the method is as follows:

[0122] Mouse orthotopic breast cancer model; tumor volume is about 50mm 3 Each group was injected with 10 μL of different solutions, including HfO2 or IG41, and then the tumors were isolated after 4 hours and imaged using a synchrotron-based uCT device (Beijing Synchrotron Radiation Facility).

[0123] The groups used were divided into hafnium oxide group (left) and IG4:1 group (right).

[0124] Results The intratumoral distribution of hafnium oxide and iodized oil emulsion (IG4:1) was compared. Fig.11 ), showing that liquid radiotherapy sensitizers have a much better diffusion effect than solid nanoparticle sensitizers used clinically, and are more conducive to tumor treatment

[0125] 12. Iodine oil itself has no therapeutic effect, nor does it have a radiosensitization effect.

[0126] BALB / c mice, 6 weeks old; mouse subcutaneous breast cancer model; tumor volume 50-100mm 3 At the beginning of treatment, 50 μL of different drugs were injected into each group. After the injection treatment, the tumor volume was measured at regular intervals.

[0127] The groups used included blank control, iodized oil, X-ray group, IO+X-ray group, iohexol+X-ray group

[0128] The X-ray irradiation method was: a single irradiation of 6 Gy on the 8th day.

[0129] The results are as follows Fig.12 As shown, IO (iodized oil) itself was the same as the control without X-ray, and did not inhibit tumor size; after radiotherapy, iodized oil (IO) and iohexol also had no radiosensitization effect, which was consistent with the results of the X-ray group.

[0130] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A radiotherapy sensitizer, characterized in that: The radiotherapy sensitizer consists of an oil phase and an aqueous phase; the oil phase includes iodized oil, and the volume percentage of the oil phase in the iodized oil emulsion is 30-90%; the volume percentage of the iodized oil in the oil phase is above 30%.

2. A radiotherapy sensitizer, characterized in that: The radiotherapy sensitizer consists of an oil phase, an aqueous phase and a surfactant; the oil phase includes iodized oil, and the volume percentage of the oil phase in the iodized oil emulsion is 30-90%.

3. The radiosensitizer according to claim 1 or 2, characterized in that: The oil phase also includes: one or more of vegetable oil, glycerol, octadecyl alcohol or stearic acid; and / or, the aqueous phase includes: one or more of non-ionic contrast agent solution, sodium chloride solution, water, glucose aqueous solution, Ringer's solution, sodium lactate Ringer's solution, acetate Ringer's solution, compound sodium acetate Ringer's solution, sodium bicarbonate Ringer's solution, hydroxyethyl starch, succinylated gelatin, dextran, sugar saline, etc.

4. The radiosensitizer according to claim 2, characterized in that The surfactants include: One or more of nonionic surfactants, anionic surfactants, cationic surfactants, natural surfactants, liposomes and polymers.

5. A radiotherapy drug preparation, characterized in that: The radiotherapy drug preparation comprises: A drug or a prodrug thereof having a tumor therapeutic effect, and the radiosensitizer according to any one of claims 1 to 4.

6. The radiotherapy drug preparation according to claim 5, characterized in that: The drugs having chemotherapeutic effects include any one or more of the following: i) Compounds that affect tissue growth, cell growth or cell differentiation; ii) compounds that induce biological effects; iii) Nanomedicines with the ability to promote radiosensitization or induce cellular changes.

7. The radiotherapy drug preparation according to claim 6, characterized in that: The drugs having tumor therapeutic effects include: One or more of chemotherapeutic drugs, protein drugs, antibody drugs, anti-tumor vascular drugs, anti-tumor targeted drugs or anti-tumor nano drugs.

8. A kit, characterized in that: The kit comprises the radiotherapy sensitizer according to any one of claims 1 to 4, or the radiotherapy drug preparation according to claim 5.

9. The use of iodized oil emulsion as a radiotherapy sensitizer or lymph node tracer; The iodized oil emulsion comprises: Oil phase and water phase; The oil phase comprises iodized oil, and the volume percentage of the oil phase in the iodized oil emulsion is 30-90%; the volume percentage of the iodized oil in the oil phase is above 30%.

10. The use according to claim 7, characterized in that: The oil phase also includes: one or more of vegetable oil, glycerol, octadecyl alcohol or stearic acid; and / or, the aqueous phase includes: one or more of non-ionic contrast agent solution, sodium chloride solution, water, glucose aqueous solution, Ringer's solution, sodium lactate Ringer's solution, acetate Ringer's solution, compound sodium acetate Ringer's solution, sodium bicarbonate Ringer's solution, hydroxyethyl starch, succinylated gelatin, dextran, sugar saline, etc.

11. The use according to claim 9 or 10, characterized in that: The iodized oil emulsion also includes a surfactant.

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