CN114681612A - Bladder perfusion pharmaceutical composition and preparation method and application thereof - Google Patents

Bladder perfusion pharmaceutical composition and preparation method and application thereof Download PDF

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CN114681612A
CN114681612A CN202011609565.1A CN202011609565A CN114681612A CN 114681612 A CN114681612 A CN 114681612A CN 202011609565 A CN202011609565 A CN 202011609565A CN 114681612 A CN114681612 A CN 114681612A
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hydrochloride
bladder
pharmaceutical composition
perfusion
drug
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刘庄
邓中清
吴松
吴宇辰
李广志
许欢
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Suzhou Baimai Biomedical Co ltd
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Priority to CN202180088555.4A priority patent/CN116710106A/en
Priority to PCT/CN2021/143056 priority patent/WO2022143893A1/en
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Abstract

The invention discloses a bladder perfusion pharmaceutical composition, which comprises soluble salt of an immunologic adjuvant and a chemical drug capable of causing immunogenic cell death. Can be used for treating bladder cancer or used for treating the bladder cancer. When the soluble salt of the immunologic adjuvant and a chemical drug which can cause immunogenic cell death are used as bladder perfusion drugs in a combined way, the side effect of the chemical drug can be reduced, the synergistic anticancer effect is generated, the cancer metastasis and recurrence probability is reduced, the existence of the immunologic adjuvant prompts a large number of macrophages to be enriched around tumor tissues of the bladder, the macrophages can phagocytose a large number of chemotherapy drugs which are free outside tumor cells after the ICD drugs play the primary chemotherapy and immune excitation effects, the damage of the chemotherapy drugs to normal tissues can be reduced, and the systemic toxic and side effect of the ICD chemical drugs can be reduced.

Description

Bladder perfusion pharmaceutical composition and preparation method and application thereof
Technical Field
The invention relates to the field of medicaments for treating tumors, in particular to a bladder perfusion medicinal composition, a preparation method and a medicinal application thereof.
Background
Bladder cancer is a common urological tumor, and although it has a lower morbidity and mortality rate than lung and gastrointestinal tumors, its high recurrence rate has made bladder cancer one of the most expensive clinical treatments. The perfusion chemotherapy after the resection of the bladder cancer tumor through the urethra is the first choice for the treatment of the bladder cancer, but the prior perfusion therapy has low clinical absolute remission rate, high tumor recurrence rate, great toxic and side effects and poor patient prognosis. Meanwhile, the incidence of bladder cancer in China is on the trend of rising year by year in recent years and is higher than the average level in the world, and in recent 30 years, the research on novel perfusion of small molecular drugs is slow, so that China faces a serious clinical problem in prevention and treatment of bladder cancer.
Studies have shown that some chemotherapeutic drugs can induce the expression of immunogenic protein molecules on the cell surface by inducing apoptosis or other programmed death of tumor cells, and then stimulate the body's anti-tumor immune response, which is called tumor Immunogenic Cell Death (ICD). Therefore, the method is possibly one of the approaches for preparing and improving the chemotherapy-immune combination therapy drug system. Currently, only a few clinically relevant drugs have been shown to trigger ICD phenomena in clinical applications. These drugs mainly include: (1) adriamycin and anthracycline drugs, which have been used for the treatment of cancers such as small cell lung cancer; (2) epirubicin, an anthracycline approved for use in breast cancer patients; (3) idarubicin, an anthracycline currently used to treat acute myeloid leukemia; (4) mitoxantrone, an anthracycline approved for breast, non-hodgkin's lymphoma and prostate cancer patients; (5) bleomycin, a glycopeptide antibiotic used for the palliative treatment of testicular cancer, squamous carcinoma of the head and neck, cervix and vulva; (6) velcade bortezomib, a proteasome inhibitor for patients with multiple myeloma and T-cell lymphoma; (7) oxaliplatin is used in combination with 5-fluorouracil and folinic acid for the treatment of advanced colorectal cancer. However, most ICD drugs are not effective and durable in promoting the immune killing of tumor cells, because immune cells are not capable of effectively recognizing and killing cancer cells with tumor-associated antigens. The killer T cells are activated T cells among immune cells, and play a role in killing cancer cells. T cells require Antigen Presenting Cells (APC) to take up, process and present these antigens to themselves before they can be activated to exert their true effect, whereas antigen presenting cells require the assistance of an immunological adjuvant to present the antigen more efficiently.
Toll-like receptors (TLRs) are pattern recognition receptors that are important components of the innate immune system and function to sense and recognize pathogen-associated molecular patterns (PAMPs). 10 mammalian TLRs and their agonists have been found to be reported. For example, imiquimod (R837) and the immunostimulatory agent oligonucleotide CpG recognize and stimulate TLR7 and TLR9, respectively, and synthetic immunomodulatory agent R848(resiquimod) activates TLR7 and TLR 8. A great deal of research reports that TLRs agonists have the function of immunoadjuvants and have great potential for tumor treatment, but the effectiveness and the applicability of TLRs agonists are limited by the side effect of systemic release of proinflammatory factors and cytokines. Therefore, in vivo treatment with TLR7 as a ligand has mainly focused on the application of TLR7 as an immunoadjuvant target, such as antiviral or antitumor local therapy.
The simple perfusion chemotherapy has poor effect of inhibiting the progress of the bladder cancer, is easy to generate toxic and side effects and adverse reactions, is easy to be tolerated by patients and has undesirable prognosis. How to improve the treatment effect of bladder perfusion chemotherapy is a major topic in the bladder perfusion treatment technology.
Disclosure of Invention
In order to solve the related technical problems, the research and development team discovers that when soluble salt of an immunologic adjuvant and a chemical drug (ICD (endogenous cell death)) capable of causing immunogenic cell death are used as bladder perfusion drugs in combination, the anticancer drug composition can generate a synergistic anticancer effect and reduce the probability of cancer metastasis and recurrence, can effectively kill in-situ tumors and can inhibit the growth of distal metastatic tumors and reduce the probability of tumor recurrence through immunoreaction. Meanwhile, the attenuation effect of the system is different from the action mechanism of reducing the toxicity of a medicine system by changing the local and systemic absorption of a perfusion medicine through a dosage form in the past, the invention remarkably reduces the toxic and side effects of the chemotherapy medicine on normal tissues by improving the phagocytosis channel of macrophage on tumor cell external free chemotherapy medicine in the tissues to enter into a focus through the perfusion administration of the medicine combination on the basis of the immunogenicity effect of the chemotherapy medicine, and the medicine entering mode is firstly tried and observed in the perfusion research.
The invention provides a bladder perfusion pharmaceutical composition which comprises the following components in parts by weight: including soluble salts of immunoadjuvants and chemotherapeutics that cause immunogenic cell death. Furthermore, the mass ratio of the soluble salt of the immunologic adjuvant to the chemical drug capable of causing immunogenic cell death is 1: 100-6: 1.
Further preferably, the mass ratio of the soluble salt of the immunologic adjuvant to the chemical drug capable of causing immunogenic cell death is 2: 1-4: 1.
Further, the chemical drug capable of causing immunogenic cell death comprises anthracycline chemotherapeutic drug, platinum chemotherapeutic drug, fluorouracil or gemcitabine; optionally, the anthracycline chemotherapeutic comprises doxorubicin hydrochloride, epirubicin hydrochloride, pirarubicin hydrochloride, mitoxantrone hydrochloride; the platinum chemotherapeutic drug comprises nedaplatin, carboplatin, lobaplatin or oxaliplatin.
Further, the soluble salt of the immunoadjuvant comprises at least one of imiquimod R837 hydrochloride or other pharmaceutically acceptable soluble salt, Rasimmod R848 hydrochloride or other pharmaceutically acceptable immunoadjuvant soluble salt, CpG, polyIC, polyICLC, STING stimulant (with a compound that may include IMSA-101, GSK-3745417, BMS-986301, SB-11285, MK-1454).
Further, the mass ratio of the imiquimod R837 hydrochloride to the chemical drug capable of causing immunogenic death is 1: 20-1: 1, wherein the chemical drug capable of causing immunogenic death is fluorouracil or gemcitabine.
Further, the mass ratio of the imiquimod R837 hydrochloride to the chemical drug capable of causing immunogenic death is 1: 1-6: 1, wherein the chemical drug comprises an anthracycline chemotherapeutic drug or a platinum chemotherapeutic drug, and the anthracycline chemotherapeutic drug comprises doxorubicin hydrochloride, epirubicin hydrochloride, pirarubicin hydrochloride and mitoxantrone hydrochloride; the platinum chemotherapeutic drug comprises nedaplatin, carboplatin, lobaplatin or oxaliplatin.
Further, the mass ratio of the Rasimotent R848 hydrochloride to the chemical drug capable of causing immunogenic cell death is 1: 10-1: 1, wherein the chemical drug capable of causing immunogenic cell death comprises an anthracycline chemotherapeutic drug or a platinum chemotherapeutic drug, and the anthracycline chemotherapeutic drug comprises doxorubicin hydrochloride, epirubicin hydrochloride, pirarubicin hydrochloride and mitoxantrone hydrochloride; the platinum chemotherapeutic drug comprises nedaplatin, carboplatin, lobaplatin or oxaliplatin.
Further, the mass ratio of the Rasimethide R848 hydrochloride to the chemical drug capable of causing immunogenic death is 1: 100-1: 10, wherein the chemical drug capable of causing immunogenic death comprises fluorouracil or gemcitabine.
Further, a freeze-drying cosolvent (such as mannitol, lactose and the like) and a pH regulator are also included.
Further, the concentration range of the soluble salt of the immunologic adjuvant is 0.5 mg/mL-30 mg/mL.
Further, the preparation is freeze-dried powder.
The invention also provides a preparation method of the bladder perfusion pharmaceutical composition, which comprises the following steps:
scheme 1:
s1: dissolving imiquimod R837 or Rasimmod R848 in dilute acid solution (such as hydrochloric acid, lactic acid, acetic acid) or other pharmaceutically acceptable immunological adjuvant (such as glucopyranoside lipid A (MPLA)) soluble salt solution, adding chemical agent capable of inducing immunogenic cell death into the solution, and mixing to dissolve;
s2: adding a suitable lyophilization cosolvent (such as mannitol, lactose and the like), a pH regulator and controlling the pH value to be between 2.0 and 5.5 into the solution of S1;
s3: the solution obtained in step S2 is subjected to lyophilization.
Scheme 2:
a preparation method of a bladder perfusion pharmaceutical composition is characterized by comprising the following steps:
s1: adding immune adjuvants CpG, polyIC, polyICLC, water soluble STING stimulant and chemical drug capable of causing immunogenic cell death into water for injection, and mixing uniformly to dissolve;
s2: to the solution of S1, a suitable lyophilization cosolvent (e.g., mannitol, lactose, etc.) is added and the solution is subjected to a lyophilization process.
The invention also provides application of the combined medicine in preparation of a bladder perfusion medicine.
By adopting the technical scheme of the invention, the invention has the following beneficial technical effects:
the systemic toxic and side effects of the ICD chemical drugs can be reduced, and the action mechanism of the phenomenon is preliminarily deduced according to the mastered evidence, namely the combined immune adjuvant improves the phagocytosis of macrophages on the free chemotherapeutic drugs outside tumor cells in tissues, so that the toxic and side effects of the chemotherapeutic drugs on normal tissues are obviously reduced. When the bladder cancer is perfused after the transurethral resection of tumor, the ICD medicine can induce the immunogenic cell death of tumor cells, so as to activate the immune system and specifically eliminate the cancer cells. After phagocytosis of dead cancer cells by antigen presenting cells, the immune system can be guided to track, recognize and kill other cancer cells. Therefore, after the ICD chemotherapeutic drug causes immunogenic death of cancer cells, tumor-associated antigens in cancer cell residues are exposed to immune cells, providing targets for the immune cells to recognize cancer cells and helping the immune system establish tumor-cell specific immune responses. After being recognized by TLR, the soluble immunologic adjuvant activates a series of downstream signals, induces the secretion of inflammatory cytokines, chemokines and type I interferon, and promotes the tumor-related antigen to be more effectively presented to T cells with tumor killing effect by antigen presenting cells. Therefore, when the ICD chemotherapeutic drug dies cancer cells to become tumor-associated antigens, the introduction of the immunoadjuvant can further stimulate the antigen presenting cells to take up and process the antigens, and more effectively present the antigens to T cells, thereby amplifying the anti-tumor immune response. Meanwhile, the existence of the immunologic adjuvant also promotes the enrichment of a large number of macrophages around the tumor tissue of the bladder, phagocytoses a large number of chemotherapy drugs which are free outside tumor cells after the ICD drugs play a role in primary chemotherapy and immune excitation, and can reduce the damage of the chemotherapy drugs to normal tissues, thereby reducing the systemic toxic and side effects of the ICD chemical drugs, and also improving the dosage of the ICD drugs in a certain range or improving the overall treatment effect.
The local combined administration of the soluble immunologic adjuvant and the ICD chemotherapeutic drug can obviously improve the tumor treatment and metastasis recurrence prevention effects of the chemotherapeutic drug, when the ICD chemotherapeutic drug leads cancer cells to die and become tumor-related antigens, the introduction of the immunologic adjuvant can further stimulate APC cells to take in and treat the antigens and more effectively present the antigens to T cells, thereby amplifying the anti-tumor immune response, and the combined perfusion application of the immunologic adjuvant and the ICD chemotherapeutic drug has good improvement effect on the treatment and recurrence prevention of the bladder cancer. Like a tumor vaccine generated in vivo, under the combined action of the ICD chemotherapeutic drug and the immunologic adjuvant, the in-situ tumor is killed and becomes the tumor vaccine. Therefore, the ICD chemotherapeutic drug and immune adjuvant combined drug system has the technical effect of efficiently treating and preventing the metastasis and recurrence of bladder cancer.
Drawings
FIG. 1 is an ultrasound image of bladder sites at various times following treatment of bladder orthotopic tumors by combined infusion of doxorubicin hydrochloride (DOX) and imiquimod hydrochloride (R837);
FIG. 2 is a physical diagram of the final sizes of different groups of tumor bodies in a bladder in-situ tumor experiment of combined perfusion treatment of pirarubicin hydrochloride (THP) and imiquimod hydrochloride (R837);
FIG. 3 is a graph of fluorescence images of mice in vivo at different time points in a combined perfusion therapy bladder orthotopic tumor experiment with different ratios of pirarubicin hydrochloride (THP) and imiquimod hydrochloride (R837);
FIG. 4 is a statistical graph of mean fluorescence intensity at bladder sites of mice at different time points in a combined perfusion therapy bladder orthotopic tumor experiment of pirarubicin hydrochloride (THP) and imiquimod hydrochloride (R837) in different mixture ratios;
FIG. 5 is a fluorescence imaging of tumor in bladder in situ tumor experiments by combined perfusion treatment of epirubicin hydrochloride (EPI) and imiquimod hydrochloride (R837);
FIG. 6 is a graph of fluorescence intensity statistics at the tumor site at the end of combined infusion therapy of epirubicin hydrochloride (EPI) and imiquimod hydrochloride for bladder orthotopic tumors;
FIG. 7 is a graph of tumor growth in mice for the perfusion treatment of bladder cancer using EPI in combination with R837;
FIG. 8 is a graph of the change in body weight of mice between 1 and 9 days after infusion administration in a toxicity test using a combination of EPI and R837 (dose ratio of 1: 6);
FIG. 9 is a graph of the change in body weight of mice over 1-4 days after infusion administration in a toxicity test using a combination of EPI and R837 (dose ratio of 1: 10);
FIG. 10 is a statistical plot of the EPI content in mouse blood;
FIG. 11 is a statistical plot of fluorescence intensity of EPI content in mouse bladder tissue;
FIG. 12 is a statistical plot of the intensity of EPI fluorescence signals in macrophages in mouse bladder tissue.
Detailed Description
Example A: preparation compatibility
Example A1 weighing 10mg of R837 and adding 5mL of 0.015M hydrochloric acid, shaking until the solution is completely clear. The ICD chemotherapy drug doxorubicin hydrochloride is added into the solution, and the mass ratio of imiquimod to doxorubicin hydrochloride is 1:1, 2:1, 4:1, 6:1 and 10: 1. Adding suitable lyophilization cosolvent such as mannitol, adding pH regulator such as sodium hydroxide, and controlling pH to 2.0-5.5, and lyophilizing to obtain lyophilized powder.
Example A2 weighing 10mg of R837 and adding 5mL of 0.015M hydrochloric acid, shaking until the solution is completely clear. The ICD chemotherapy drug epirubicin hydrochloride is added into the solution, and the mass ratio of imiquimod to epirubicin hydrochloride is 1:1, 2:1, 4:1, 6:1 and 10: 1. Adding suitable lyophilization cosolvent such as mannitol, adding pH regulator such as sodium hydroxide, and controlling pH to 2.0-5.5, and lyophilizing to obtain lyophilized powder.
Example A3 weighing 10mg of R837 and adding 5mL of 0.015M hydrochloric acid, shaking until the solution is completely clear. Adding an ICD chemotherapy drug pirarubicin hydrochloride into the solution, wherein the mass ratio of imiquimod to pirarubicin hydrochloride is (1: 1), (2: 1), (4: 1), (6): 1 and 10: 1. Adding suitable lyophilization cosolvent such as mannitol, adding pH regulator such as sodium hydroxide, and controlling pH to 2.0-5.5, and lyophilizing to obtain lyophilized powder.
Example A4 weighing 10mg of R837 and adding 5mL of 0.015M hydrochloric acid, shaking until the solution is completely clear. ICD chemotherapy drug mitoxantrone hydrochloride is added into the solution, and the mass ratio of imiquimod to mitoxantrone hydrochloride is 1:1, 2:1, 4:1, 6:1 and 10: 1. Adding suitable lyophilization cosolvent such as mannitol, adding pH regulator such as sodium hydroxide, and controlling pH to 2.0-5.5, and lyophilizing to obtain lyophilized powder.
Example A5 weighing 10mg of R837 and adding 5mL of 0.015M lactic or acetic acid (hydrochloric acid not used) and shaking until the solution is completely clear. The ICD chemotherapeutic drug oxaliplatin is added into the solution, and the mass ratio of imiquimod to oxaliplatin is 1:1, 2:1, 4:1, 6:1 and 10: 1. Adding suitable lyophilization cosolvent such as mannitol, adding pH regulator such as sodium hydroxide, and controlling pH to 4.5-6.0, and lyophilizing to obtain lyophilized powder.
Example A6 weighing 2mg of R837, adding 5mL of 0.005M hydrochloric acid, shaking until the solution is completely clear. ICD chemotherapy drug fluorouracil is added into the solution, and the mass ratio of imiquimod to fluorouracil is 1:1, 1:2, 1:5, 1:10 and 1: 20. Adding suitable lyophilization cosolvent such as mannitol, adding pH regulator such as sodium hydroxide, and controlling pH to 3.0-6.0, and lyophilizing to obtain lyophilized powder.
Example A7 weighing 2mg of R848, 5mL of 0.005M hydrochloric acid were added and shaken until the solution was completely clear. The ICD chemotherapeutic drug doxorubicin hydrochloride is added into the solution, and the mass ratio of R848 to doxorubicin hydrochloride is 1:1, 1:2, 1:5, 1:10 and 1: 20. Adding suitable lyophilization cosolvent such as mannitol, adding pH regulator such as sodium hydroxide, and controlling pH to 2.0-5.5, and lyophilizing to obtain lyophilized powder.
Example A8 weighing 2mg of R848, 5mL of 0.005M hydrochloric acid were added and shaken until the solution was completely clear. The ICD chemotherapeutic drug epirubicin hydrochloride is added into the solution, and the mass ratio of R848 to epirubicin hydrochloride is 1:1, 1:2, 1:5, 1:10 and 1: 20. Adding suitable lyophilization cosolvent such as mannitol, adding pH regulator such as sodium hydroxide, and controlling pH to 2.0-5.5, and lyophilizing to obtain lyophilized powder.
Example A9 1mg of R848 is weighed out, 2.5mL of 0.005M hydrochloric acid are added, 5-15mL of water for injection are added and the solution is shaken until it is completely clear. And (3) adding the ICD chemotherapeutic drug fluorouracil into the solution, wherein the mass ratio of R848 to fluorouracil is 1: 10. 1:25, 1:100, and 1: 200. Adding suitable lyophilization cosolvent such as mannitol, adding pH regulator such as sodium hydroxide, and controlling pH to 3.0-6.0, and lyophilizing to obtain lyophilized powder.
Example a 10: gemcitabine hydrochloride and CpG are mixed according to the mass ratio of 100: 1, mixing in water solution, adding appropriate freeze-drying cosolvent mannitol and lactose, controlling pH value between 2.5-4.0, and preparing into freeze-dried powder.
Example B: design and implementation application of comparative experiment
Example B1: the combined medicine system is used for the perfusion treatment of the bladder cancer, and compared with a single chemotherapeutic medicine or a single immunologic adjuvant (imiquimod), the curative effect is obviously improved;
the effect of the combination of doxorubicin hydrochloride (DOX) and imiquimod hydrochloride (R837) in the treatment of bladder orthotopic tumors was evaluated in conjunction with fig. 1. Healthy C57BL/6 female mice (18-20g) were divided into four groups of 4 mice each, and fLuc-MB49 cells (1X 10) were injected through the bladder wall5Respectively) establishing a bladder cancer in-situ model, carrying out living body imaging observation on a mouse after inoculation for one week to confirm establishment of a tumor model, then injecting pentobarbital into the abdominal cavity of the mouse for anesthesia, and respectively infusing the following medicine combinations into the bladder:
group B1-1: blank set (ultrapure water ddH)2O，100μL)；
Group B1-2: r837(1.5mg/mL, 100. mu.L);
group B1-3: DOX (1.5mg/mL, 100. mu.L);
group B1-4: DOX + R837(1.5mg/mL, 100. mu.L, 1: 1).
The perfusion time is 1 hour, once per week and twice, and the size of the tumor in situ is detected by a photoacoustic imaging system before treatment every week. Fig. 1 shows the photoacoustic imaging of bladder in situ tumor, wherein the area in the outer dotted line is the mouse bladder area, and the area between the two dotted lines is tumor tissue. The area of the area between the two dotted lines can be compared to judge that the inhibition effect of the R837 and DOX combined perfusion group (B1-4) on bladder in-situ tumor is obviously stronger than that of the pure R837 group (B1-2) and the pure DOX group (B1-3); fig. 2 is an image of an in situ tumor body of a bladder obtained from a mouse dissected one week after the second perfusion treatment, and the result shows that the in situ tumor body of the bladder of a mouse in a combined group of DOX and R837 perfusion (B1-4) is smaller in size and has a more significant tumor inhibition effect, so that it is inferred that the combined use of DOX and R837 perfusion can improve the curative effect of chemotherapeutic drugs.
Example B2: evaluation of the experiment of using R837 hydrochloride and pirarubicin hydrochloride (hereinafter referred to as THP) together for perfusion treatment of bladder in situ tumor. The drugs in the above are hydrochloride of chemotherapeutic drugs and hydrochloride of R837, the clinical dosage form of R837 is ointment which is not suitable for perfusion application, the prior patent dosage form of bladder perfusion is emulsion (TMX-101), and the treatment effect of combined perfusion of R837 hydrochloride and THP is examined here.
Establishing orthotopic bladder tumor of the mice by adopting a similar method as described in example B1, carrying out living body imaging observation of the mice after one week of inoculation to confirm the establishment of a tumor model, randomly dividing the tumor model into 3 groups, then carrying out intraperitoneal injection of pentobarbital for anesthesia on the mice, and respectively infusing the bladders with the following drug combinations:
group B2-1: blank set (ultrapure water ddH)2O，100μL)；
Group B2-2: THP (0.6mg/mL, 100 μ L);
group B2-3: THP (0.6mg/mL, 100. mu.L) + R837(0.6mg/mL, 100. mu.L).
The bladder is perfused for 1 hour, once a week and four times, the bladder tumor of the mouse is detected by a small animal imaging system before each perfusion treatment, and the tumor size is characterized by the average fluorescence intensity of tumor tissues. Data for 0-35 day mouse in vivo imaging are shown in FIG. 3, and in Table 1 are mean fluorescence intensity of tumor tissue in situ in the mouse bladder and survival rate of each group in FIG. 3. The fluorescence intensity of the tumor of the bladder part of the mice in the THP and R837 hydrochloride combined perfusion group (B2-3) is obviously smaller than that of other control groups, and the mice in the group have good survival rate (100%) up to 35 days, so that the conclusion is that the R837 hydrochloride has good water solubility and high perfusion bioavailability, and the combination of the R837 hydrochloride and the THP can improve the tumor inhibition effect of chemotherapeutic drugs and improve the survival rate of tumor-bearing mice.
TABLE 1 mean fluorescence intensity of mouse bladder orthotopic tumor tissue and survival Rate of each group
Figure BDA0002872726400000091
Example B3: the effect of the combination perfusion therapy of the pirarubicin hydrochloride (hereinafter referred to as THP) and the R837 hydrochloride in different mixture ratios on bladder orthotopic tumor is evaluated.
In order to simulate the perfusion treatment after clinical cystectomy, the experiment adopted a treatment scheme that the perfusion treatment is started the next day after inoculation, the growth of the tumor is detected by a small animal living body imaging system before treatment, and the inhibition level of the tumor is evaluated by the average fluorescence intensity of tumor tissues. The bladder perfusion drug combinations in the experiment were as follows:
group B3-1: blank set (ultrapure water ddH)2O，100μL)；
Group B3-2: THP (0.25mg/mL, 100 μ L);
group B3-3: THP (0.25mg/mL, 100. mu.L) + R837(0.8mg/mL, 100. mu.L);
group B3-4: THP (0.25mg/mL, 100. mu.L) + R837(0.4mg/mL, 100. mu.L);
group B3-5: THP (0.25mg/mL, 100. mu.L) + R837(0.2mg/mL, 100. mu.L);
group B3-6: r837(0.8mg/mL, 100 μ L);
group B3-7: THP (0.25mg/mL, 100. mu.L) + BCG (2.6mg/mL, 100. mu.L).
Three treatments with 1 hour weekly perfusion, day 16, fluorescence statistics for in situ tumors in the bladders of each group of mice are shown in fig. 3, where higher mean fluorescence intensity represents larger tumor tissue. In fig. 3, the mean fluorescence intensity of the group R837 (B3-6) and the blank group (B3-1) has no significant difference, which indicates that the single R837 has no significant tumor inhibition effect under the dosage, and the tumor fluorescence intensity of the THP and R837 combined group (B3-3-5) is significantly lower than that of the THP single group and the BCG positive control group (B3-7), which indicates that the THP and R837 combined group has significant synergistic treatment effect, and the treatment effect is also improved along with the increase of the proportion of R837, and the treatment effect is significantly better than that of the BCG positive control group. Thus, the data again demonstrate the inference that R837 in combination with ICD drugs has a synergistic anti-tumor effect.
Example B4: evaluation of epirubicin hydrochloride (EPI) and different R837 hydrochloride ratio in combination with perfusion bladder in situ tumor experiments.
To further verify the conclusion that co-infusion of ICD drugs with TLR7 agonists can improve the therapeutic effect and reduce the toxic side effects of chemotherapeutic drugs, we evaluated the in situ tumor treatment effect of the bladder of mice co-infused with different ratios of EPI (60 μ g) and R837 hydrochloride (60-240 μ g) with non-ICD drug mitomycin c (mmc) as control, and the results are shown in fig. 4. A mouse in situ tumor model was established as in example B1, perfusion treatment was started 5 days after inoculation of the mice with cells (set to day 0), and the mice were randomly grouped as follows:
group B4-1: blank set (ultrapure water dd H)2O)；
Group B4-2: r837(240 μ g);
group B4-3: EPI (60. mu.g);
group B4-4: EPI (60. mu.g) + R837 (60. mu.g);
group B4-5: EPI (60. mu.g) + R837 (120. mu.g);
group B4-6: EPI (60. mu.g) + R837 (240. mu.g);
group B4-7: MMC (60. mu.g) + R837 (120. mu.g).
Mice in each group were perfused with a volume of 100 μ L each for 1 hour and once a week for 2 times. FIG. 5 is a live fluorescence imaging of mice one week before and after the first and second perfusion treatments, and Table 2 shows the mean fluorescence intensity of orthotopic tumors of the mouse bladder and the survival rate of each group of mice on day 14. According to the experimental result, with the continuous increase of the feeding proportion of the combination of the R837 hydrochloride and the EPI, the average fluorescence intensity of the mouse in situ tumor is weakened, the survival time of the mouse is improved, and the death of the mouse in the combination of the MMC and the R837 caused by the toxicity of the MMC appears in the early stage of the experiment, so that the combined application effect of the EPI and the R837 is obviously better than that of the combination of the MMC and the R837. FIG. 6 shows the body weight of mice in the EPI group alone (B4-2) significantly reduced from the body weight of mice in the blank group (B4-1) compared to the body weight of mice in the histogram at day 9 after the start of administration, and the body weight of mice in the group with R837 (B4-4-6) decreased with the increase in the proportion of R837, thus indicating the attenuation of the ICD drug in combination with R837.
TABLE 2 mean fluorescence intensity of mouse bladder orthotopic tumor tissue and survival rate of each group
Figure BDA0002872726400000111
Figure BDA0002872726400000121
Example C:
example C1: ICD drug and R837 are used in the bladder cancer perfusion treatment, inhibit the evaluation experiment of distal tumor growth.
The experiment proves that the combined use of the EPI of the ICD drug and the immunologic adjuvant R837 has the growth inhibition and chemotherapy attenuation effects on bladder in-situ tumors, and the combined treatment effect is more obvious along with the increase of the dosage of the immunologic adjuvant R837 in a certain dosage range. To further evaluate the inhibition of distal tumor growth by ICD drugs in combination with R837, the EPI + R837 (360. mu.g) group and healthy naive mice (C57 BL/6) were given subcutaneous MB49 cells (1X 10 BL/32) at two weeks (day 28) after completion of perfusion treatment (third) on day 14 (day 28)6One) and observing the growth of the tumor. Subcutaneous tumor size was recorded starting on day 4 after subcutaneous tumor inoculation and measured every other day with the formula V ═ length x width2)/2. FIG. 7 shows that the subcutaneous tumor volume of mice in the EPI + R837 group is significantly smaller than that of the control group, i.e., it is confirmed that the combination of EPI and R837 produces tumor-specific immune distal tumor inhibition, which reduces the recurrence and metastasis of bladder tumor.
Example C2: the attenuation effect and mechanism evaluation of ICD drug and R837 in different mass ratios (1: 6, 1:10) are combined.
In order to further confirm the inference that the combination of R837 and ICD can reduce the toxic side effect of chemotherapeutic drugs and the maximum dose range of the combination, healthy C57BL/6 female mice are selected for further toxicity evaluation. Four groups of mice were each 6 mice each, and each was perfused with an equal dose of blank groups of ultrapure water (ddH)2O), R837 (360. mu.g), EPI (60. mu.g) and EPI (60. mu.g) + R837 (360. mu.g), infused 1 hour, weekly, 2 times, and body weight recorded every other day. As shown in FIG. 8, after two perfusion administrations (1-9 days), the weight of the mice in the EPI (60 μ g) group is obviously reduced compared with that in the blank group and the R837(360 μ g) group, while the weight of the mice in the group with the same administration dosage of the EPI and the R837 in a mass ratio (1: 6) is not obviously reduced, and the subsequent macrophage phagocytosis experiment proves the effect. Next we use a similar methodThe method was carried out to evaluate whether or not there was a dose range of attenuation when EPI and R837 were used in combination at a mass ratio of 1: 10. Four groups of mice were each 6 mice each, and each was perfused with an equal dose of blank groups of ultrapure water (ddH)2O), R837 (600. mu.g), EPI (60. mu.g) and EPI (60. mu.g) + R837 (600. mu.g), perfused for 1 hour and body weight recorded every other day. As shown in FIG. 9, the weight of the mice in the EPI/R837 mass ratio (1:10) combination group is obviously reduced compared with the weight of the mice in other control groups, and it is presumed that when the mass ratio of R837 is continuously increased, the dosage of R837 is increased to cause new toxic and side effects to be increased, thereby offsetting the attenuation effect in the original combination. Meanwhile, the experimental result of the part B can be combined to conclude that the toxic and side effects of the chemotherapeutic drug can be obviously reduced by combining the R837 and the ICD chemotherapeutic drug and performing perfusion administration in a proper combined dosage range.
To explain the reason for the attenuation of the combination, the difference in the contents of the chemotherapeutic drugs in the blood and bladder tissues of the mice 4 hours after the administration of the bladder perfusion was first examined. Fig. 10 shows that the EPI content in the blood of the mice 4 hours after the perfusion administration was detected by a fluorescence spectrophotometer, and the experimental data shows that there is no significant difference between the EPI and the EPI + R837 combination in the blood concentration of the chemotherapy EPI in the two groups of mice. Meanwhile, the total amount of EPI phagocytosis in the bladder tissue is evaluated by flow, FIG. 11 is EPI flow fluorescence analysis data of mouse bladder tissue cells, and experimental results show that the uptake rate of EPI used alone and combined with R837 in mouse bladder tissue has no obvious difference, namely the combination with R837 does not influence the systemic and local absorption of the chemotherapeutic drug EPI. However, in the flow analysis and detection experiment of the positive proportion of EPI in macrophages in mouse bladder tissue, it is found that the phagocytic capacity of the macrophages in the bladder tissue of the EPI + R837 combination group to the chemotherapeutic drug is stronger than that of the EPI group alone (fig. 12), and by combining the above-mentioned phenomenon of improving the treatment effect, it can be concluded that a large amount of extracellular free chemotherapeutic drug is phagocytosed by the macrophages after the immunogenic cell death of the chemotherapeutic drug occurs, so the toxic and side effects of the extracellular chemotherapeutic drug to normal tissues are reduced. However, R837 has the effect of immune regulation and control as an immunostimulant, although the toxic and side effects of the chemical drugs can be reduced by increasing the proportion of R837 by a proper amount, the excessive R837 and the chemical drugs can cause strong mucosa stimulation and adversely affect mice. Thus, it is demonstrated by this example that the preferred ratio of chemotherapeutics/R837 is not less than 1: 10. Therefore, when the immunologic adjuvant and the chemical drug which can cause immunogenic cell death are used together as the bladder perfusion drug composition, the competition of attenuation and new toxic and side effects exists, so that a certain proportion relation of the drug composition exists, and although the difference of the properties of different drugs causes the difference of the proportion relation, when the immunologic adjuvant and the chemical drug which can cause immunogenic cell death are used together as the bladder perfusion drug composition, the systemic toxic and side effects of the ICD chemical drug can be reduced through the technical scheme provided by the invention, the dosage of the ICD drug can be increased within a certain range, and the treatment effect of the drug can be obviously improved.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art. The present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and features disclosed herein.

Claims (14)

1. A bladder perfusion pharmaceutical composition, comprising: including soluble salts of immunoadjuvants and chemotherapeutics that cause immunogenic cell death.
2. The bladder perfusion pharmaceutical composition of claim 1, wherein: the mass ratio of the soluble salt of the immunologic adjuvant to the chemical drug capable of causing immunogenic cell death is 1: 100-6: 1.
3. The bladder perfusion pharmaceutical composition of claim 1, wherein: the chemical drug capable of causing immunogenic cell death comprises anthracycline chemotherapeutic drug, platinum chemotherapeutic drug, fluorouracil or gemcitabine; optionally, the anthracycline chemotherapeutic comprises doxorubicin hydrochloride, epirubicin hydrochloride, pirarubicin hydrochloride, mitoxantrone hydrochloride; the platinum chemotherapeutic drug comprises nedaplatin, carboplatin, lobaplatin or oxaliplatin.
4. The bladder perfusion pharmaceutical composition of any one of claims 1-3, wherein: the soluble salt of the immunological adjuvant comprises at least one of imiquimod R837 hydrochloride, Rasimmod R848 hydrochloride or other pharmaceutically acceptable salts, CpG, polyIC, polyICLC, and STING stimulant.
5. The bladder perfusion pharmaceutical composition of claim 4, wherein: the mass ratio of the imiquimod R837 hydrochloride to the chemical drug capable of causing immunogenic death is 1: 20-1: 1, wherein the chemical drug capable of causing immunogenic death is fluorouracil or gemcitabine.
6. The bladder perfusion pharmaceutical composition of claim 4, wherein: the mass ratio of the imiquimod R837 hydrochloride to the chemical drug capable of causing immunogenic death is 1: 1-6: 1, wherein the chemical drug comprises an anthracycline chemotherapeutic drug or a platinum chemotherapeutic drug, and the anthracycline chemotherapeutic drug comprises doxorubicin hydrochloride, epirubicin hydrochloride, pirarubicin hydrochloride and mitoxantrone hydrochloride; the platinum chemotherapeutic drug comprises nedaplatin, carboplatin, lobaplatin or oxaliplatin.
7. The bladder perfusion pharmaceutical composition of claim 4, wherein: the mass ratio of the Rasimotede R848 hydrochloride to the chemical drug capable of causing immunogenic cell death is 1: 20-1: 1, wherein the chemical drug capable of causing immunogenic cell death comprises an anthracycline chemotherapeutic drug or a platinum chemotherapeutic drug, and the anthracycline chemotherapeutic drug comprises doxorubicin hydrochloride, epirubicin hydrochloride, pirarubicin hydrochloride and mitoxantrone hydrochloride; the platinum chemotherapeutic drug comprises nedaplatin, carboplatin, lobaplatin or oxaliplatin.
8. The bladder perfusion pharmaceutical composition of claim 4, wherein: the mass ratio of the Rasimethide R848 hydrochloride to the chemical drug capable of causing immunogenic death is 1: 100-1: 10, wherein the chemical drug capable of causing immunogenic death comprises fluorouracil or gemcitabine.
9. The bladder perfusion pharmaceutical composition of claim 1, wherein: also comprises a freeze-drying cosolvent and a pH regulator.
10. The bladder perfusion pharmaceutical composition of claim 1, wherein: the concentration range of the soluble salt of the immunologic adjuvant is 0.5 mg/mL-30 mg/mL.
11. The bladder instillation pharmaceutical composition of any one of claims 1 to 10, wherein: the preparation is freeze-dried powder.
12. A preparation method of a bladder perfusion pharmaceutical composition is characterized by comprising the following steps:
s1: adding chemical medicine capable of causing immunogenic cell death into diluted acid solution of immune adjuvant imiquimod R837 or Rasimmod R848 or other pharmaceutically acceptable immune adjuvant soluble salt solution, and mixing uniformly until dissolving;
s2: adding a suitable freeze-drying cosolvent and a pH regulator into the solution of S1, and controlling the pH value to be between 2.0 and 5.5;
s3: the solution obtained in step S2 is subjected to lyophilization.
13. A preparation method of a bladder perfusion pharmaceutical composition is characterized by comprising the following steps:
s1: adding immune adjuvants CpG, polyIC, polyICLC, water soluble STING stimulant and chemical drug capable of causing immunogenic cell death into water for injection, and mixing uniformly to dissolve;
s2: to the solution of S1, a suitable lyophilization co-solvent (e.g., mannitol, lactose) is added and the solution is subjected to a lyophilization process.
14. Use of the bladder perfusion pharmaceutical composition of any one of claims 1-10 in the preparation of a bladder perfusion formulation.
CN202011609565.1A 2020-12-30 2020-12-30 Bladder perfusion pharmaceutical composition and preparation method and application thereof Pending CN114681612A (en)

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