CN118059234A - Application of anti-PD-1 monoclonal antibody combined mitoxantrone liposome in preparation of medicines for treating tumor heart complications - Google Patents
Application of anti-PD-1 monoclonal antibody combined mitoxantrone liposome in preparation of medicines for treating tumor heart complications Download PDFInfo
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Abstract
The invention belongs to the technical field of biological medicines, and discloses application of an anti-PD-1 monoclonal antibody combined mitoxantrone liposome in preparation of medicines for treating tumor heart complications. Compared with a model group and a single administration group, the terlipressin Li Shan antibody and mitoxantrone hydrochloride liposome can obviously improve heart rate, heart related serum index, heart index and other abnormalities and have the function of treating tumors. Therefore, the anti-PD-1 monoclonal antibody combined mitoxantrone liposome administration strategy provided by the invention can be applied to treating tumor heart complications and/or relieving heart toxicity, can expand new indications of marketed medicines, and increases the market application prospect of similar medicines.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to application of a combined medication scheme in preparing medicines for treating tumor heart complications and/or relieving heart toxicity, and in particular relates to application of an anti-PD-1 monoclonal antibody combined mitoxantrone liposome in preparing medicines for treating tumor heart complications.
Background
Tumor cardiology (cardio-oncology/onco-cardiology), also known as tumor cardiac complications, is an emerging concept in recent years, a interdisciplinary of traditional oncology and cardiology. Narrow-sense tumor cardiac complications are mainly used for researching cardiovascular toxicity generated in the anti-tumor treatment process; the generalized tumor heart complications also comprise heart tumors (primary and secondary), tumor-associated cardiovascular diseases and the like, and special therapeutic drugs are not yet available in clinic.
The incidence rate of heart disease of tumor patients is obviously higher than that of normal people, the heart disease has close relation with anti-tumor disease and treatment, and the heart disease and the cerebrovascular disease are the most common adverse reactions in tumor treatment and are particularly important to the survival influence of patients. In addition, cardiovascular diseases become the first large 'killer' of human beings, and along with the proliferation and the younger of cardiovascular disease diseased people, the number of patients suffering from tumor increases year by year, so that the discovery of a novel combined drug strategy for treating the heart complications of tumor has important significance.
PD-1 (programmed death receptor 1) is an immunosuppressive molecule that can prevent autoimmune diseases and prevent the immune system from killing cancer cells by down-regulating the immune system's response to human cells and by inhibiting T-cell inflammatory activity to regulate the immune system and promote self-tolerance. The national drug administration in 12 months 2018 conditionally approves the domestic PD-1 monoclonal antibody (teriptransit Li Shan antibody) injection to be marketed for treating six indications such as lymphoma, liver cancer, gastric cancer, lung cancer and esophageal cancer, and becomes the only PD-1 inhibitor which is obtained in the first line treatment of five high tumor species. Other PD-1 mabs that have been marketed for lymphoma treatment also include rituximab, signal-di Li Shan antibody, tirelimumab, karilimumab, pi An Puli mab, sapalimumab, and the like.
The treatment conditions of lymphoma patients are complex and various, and the currently reported combined drug strategies involving monoclonal antibodies in treatment schemes comprise: the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-COP regimen (rituximab, cyclophosphamide, vincristine, prednisone), RCHOPE regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide), FCR regimen (rituximab, fludarabine, cyclophosphamide) and R-TOPP regimen (rituximab, temozolomide, vincristine, methylbenzyl hydrazine, prednisone) are mainly used in combination with chemotherapeutics, hormones and the like, and the forbidden population includes patients with severe barycentric failure, so that the PD-1 monoclonal antibody alone or in combination has a certain cardiac complication risk.
Mitoxantrone belongs to a synthetic anthracycline broad-spectrum antitumor drug, and has slightly higher or similar curative effects than daunorubicin and doxorubicin, lower toxic and side effects, and particularly lower cardiotoxicity. Mitoxantrone hydrochloride liposome injection, commercially available as Duoda, was approved by the national drug administration for marketing in 2022, 1 month, and was indicated for patients with recurrent or refractory peripheral T-cell lymphomas (PTCL). The pharmacokinetics behavior, tissue distribution, drug effect and toxicity of the liposome preparation form are obviously changed, and the curative effect and safety are obviously improved.
In the prior art, the doxorubicin also belongs to anthracyclines, is clinically common antitumor drugs, has the most serious cardiotoxic effect, can be clinically applied in combination with other protective drugs, including antioxidant vitamin E, free radical scavengers such as coenzyme Q10, reduced glutathione, dexrazoxane, calcium ion antagonists, apoptosis inhibitors and the like, wherein the dexrazoxane is the only drug on the market at present for effectively protecting the cardiotoxic effect of the doxorubicin, and has obvious cardioprotection effect. The combined application of the anti-PD-1 monoclonal antibody and mitoxantrone hydrochloride liposome in treating tumor heart complications has not been reported yet. Therefore, the invention provides a novel mode of combined medication for patients suffering from heart diseases and accompanied with tumors or patients suffering from heart complications caused by the tumors or using antitumor drugs, and has important application value.
By searching, the publications related to the patent application of the present invention are found:
1. Journal magazine: zhang Guowen influence of dexrazoxane single drug and combined cinobufagin injection treatment on doxorubicin-induced related cardiotoxicity in patients with acute tumor. Journal of utility cancers, 2016, 31, 1202-1206. The dexrazoxane and cinobufagin injection has a certain protection effect on the cardiotoxicity caused by the doxorubicin, and the combined administration can obviously reduce the occurrence rate and the toxicity degree of the cardiotoxicity, maintain normal electrocardiogram, myocardial enzyme and cardiac function change, thereby enhancing the tolerance of malignant tumor patients to the toxic and side effects of chemotherapy drugs and improving the treatment effect of tumor patients. Dexrazoxane is the only drug on the market at present for effectively protecting the toxic action of doxorubicin heart, has obvious cardioprotective effect, and the report of the combined application of the drugs is distinct from the invention.
2. Journal magazine: han Sen, etc., cardiovascular complications related to lymphoma treatment, chinese tumor clinic, 2019, 46, 1260-1264. This document reports the administration of a series of cardiovascular complications associated with lymphoma treatment, but does not mention the combination of the invention.
By contrast, the present invention is essentially different from the above publications, mitoxantrone hydrochloride liposome injection is approved for marketing in month 1 of 2022, and the indication is recurrent or refractory peripheral T cell lymphoma patients, and no combination drug with other drugs has been reported for treating tumor cardiac complications. The teripprin Li Shan anti-injection is approved to be marketed in 12 months 2018 for treating six indications such as lymphoma, liver cancer, gastric cancer, lung cancer and esophageal cancer, becomes the only PD-1 inhibitor which is obtained in batch for first-line treatment of five high-grade tumor species, and is not used for treating tumor heart complications by combined use with other medicines. Therefore, the invention provides a novel combined mode for patients suffering from heart diseases and accompanied with tumors or patients suffering from heart complications caused by the tumors or using antitumor drugs, and is the motivation of the technical scheme of the invention.
Tumor cardiac complications are the interdisciplinary of traditional oncology and cardiology, and unlike traditional oncology and cardiology, there is a lack of specialized therapeutic drugs in the clinic. The application of the anti-PD-1 monoclonal antibody combined mitoxantrone liposome in preparing medicines for treating heart complications is not known in the prior art.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a novel application of anti-PD-1 monoclonal antibody combined mitoxantrone liposome in preparing medicines for treating tumor heart complications.
The technical scheme adopted for solving the technical problems is as follows:
An application of anti-PD-1 monoclonal antibody and mitoxantrone liposome in preparing medicine for treating tumor heart complications.
The application of the anti-PD-1 monoclonal antibody and mitoxantrone liposome in preparing medicaments for treating tumor heart complications and tumor.
An application of anti-PD-1 monoclonal antibody and mitoxantrone liposome combination in preparing medicines for relieving tumor heart complications caused by monoclonal anti-PD-1 monoclonal antibody or mitoxantrone liposome alone.
Further, the anti-PD-1 mab is terlipressin Li Shan.
Further, the mass ratio of the terlipp Li Shan antibody to the mitoxantrone liposome is 1-100: and 0.1-50, wherein the combined administration mode is simultaneous administration and/or sequential administration.
Further, the complications of the tumor heart disease are as follows: heart related diseases due to a tumor or due to a tumor treatment, and/or patients suffering from heart disease are suffering from cancer.
Further, the tumor is a lymphoma.
The invention has the advantages and positive effects that:
1. Because of very limited medicines for clinically treating tumor complications, the invention discloses a novel application of the anti-PD-1 monoclonal antibody combined mitoxantrone liposome in preparing medicines for treating tumor heart complications and/or relieving heart toxicity for the first time, and the novel application has important application value.
2. The invention discloses a novel combined drug strategy, which can be used for treating heart complications of tumors and tumors.
3. The combination of the terlipressin Li Shan antibody and the mitoxantrone liposome does not increase toxicity, and the dosage of the mitoxantrone liposome can be reduced.
4. The anti-PD-1 monoclonal antibody combined mitoxantrone liposome medication strategy provided by the invention can expand the new indications of the marketed medicines and increase the market application prospect of the similar medicines.
5. Compared with a model group and a single administration group, the terlipressin Li Shan antibody and mitoxantrone hydrochloride liposome can obviously improve heart rate, heart related serum index, heart index and other abnormalities and have the function of treating tumors. Therefore, the anti-PD-1 monoclonal antibody combined mitoxantrone liposome administration strategy provided by the invention can be applied to treating tumor heart complications and/or relieving heart toxicity, can expand new indications of marketed medicines, and increases the market application prospect of similar medicines.
Drawings
FIG. 1 is a graph showing the comparison of the external appearance of organs of mice in each group according to example 1 of the present invention; wherein, 1 heart; 2 liver; 3 spleen; 4 lung; 5 kidney; 6 intestines; 7 tumor;
FIG. 2 is a graph showing the change in tumor size according to the present invention; wherein, mean test results ± SEM (n=9); mitoxantrone hydrochloride liposomes 15 mg/kg + terlipressin Li Shan anti-10 mg/kg (co-mig); mitoxantrone hydrochloride liposome 6 mg/kg + terlipressin Li Shan anti-10 mg/kg (co-milow); teripjeep Li Shan against 10 mg/kg (PD-1); mitoxantrone hydrochloride liposome 20 mg/kg (mitoxantrone-high); mitoxantrone hydrochloride liposome 15 mg/kg (mitoxantrone-medium); mitoxantrone hydrochloride liposome 6 mg/kg (mitoxantrone-low);
FIG. 3 is a graph showing the comparison of the external appearance of the viscera of mice in each group in example 2 of the present invention; wherein, 1 heart; 2 liver; 3 spleen; 4 lung; 5 kidney; 6 intestines; 7 tumor;
FIG. 4 is a graph showing the tumor suppressing effect of example 2 of the present invention; wherein, A is a tumor size change curve chart of 14 days of administration; b is a tumor volume size plot at day 14 of dosing; * P <0.01, P <0.001 compared to model group, or pairwise;
FIG. 5 is a graph showing the detection of myocardial-associated serum indicators in the present invention; a is creatine kinase activity diagram, B is creatine kinase isoenzyme content diagram, C is alpha-hydroxybutyrate dehydrogenase activity diagram, D is cardiac troponin T content diagram; wherein, # P <0.05, # P <0.01, # P <0.001 is compared to the normal group; p <0.05, P <0.01, P <0.001 compared to model group;
FIG. 6 is an electrocardiogram comparison of mice of each group according to the present invention; wherein, normal group: maximum 2.064, minimum-0.771, average-0.000, heart rate 367.722; model group: maximum 1.622, minimum-0.906, average-0.008, heart rate 453.564; mito-low group: maximum value 1.603, minimum value-0.803, average value-0.013, heart rate 320.856; rice support-high group: maximum 1.578, minimum-0.592, average-0.011, heart rate 257.88; PD-1 group: maximum 13.098, minimum-7.805, average 0.144, heart rate 471.38; joint-meter low group: maximum value 1.290, minimum value-0.906, average value-0.017, heart rate 369.458; joint-meter height group: maximum value 1.674, minimum value-0.912, average value-0.013, heart rate 374.065;
FIG. 7 is a graph showing the comparison of organs of mice in each group according to example 3 of the present invention; wherein, 1 heart; 2 liver; 3 spleen; 4 lung; 5 kidney; 6 intestines; 7 tumors.
Detailed Description
The invention will now be further illustrated by reference to the following examples, which are intended to be illustrative, not limiting, and are not intended to limit the scope of the invention.
The various experimental operations involved in the specific embodiments are conventional in the art, and are not specifically noted herein, and may be implemented by those skilled in the art with reference to various general specifications, technical literature or related specifications, manuals, etc. before the filing date of the present invention.
An application of anti-PD-1 monoclonal antibody and mitoxantrone liposome in preparing medicine for treating tumor heart complications.
The application of the anti-PD-1 monoclonal antibody and mitoxantrone liposome in preparing medicaments for treating tumor heart complications and tumor.
An application of anti-PD-1 monoclonal antibody and mitoxantrone liposome combination in preparing medicines for relieving tumor heart complications caused by monoclonal anti-PD-1 monoclonal antibody or mitoxantrone liposome alone.
Preferably, the anti-PD-1 mab is terlipressin Li Shan.
Preferably, the mass ratio of the terlipp Li Shan antibody to the mitoxantrone liposome is 1-100: and 0.1-50, wherein the combined administration mode is simultaneous administration and/or sequential administration.
Preferably, the tumor heart disease complications are: heart related diseases due to a tumor or due to a tumor treatment, and/or patients suffering from heart disease are suffering from cancer.
Preferably, the tumor is a lymphoma.
Specifically, the related preparation and detection are as follows:
examples
Effects of terlipressin Li Shan anti-co-mitoxantrone liposomes on doxorubicin-induced H9c2 cell viability
H9C2 cells were cultured in a 5% CO 2 incubator at 37℃using DMEM medium containing 10% fetal bovine serum, 100 UI/mL penicillin and 100. Mu.g/mL streptomycin. Cells in the logarithmic growth phase (5X 104/mL) were inoculated into 96-well plates, after 24h, drug treatment 2h was added, treatment was continued with doxorubicin 48 and h, 20. Mu.L of 5mg/mL thiazole blue solution was added to each well, shaking was performed at constant temperature at 37℃for 10 min, and OD values at 492 and 630nm were read with an ELISA reader. The activity data are shown in Table 1.
As shown in Table 1, doxorubicin was differentially toxic to cardiomyocytes H9c2 at various concentrations, and a concentration of doxorubicin that killed about 50% (0.04. Mu.M) was selected for in vitro cell testing of the combination. The concentrations of mitoxantrone hydrochloride liposomes (3.5, 0.7, 0.14 ng/mL) and doxorubicin (0.04. Mu.M) that are selected to be lethal to lymphoma cells but not cardiomyocyte H9c2 treated cells, it can be seen that the toxicity caused by doxorubicin is substantially not ameliorated; cells were treated with different concentrations of terlipressin Li Shan (17.5, 3.5, 0.7 ng/mL) and doxorubicin (0.04 μm), with slightly improved terlipressin Li Shan at 3.5 ng/mL and 0.7 ng/mL. In contrast, the combination of mitoxantrone hydrochloride liposome and terlipressin Li Shan can cover cytotoxicity caused by doxorubicin to different degrees, especially the combination of mitoxantrone hydrochloride liposome of 0.14 ng/mL and terlipressin Li Shan antibody (17.5, 3.5 and 0.7 ng/mL) of three different concentrations has good protection effect, and although the action mechanism is not clear, the combination of mitoxantrone hydrochloride liposome and terlipressin Li Shan antibody has good protection effect on myocardial cells in the test system.
TABLE 1 Effect of terlipressin Li Shan anti-combination mitoxantrone liposomes on doxorubicin-induced H9c2 cell viability
Example 1
Effects of terlipressin Li Shan anti-co-mitoxantrone liposomes on cardiac complications in lymphoma mice
(1) The experimental method comprises the following steps:
Female C57BL/6N mice, 41 total, purchased from Experimental animal technologies Inc. of Beijing, uighur, six weeks of age. Mouse T lymphoma cells E.G7-OVA purchased from North Naaccess Biotechnology Inc. of Suzhou. Mitoxantrone hydrochloride liposome injection provided by the Ministry of medicine (Shijia) and anti-PD-1 monoclonal antibody is terlipressin Li Shan injection provided by Shanghai jun solid biological medicine science and technology Co.
E.G7-OVA cells in the logarithmic growth phase and in good condition were selected, centrifuged at 1000 rpm and 5 to min to obtain cell pellets, which were washed 2 times with pre-chilled phosphate buffer and counted. The cell number was adjusted according to the cell density using pre-chilled saline, and the cell concentration was adjusted to 2X 10 7/mL of suspension, placed in a tube and placed on ice for use.
After one week of adaptive feeding, the mice were injected with E.G7-OVA cell suspension. After fixing the mice, the left inguinal of the mice were sterilized using 75% medical cotton balls. The cell suspension was aspirated using a sterile syringe, and the excess air bubbles were expelled and injected into the left inguinal subcutaneous sites of the mice, each of which was injected with 0.1 mL.
When the tumor volume of the mice increases to about 150 mm 3, the tumor model is successfully established, the mice meeting the requirements are grouped, and the weight and the tumor volume of each group are kept to have no obvious difference.
Model build day 11 dosing treatment, grouping as follows: (I) normal group: nude mice not injected with tumor cells were given glucose at a concentration of 5% by mass of 0.1 mL%; (II) model set: glucose was administered at a concentration of 5% by mass of 0.1 mL; (III) control group 1 (mito-low): 6 mg/kg mitoxantrone hydrochloride liposome single administration, glucose injection dilution; (IV) control group 2 (mito-middle): 15 Single administration of mitoxantrone hydrochloride liposome of mg/kg, glucose injection dilution; (V) control group 3 (mito-high): 20 Single administration of mitoxantrone hydrochloride liposome of mg/kg, glucose injection dilution; (VI) control group 4 (PD-1): 10 mg/kg terlipressin Li Shan antibody, administered once every 3 days, for five times, diluted with physiological saline; (VII) experimental group 1 (combination-meter low): 6 mg/kg mitoxantrone hydrochloride liposome single dose + 10 mg/kg terlipressin Li Shan antibody once every 3 days for five times; (VII) experimental group 2 (combination-meter height): 15 A single administration of mitoxantrone hydrochloride liposomes at mg/kg + 10 mg/kg terlipressin Li Shan is administered once every 3 days for a total of five times.
(2) Experimental results:
① Effects on the various groups of organs: after the mice were euthanized, the individual organs were photographed, as shown in fig. 1, with the organs in the order: 1 heart; 2 liver; 3 spleen; 4 lung; 5 kidney; 6 intestines; 7 tumors. The organ indexes calculated after weighing are shown in Table 2, and the heart of the tumor-bearing mice is obviously reduced, which suggests that heart complications possibly occur, the single-administration terlipressin Li Shan antibody group cannot be improved, and the combined administration group is obviously improved. However, due to the large dose of mitoxantrone liposome, there was no significant difference between the combination administration group and the single mitoxantrone liposome group. However, it can also be shown that the effect of the combination administration group on improving heart enlargement is better than that of the single terlipressin Li Shan antibody group. In addition, although the administration dose was large, the combination did not cause toxicity in terms of appearance of liver, kidney, intestine and organ index in table 2.
Table 2 example 1 Each group of mice has organ indexes (organ mg/body weight g)
Note that: mean test results ± SEM (n=9); analysis of significance differences from the normal group, # # P <0.001, # P <0.05; analysis of significant differences from model group P <0.001, P <0.01; mitoxantrone hydrochloride liposomes 15 mg/kg + terlipressin Li Shan anti-10 mg/kg (co-mig); mitoxantrone hydrochloride liposome 6 mg/kg + terlipressin Li Shan anti-10 mg/kg (co-milow); teripjeep Li Shan against 10 mg/kg (PD-1); mitoxantrone hydrochloride liposome 20 mg/kg (mitoxantrone-high); mitoxantrone hydrochloride liposome 15 mg/kg (mitoxantrone-medium); mitoxantrone hydrochloride liposome 6 mg/kg (mitoxantrone-low).
② Effect of tumor volume: as shown in fig. 2, the single-administration terlipressin Li Shan antibody group did not inhibit tumor growth, while the combination administration group inhibited tumor, but the combination administration group was not significantly different from the single-administration mitoxantrone liposome group due to the larger administration dose of mitoxantrone liposome.
Thus, the results of example 1 can be seen that mice with T cell lymphoma show signs of cardiac complications, with the combination group being superior to the single PD-1 mab group, but with no significant differences from the single mitoxantrone liposome group due to the larger dose of mitoxantrone liposome. In addition, although the administration dose is large, the combination does not cause toxicity from the aspects of liver, kidney and intestine and organ indexes. Thus, the following reduction of mitoxantrone liposome dosage was further investigated for the effect on cardiac complications.
Example 2
Effects of terlipressin Li Shan anti-co-mitoxantrone liposomes on cardiac complications in lymphoma mice
(1) The experimental method comprises the following steps:
Experimental materials and methods the same as in example 1, the dosing, grouping, dosing time points were further optimized. Mitoxantrone liposome dosing was reduced from 6, 15, 20 mg/kg to 3 and 6 mg/kg; PD-1 dosing increased from 10 mg/kg to 15 mg/kg.
Model build day 8 for dosing treatment, grouping as follows: (I) normal group: nude mice not injected with tumor cells were given 0.1 mL mass% glucose; (II) model set: glucose was administered at a concentration of 5% by mass of 0.1 mL; (III) control group 1 (mito-low): 3 mg/kg mitoxantrone hydrochloride liposome single administration, glucose injection dilution; (IV) control group 2 (mito-high): 6 mg/kg mitoxantrone hydrochloride liposome single administration, glucose injection dilution; (V) control group 3 (PD-1): 15 mg/kg terlipressin Li Shan antibody, administered once every 3 days, for five times, diluted with physiological saline; (VI) combination dosing group: 3 mg/kg mitoxantrone hydrochloride liposomes were administered once per day + 15 mg/kg terlipressin Li Shan for five times every 3 days.
(2) Experimental results:
① Effects on the various groups of organs: after euthanasia of the mice, each organ was taken for photographing, and as shown in fig. 3, the organs were in order: 1 heart; 2 liver; 3 spleen; 4 lung; 5 kidney; 6 intestines; 7 tumors. The calculated organ indexes after weighing are shown in table 3, the heart of the tumor-bearing mice is obviously reduced, the heart complications possibly occur, the single-administration terlipressin Li Shan antibody group cannot be improved, the combined administration group is obviously improved, and the single-administration of 3 mg/kg mitoxantrone hydrochloride liposome and the combined administration group (combined-meter low) of 15 mg/kg terlipressin Li Shan antibody are more remarkable than the single-administration (meter low) of 3 mg/kg mitoxantrone hydrochloride liposome. It can also be seen that the combined administration of mitoxantrone hydrochloride liposomes and terlipressin Li Shan antibody in the present invention can synergistically improve the relevant indexes for treating cardiac complications of tumors.
Table 3 example 2 organ index (organ mg/body weight g) of mice of each group
And (3) injection: mean test results ± SEM (n=12); analysis of significance differences from the normal group, # # P <0.001, # # P <0.01, # P <0.05; analysis of significant differences from model groups P <0.001, P <0.01, P <0.05; teripjeep Li Shan against 15 mg/kg (PD-1); mitoxantrone hydrochloride liposome 3 mg/kg + terlipressin Li Shan anti-15 mg/kg (co-milow); mitoxantrone hydrochloride liposome 3 mg/kg (mitoxantrone-low); mitoxantrone hydrochloride liposome 6 mg/kg (mitoxantrone-high).
② Effect of tumor volume: as shown in fig. 4, after increasing the dose, the single terlipressin Li Shan antibody group can inhibit the tumor growth, and a significant difference appears after 10 days, and as can be seen in combination with fig. 3 and fig. 4, the small dose mitoxantrone liposome has individual differences, the tumor of three mice is bigger, the combined administration group can inhibit the tumor, and the individual differences are smaller (combined-meter low compared with mitoxantrone-low in fig. 3). It can also be seen that the combined administration of mitoxantrone hydrochloride liposomes and terlipressin Li Shan antibody in the present invention can synergistically improve the relevant indexes for treating cardiac complications of tumors.
Thus, the results of example 2 can be seen that mice with T cell lymphoma also show signs of cardiac complications, with the combination group being superior to the PD-1 mab-alone group and the mitoxantrone hydrochloride liposome-alone group, and superior to the single administration of the same dose of mitoxantrone hydrochloride liposome. The following continued reduction of mitoxantrone liposome dosing was further investigated for the effects on cardiac complications.
Example 3
Effects of terlipressin Li Shan anti-co-mitoxantrone liposomes on cardiac complications in lymphoma mice
(1) The experimental method comprises the following steps:
Experimental materials and methods the same as in example 1, the dosing and grouping were further optimized. The administration dosage of mitoxantrone liposome is reduced to 1 mg/kg and 3 mg/kg, and the PD-1 administration dosage is kept 15 mg/kg, so that the detection index for heart is increased.
Model build day 8 for dosing treatment, grouping as follows: (I) normal group: glucose was administered at a concentration of 5% by mass of 0.1 mL; (II) model set: glucose was administered at a concentration of 5% by mass of 0.1 mL; (III) control group 1 (mito-low): 1 mg/kg mitoxantrone hydrochloride liposome single administration, glucose injection dilution; (IV) control group 2 (mito-high): 3 mg/kg mitoxantrone hydrochloride liposome single administration, glucose injection dilution; (V) control group 3 (PD-1): 15 mg/kg terlipressin Li Shan antibody, administered once every 3 days, for five times, diluted with physiological saline; (VI) experimental group 1 (combination-meter low): 1 mg/kg mitoxantrone hydrochloride liposome single dose + 15 mg/kg terlipressin Li Shan antibody once every 3 days for five times; (VII) experimental group 2 (combination-meter height): 3 mg/kg mitoxantrone hydrochloride liposomes were administered once per day + 15 mg/kg terlipressin Li Shan for five times every 3 days.
(2) Experimental results:
① Serum index detection: the orbital blood was collected, serum was isolated, and the levels of cardiac troponin T (cTnT), alpha-hydroxybutyrate dehydrogenase (alpha-HBDH), creatine Kinase (CK) and creatine kinase isozyme (CK-MB) were measured by the kit method, and the results are shown in FIG. 5. (i) Creatine Kinase (CK), also known as creatine phosphokinase, is a kinase that plays an important role in intracellular energy conversion, muscle contraction, etc. Creatine kinase has different isoenzymes, wherein the release from cardiac muscle is called CK-MB, and the size of myocardial infarction, myocardial injury area and the like can be judged. As shown in panels a and B of fig. 5, the decrease in CK enzyme activity in the model group indicates that myocardial damage occurred and that single-dose mitoxantrone liposomes were unable to be alleviated, whereas terlipressin Li Shan antibody and mitoxantrone liposome low dose group (combination-mitoxantrone) were able to be alleviated and were closer to normal than single-dose PD-1 group; model groups also decreased CK-MB levels, with both terlipressin Li Shan antibody and mitoxantrone liposomes showing significant differences in relief. (ii) Alpha-hydroxybutyrate dehydrogenase is an enzyme in the myocardial zymogram and the elevation of alpha-HBDH activity is common in acute myocardial infarction. As shown in figure 5, panel C, the model group had elevated α -HBDH activity, but the co-administered group did not experience remission, and it was speculated that the co-administration did not alleviate acute myocardial infarction. (iii) Cardiac troponin T, a muscle contraction regulating protein specifically expressed by cardiac muscle cells, is a serum marker reflecting myocardial injury. The model group showed significantly reduced cardiac troponin T levels, no significant improvement in the mitoxantrone low dose group and PD-1 group, whereas terlipressin Li Shan antibody and mitoxantrone liposome high dose group (combination-mig) showed significantly up-regulated cardiac troponin T levels, exhibited significant differences compared to the model group, and no significant differences compared to the normal group. Taken together, the combination may alleviate myocardial damage, but may not alleviate acute myocardial infarction.
② Electrocardiographic detection: the biological signal acquisition and processing system MD3000 is used for detecting the electrocardiograms of each group at the later period of administration, and the result is shown in FIG. 6. Female six-week-old C57BL/6N mice, normal group electrocardiogram peak value 2.064, minimum value-0.771, heart rate 367; model group vaccinated with T lymphoma each mice had a faster heart rate, reaching 453.564, indicating signs of heart complications. After administration of 15 mg/kg terlipressin Li Shan for five times, the signs of tachycardia were not relieved and the peak heart rate was at a maximum 13.098 and at a minimum of-7.805, indicating tachycardia and increased heart rate variability. After the tumor-bearing mice are singly given to mitoxantrone liposome, the heart rate is reduced to 320.856 at low dose and is reduced to 257.88 at high dose; notably, both heart rate and heart rate fluctuations recovered similar to normal mice following the combination of terlipressin Li Shan antibody and mitoxantrone liposomes, terlipressin Li Shan antibody and mitoxantrone liposomes low dose group: maximum value 1.290, minimum value-0.906, average value-0.017, heart rate 369.458; terlipp Li Shan antibody and mitoxantrone liposome high dose group: maximum value 1.674, minimum value-0.912, average value-0.013, heart rate 374.065.
③ And (3) viscera detection: after euthanasia of the mice, each organ was photographed as shown in fig. 7. The viscera are in turn: 1 heart; 2 liver; 3 spleen; 4 lung; 5 kidney; 6 intestines; 7 tumors. The organ index was calculated after weighing and is shown in table 4. In addition to the lungs, the various organs of the model set exhibit varying degrees of variation. In particular, cardiac index was significantly reduced, and cardiac index was further reduced in the terlipressin Li Shan anti-group, whereas cardiac index was significantly improved in the two-dose group given in combination, and the values were very similar to those of the normal group. In addition, liver, spleen, kidney, intestine index of the two dose groups of the combined administration was also significantly improved. It can also be seen that the combined administration of mitoxantrone hydrochloride liposomes and terlipressin Li Shan antibody in the present invention can synergistically improve the relevant indexes for treating cardiac complications of tumors.
TABLE 4 organ index (organ mg/body weight g) of mice in each group
Note that: mean test results ± SEM (n=10); analysis of significance differences from the normal group, # # P <0.001, # # P <0.01, # P <0.05; analysis of significant differences from model groups P <0.001, P <0.01, P <0.05; teripjeep Li Shan against 15 mg/kg (PD-1); mitoxantrone hydrochloride liposome 1 mg/kg + terlipressin Li Shan anti-15 mg/kg (co-milow); mitoxantrone hydrochloride liposomes 3mg/kg + terlipressin Li Shan anti-15 mg/kg (co-mig); mitoxantrone hydrochloride liposome 1 mg/kg (mitoxantrone-low); mitoxantrone hydrochloride liposome 3mg/kg (mitoxantrone-high).
In conclusion, the invention discovers that the terlipressin Li Shan antibody and mitoxantrone hydrochloride liposome combined drug can be used for preparing the drug for treating the heart complications of tumors for the first time. In addition, although the dosage of the combination is increased, the combination does not produce toxicity in terms of appearance and organ indexes of liver, kidney, intestine and heart, but treats tumor and heart complications at the same time of treating tumor. The heart complication of tumor is a disease type independent of tumor treatment, because of many reasons of disease and great treatment difficulty, and no special treatment medicine, the invention provides a combined medicine mode for patients suffering from heart disease and suffering from tumor, or patients suffering from tumor or using anti-tumor medicine to cause heart toxicity, and has important application value.
Although embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that: various substitutions, changes and modifications are possible without departing from the spirit and scope of the invention and the appended claims, and therefore the scope of the invention is not limited to the disclosure of the embodiments.
Claims (7)
1. An application of anti-PD-1 monoclonal antibody and mitoxantrone liposome in preparing medicine for treating tumor heart complications.
2. The application of the anti-PD-1 monoclonal antibody and mitoxantrone liposome in preparing medicaments for treating tumor heart complications and tumor.
3. An application of anti-PD-1 monoclonal antibody and mitoxantrone liposome combination in preparing medicines for relieving tumor heart complications caused by monoclonal anti-PD-1 monoclonal antibody or mitoxantrone liposome alone.
4. A use according to any one of claims 1 to 3, characterized in that: the anti-PD-1 monoclonal antibody is terlipressin Li Shan antibody.
5. The use according to claim 4, characterized in that: the mass ratio of the terlipressin Li Shan antibody to the mitoxantrone liposome is 1-100: and 0.1-50, wherein the combined administration mode is simultaneous administration and/or sequential administration.
6. A use according to any one of claims 1 to 3, characterized in that: the complications of the tumor heart disease are as follows: heart related diseases due to a tumor or due to a tumor treatment, and/or patients suffering from heart disease are suffering from cancer.
7. Use according to claim 1 or 2, characterized in that: the tumor is lymphoma.
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