CN118141804A - Use of indole-3-propionic acid in preparing medicament for sensitization tumor immunotherapy - Google Patents
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, relates to application of indole-3-propionic acid in preparing a medicament for sensitization immunotherapy, and in particular relates to application of indole-3-propionic acid and a medicament containing the same in preparing a product for sensitization anti-PD-1 antibody. According to the research, the indole-3-propionic acid can obviously sensitize the mice for immunotherapy, the mice tumors are obviously reduced, the infiltrated CD8 + T cells are obviously increased, and the experimental mice do not show abnormal reaction, so that the indole-3-propionic acid can sensitize the mice for immunotherapy. The indole-3-propionic acid is a natural substance existing in organisms, has no heterogeneity and serious adverse reaction, has wide application potential, can be clinically combined with an immune checkpoint inhibitor, and provides a new strategy for preventing or treating tumors.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of indole-3-propionic acid in preparation of a medicine for sensitized tumor immunotherapy.
Background
The tumor immunotherapy can restart the normal immune response of the organism, reduce the immune escape and the immune tolerance of the tumor, and effectively control and clear the tumor. Various immune checkpoint inhibitor drugs (ICIs), such as programmed cell death protein-1 (PD-1) and its ligand PD-L1 antibodies, have been used in clinical tumor immunotherapy. ICIs can enhance T cell activation, thereby increasing the toxic killing effect of immune cells on tumor cells. However, solid tumors such as colorectal cancer have low efficacy against PD-1 antibodies, which are closely related to the tumor immunosuppressive microenvironment and CD8 + T cells in tumor tissue. Multiple CD8 + T cell subsets have been found to affect anti-tumor responses. In particular, depletion of precursor T cells of TCF-1 +, characterized by high expression of the transcription factor T-cytokine 1 (TCF-1, encoded by TCF 7), is a major subset of responses to immunotherapy. The population of cells has an immune stem characteristic and is capable of self-renewal, proliferation and differentiation into effector CD8 + T cells, thereby limiting the occurrence of tumors. Since a clear correlation between Tcf7 deficiency and disruption of gut microbiota balance was observed in mice, a further study of whether gut microbiota and its metabolites could modulate the stem cell program of CD8 + T cells was needed.
Various tryptophan-indole metabolites of intestinal microbial origin, including indole-3-lactic acid (ILA), indole-3-acrylic acid (IA), indole-3-propionic acid (IPA), indole-3-acetic acid (IAA), and indole-3-acetamide (IAM), etc., have been demonstrated to have a broad range of biological effects. Specifically, IPA improves atherosclerosis, reduces radioactive toxicity and prolongs post-traumatic survival, but the effects of IPA on the management of cancer immunotherapy have not been reported.
Indole-3-propionic acid (Indolepropionic acid, IPA, CAS:830-96-6; molecular weight: 189.21; chemical formula: C 11H11NO2) is a ring of tryptophan indole metabolic pathway, and indole and its derivatives have been found to modulate immune microenvironment and are used in the prevention or treatment of rheumatoid arthritis and radiotherapy side-effects, but their effect on tumor immunotherapy is not known.
Various Immune Checkpoint Inhibitor (ICIs) drugs such as apoptosis protein-1 (PD-1) and its ligand PD-L1 mab have been used in clinical tumor immunotherapy. ICIs can enhance T cell activation, thereby increasing the toxic killing effect of immune cells on tumor cells. However, only about 15% of colorectal cancer (Colorectal Cancer, CRC) patients benefit from immune checkpoint blocking treatment, with a strong individual heterogeneity. Infiltration of T cells in colorectal cancer may better predict the patient's immunotherapeutic response compared to the mismatch repair deficiency (dMMR) or microsatellite instability (MSI) status of the tumor. Increasing evidence suggests that fecal transplantation or intestinal strain supplementation can affect tumor immunotherapy outcomes, such as fecal transplantation promoting therapeutic response of melanoma patients to PD-1 mab; bifidobacteria act synergistically to reduce tumor burden in mice; clostridium nucleatum enhances the therapeutic effect of PD-L1 mab in tumors, etc. Therefore, searching for immune checkpoint inhibitor sensitization pathway based on intestinal flora is expected to provide a new strategy for accurate immunotherapy of colorectal cancer.
In conclusion, the low effective rate of immune checkpoint inhibitors in solid tumors limits their wide clinical application. In view of this, there is a need to develop a product that is capable of sensitizing immune checkpoint inhibitors.
Disclosure of Invention
The first object of the present invention is to provide the use of indole-3-propionic acid in the manufacture of a medicament for use in the immunotherapy of sensitized tumors.
Further, the drug includes, but is not limited to, indole-3-propionic acid, and can also include pharmaceutically acceptable salts, or solvates, or prodrugs, or metabolites thereof;
further, the immunotherapy includes, but is not limited to, anti-PD-1 antibody therapy;
further, the tumors include, but are not limited to, colorectal cancer, breast cancer and melanoma.
In another aspect, the invention provides a medicament or pharmaceutical composition for use in the immunotherapy of a sensitized tumor, comprising indole-3-propionic acid and one or more pharmaceutically acceptable carriers, or comprising indole-3-propionic acid and one or more sensitizing immunotherapeutic agents.
Further, the medicament or pharmaceutical composition may also include, but is not limited to, a pharmaceutically acceptable salt of indole-3-propionic acid, or a solvate thereof, or a prodrug thereof, or a metabolite thereof;
further, the immunotherapy includes, but is not limited to, anti-PD-1 antibody therapy;
further, the tumors include, but are not limited to, colorectal cancer, breast cancer and melanoma;
Still further, the pharmaceutically acceptable carrier includes, but is not limited to, one or more of solvents, solubilizers, co-solvents, emulsifiers, flavoring agents, colorants, binders, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, pH adjusting agents, stabilizers, surfactants, preservatives, and the like;
further, the medicament or the pharmaceutical composition is a solid preparation, a semisolid preparation or a liquid preparation;
Still further, the solid formulations include, but are not limited to, tablets, capsules, granules, pills, and the like; the semi-solid formulations include, but are not limited to, gels, suppositories, ointments, and the like; such liquid formulations include, but are not limited to, emulsions, mixtures, suspensions, solutions, and the like.
Further, the drug or the drug composition is administered by intraperitoneal injection, oral lavage or intratumoral injection, wherein the dose of the indole-3-propionic acid is as follows: intraperitoneal injection or oral lavage is 60 mg/kg/day; intratumoral injection is 5-50 mu m, 50 mu L/day.
The invention has at least the following advantages and beneficial effects:
According to the invention, researches show that the indole-3-propionic acid has a remarkable sensitization effect on mouse immunotherapy, and can obviously reduce mouse tumors. The indole-3-propionic acid is a natural substance existing in organisms, has no heterogeneity and serious adverse reaction, and has wide application potential.
Drawings
FIG. 1 is an oral gavage indole-3-propionic acid sensitized colorectal carcinoma subcutaneous tumor model immunotherapy of example 1; graphically, a graph of tumor growth in mice is shown.
FIG. 2 is a model immunotherapy of example 2 against subcutaneous tumors of colorectal cancer sensitized by intratumoral injection of indole-3-propionic acid; in the figure, A is an intratumoral injection molding drawing; b is a graph of tumor growth in mice.
FIG. 3 is a comparison of the sensitization effect of the abdominal cavity injection of indole-3-propionic acid and indole-3-lactic acid in example 3 on colorectal carcinoma subcutaneous tumor model immunotherapy; graphically, a graph of tumor growth in mice is shown.
FIG. 4 is a graph showing that indole-3-propionic acid increases CD8 + T cell numbers in colorectal cancer immune microenvironment in example 4; in the figure, A is a representative graph of CD8 + T flow cytometry analysis in tumors; b is a statistical graph of the number of CD8 + T cells in the tumor.
FIG. 5 is an indole-3-propionic acid sensitized breast cancer subcutaneous tumor model immunotherapy of example 5; in the figure, A is a graph of tumor growth in mice; b is a statistical chart of the number of CD8 + T cells in the tumor; c is a statistical graph of the number of TCF-1 +CD8+ T cells in the tumor.
FIG. 6 is an indole-3-propionic acid sensitized melanoma subcutaneous tumor model immunotherapy of example 6; in the figure, A is a graph of tumor growth in mice; b is a statistical chart of the number of CD8 + T cells in the tumor; c is a statistical graph of the number of TCF-1 +CD8+ T cells in the tumor.
FIG. 7 is an in situ tumor model immunotherapy of indole-3-propionic acid sensitized breast cancer in example 7; in the figure, A is a graph of tumor growth in mice; b is a statistical chart of the number of CD8 + T cells in the tumor; c is a statistical graph of the number of TCF-1 +CD8+ T cells in the tumor.
FIG. 8 is an illustration of an indole-3-propionic acid sensitized breast cancer spontaneous tumor model immunotherapy of example 8; the graph is shown as a mouse tumor survival graph.
Detailed Description
The invention is described in further detail below with reference to the drawings and the specific embodiments.
Example 1: oral gavage indole-3-propionic acid sensitized colorectal cancer subcutaneous tumor model immunotherapy
Male C57BL/6 mice of 6-8 weeks are randomly divided into 4 groups, 7 mice in each group are freely drunk for 1 week before molding, drinking water containing 2mg/mL of metronidazole, 2mg/mL of penicillin, 2mg/mL of streptomycin and 1mg/mL of vancomycin, and the homogenized intestinal flora is respectively administrated with 0mg/kg of indole-3-propionic acid (control group), 6mg/kg (low dose group), 60mg/kg (medium dose group) and 300mg/kg (high dose group) of stomach according to the weight of the mice once per day. On the day of gavage, 1×10 6 of the mouse colon cancer cell line Mc38 cells were injected subcutaneously (100 μl per mouse). After 8 days of injection, 100 μg of anti-PD-1 antibody was given to each mouse intraperitoneally, one injection was given every three days, and tumor volumes were monitored every two days, as calculated as follows: volume = 0.5 xlxw 2, where L is the longest diameter and W is the shortest diameter. The experiment was terminated every other day after three PD-1 treatments, and tumor volumes were recorded and counted.
As shown in FIG. 1, compared with the control group, oral gavage of 6mg/kg indole-3-propionic acid cannot play a role in sensitization colorectal cancer immunotherapy, while oral gavage of 60mg/kg and 300mg/kg indole-3-propionic acid can remarkably increase the curative effect of colorectal cancer anti-PD-1 antibodies and reduce tumor load.
Example 2: intratumoral injection indole-3-propionic acid sensitized colorectal cancer subcutaneous tumor model immunotherapy
Male C57BL/6 mice of 6-8 weeks were randomly divided into 3 groups of 7 mice each, and 1 week of drinking water containing 2mg/mL metronidazole, 2mg/mL penicillin, 2mg/mL streptomycin and 1mg/mL vancomycin was freely drunk before molding, intestinal flora was homogenized, and 1X 10 6 of the Mc38 cells of the colon cancer cell line of the mice were injected subcutaneously (100. Mu.L per mouse). After 8 days of injection, 100. Mu.g of an anti-PD-1 antibody was given to each mouse by intraperitoneal injection, and 50. Mu.L of an anti-PD-1 antibody was injected by intratumoral injection into 0. Mu.M indole-3-propionic acid (control group), 5. Mu.M indole-3-propionic acid (low dose group) and 50. Mu.M indole-3-propionic acid (high dose group) at the same time as the injection. Tumor volumes were monitored every two days and the calculation formula was as follows: volume = 0.5 xlxw 2, where L is the longest diameter and W is the shortest diameter. The experiment was terminated every other day after three PD-1 treatments, and tumor volumes were recorded and counted.
As shown in fig. 2, compared with the control group, the intratumoral injection of 5 μm and 50 μm indole-3-propionic acid can significantly increase the curative effect of colorectal cancer anti-PD-1 antibody and reduce tumor load.
Example 3: intraperitoneal injection of indole-3-propionic acid sensitized colorectal cancer subcutaneous tumor model immunotherapy
Male C57BL/6 mice of 6-8 weeks are randomly divided into 2 groups, 6 mice in each group are freely drunk for 1 week before molding, drinking water containing 2mg/mL of metronidazole, 2mg/mL of penicillin, 2mg/mL of streptomycin and 1mg/mL of vancomycin, intestinal flora is homogenized, and 0mg/kg of indole-3-propionic acid (control group) and 60mg/kg of indole-3-propionic acid (experimental group) are respectively administrated according to the body weight of the mice, and the intraperitoneal injection amount is 200 mu L, and is once daily. On the day of injection, 1×10 6 of the mouse colon cancer cell line Mc38 cells were injected subcutaneously (100 μl per mouse). After 8 days of injection, 100 μg of anti-PD-1 antibody was given to each mouse intraperitoneally, one injection was given every three days, and tumor volumes were monitored every two days, as calculated as follows: volume = 0.5 xlxw 2, where L is the longest diameter and W is the shortest diameter. The experiment was terminated every other day after three PD-1 treatments, and tumor volumes were recorded and counted.
As shown in FIG. 3, compared with the control group, the experimental group (i.e. injecting 60mg/kg indole-3-propionic acid into the abdominal cavity) can remarkably increase the curative effect of the colorectal cancer anti-PD-1 antibody and reduce the tumor load.
The same experimental procedure was repeated and the results of intraperitoneal injection of indole-3-lactic acid (ILA) at 60mg/kg of mouse body weight showed no significant increase in the efficacy of the anti-PD-1 antibody against colorectal cancer as compared to the control group as shown in fig. 3.
Example 4: indole-3-propionic acid increases the number of CD8 + T cells in a colorectal carcinoma subcutaneous tumor model
The method used in example 1 was used to mold, after molding, subcutaneous tumors of mice were blunt-isolated, cut into small pieces of about 1mm 3, digested with collagenase type IV (Worthington, LS 004189) for 30 minutes and dissociated into single cells, and the number of cells in the collected single cell suspension was adjusted to 1X 10 6/mL with PBS. Each sample was first blocked for 10 minutes with 1 μg of anti-CD 16/32 antibody to Fc receptor (BioLegend, 101320). Then, the dead and live antibody FVS 510 (BD Biosciences, 564406) was added, the mixture was incubated at 4℃for 30min in the absence of light, the staining was stopped by adding an appropriate amount of FACS buffer, centrifugation was performed for 5min at 700g, and the supernatant was discarded. Antibody premix (Alexa Fluor 700-CD45(BioLegend,103128)、PECPCY5.5-CD3(BD Biosciences,551163)、BV605-CD4(BD Biosciences,563151) and APC-CY7-CD8 (BD Biosciences, 561967) were prepared, appropriate amounts of antibody were added to each sample, mixed well, incubated at 4 ℃ for 30min in the dark, stopped by adding PBS, centrifuged for 700g for 5min, the supernatant was discarded, washed 1x with PBS, resuspended in appropriate volumes and detected using flow cytometry. For TCF-1 staining, cells were incubated with the fixative working solution for 40 min at room temperature, washed with transcription factor staining buffer (Invitrogen TM, 00-5523-00), and stained with BV421-TCF-1 (BD Biosciences, 566692) for 40 min at room temperature. Appropriate volume was resuspended and then detected using a flow cytometer.
As shown in FIG. 4, oral gavage of 60mg/kg indole-3-propionic acid increased the number of CD8 + T cells in the colorectal cancer immune microenvironment.
Example 5: indole-3-propionic acid sensitized breast cancer subcutaneous tumor model immunotherapy
Female Balb/C mice of 6-8 weeks are randomly divided into 4 groups (A group, B group, C group and D group), 7 mice in each group are freely drunk for 1 week before molding, drinking water containing 2mg/mL metronidazole, 2mg/mL penicillin, 2mg/mL streptomycin and 1mg/mL vancomycin, and intestinal flora is homogenized, and 0mg/kg (A group), 60mg/kg (B group), 0mg/kg (C group) and 60mg/kg (D group) of indole-3-propionic acid are respectively administrated according to the weight of the mice, and the stomach is irrigated once per day. On the day of gastric lavage, 1×10 5 of 4T1 cells were injected subcutaneously into mice (100 μl per mouse). After 8 days of injection, each mouse was given 100 μg of intraperitoneal injection IgG antibody (group a), igG antibody (group B), anti-PD-1 antibody (group C), anti-PD-1 antibody (group D), and one injection was given every three days, and tumor volumes were monitored every two days, as follows: volume = 0.5 xlxw 2, where L is the longest diameter and W is the shortest diameter. The experiment was terminated every other day after three PD-1 treatments, and tumor volumes were recorded and counted.
As shown in fig. 5, the supplementation of indole-3-propionic acid can significantly increase the therapeutic effect of the breast cancer subcutaneous tumor model anti-PD-1 antibody, reduce tumor burden, and increase the numbers of CD8 + T cells and TCF-1 +CD8+ T cells in the breast cancer immune microenvironment.
Example 6: indole-3-propionic acid sensitized melanoma subcutaneous tumor model immunotherapy
Male C57BL/6 mice of 6-8 weeks are randomly divided into 4 groups (A group, B group, C group and D group), 7 mice of each group are freely drunk for 1 week before molding, drinking water containing 2mg/mL of metronidazole, 2mg/mL of penicillin, 2mg/mL of streptomycin and 1mg/mL of vancomycin, intestinal flora is homogenized, and 0mg/kg (A group), 60mg/kg (B group), 0mg/kg (C group) and 60mg/kg (D group) of indole-3-propionic acid are respectively administrated according to the weight of the mice, and the mice are irrigated with stomach once per day. On the day of gastric lavage, 1X 10 5 B16-F10 cells were injected subcutaneously into mice (100. Mu.L per mouse). After 8 days of injection, each mouse was given 100 μg of intraperitoneal injection IgG antibody (group a), igG antibody (group B), anti-PD-1 antibody (group C), anti-PD-1 antibody (group D), and one injection was given every three days, and tumor volumes were monitored every two days, as follows: volume = 0.5 xlxw 2, where L is the longest diameter and W is the shortest diameter. The experiment was terminated every other day after three PD-1 treatments, and tumor volumes were recorded and counted.
As shown in fig. 6, the supplementation of indole-3-propionic acid can significantly increase the efficacy of anti-PD-1 antibodies in the melanoma subcutaneous tumor model, reduce tumor burden, and increase the numbers of CD8 + T cells and TCF-1 +CD8+ T cells in the melanoma immune microenvironment.
Example 7: indole-3-propionic acid sensitized breast cancer in-situ tumor model immunotherapy
Female Balb/c mice of 6-8 weeks are randomly divided into 2 groups, 7 mice in each group are freely drunk for 1 week before molding, drinking water containing 2mg/mL of metronidazole, 2mg/mL of penicillin, 2mg/mL of streptomycin and 1mg/mL of vancomycin is homogenized, and indole-3-propionic acid is respectively administered for 0mg/kg, 60mg/kg of stomach irrigation according to the weight of the mice once daily. On the day of gastric lavage, 1×10 5 of 4T1 cells were injected onto a fourth group of mammary fat pads (100 μl per mouse). After 8 days of injection, 100 μg of anti-PD-1 antibody was given to each mouse intraperitoneally, one injection was given every three days, and tumor volumes were monitored every two days, as calculated as follows: volume = 0.5 xlxw 2, where L is the longest diameter and W is the shortest diameter. The experiment was terminated every other day after three PD-1 treatments, and tumor volumes were recorded and counted.
As shown in fig. 7, the supplementation of indole-3-propionic acid can significantly increase the curative effect of the anti-PD-1 antibody of the breast cancer in-situ tumor model, reduce tumor burden, and increase the numbers of CD8 + T cells and TCF-1 +CD8+ T cells in the breast cancer immune microenvironment.
Example 8: indole-3-propionic acid sensitized breast cancer spontaneous tumor model immunotherapy
Female MMTV-PyMT mice of 16 weeks are randomly divided into 2 groups, 10 mice in each group are freely drunk for 1 week before molding, drinking water containing 2mg/mL of metronidazole, 2mg/mL of penicillin, 2mg/mL of streptomycin and 1mg/mL of vancomycin is homogenized, and indole-3-propionic acid is respectively administrated for 0mg/kg, 60mg/kg of stomach irrigation once daily according to the weight of the mice. Each mouse was given 100 μg of anti-PD-1 antibody by intraperitoneal injection, one injection every three days, tumor volume was monitored every two days, and the calculation formula was as follows: volume = 0.5 xlxw 2, where L is the longest diameter and W is the shortest diameter. The experiment was terminated when individual tumors of the mice were grown to 1000mm 3, and survival curves were recorded and plotted.
As shown in the figure 8, the indole-3-propionic acid can be supplemented to remarkably increase the curative effect of the anti-PD-1 antibody of the spontaneous tumor model of the breast cancer, and prolong the survival time of mice.
Indole-3-propionic acid (IPA) used in examples 1-8 was purchased from Sigma company under the designation V900491; the PD-1 antibody used was InVivoMAb anti-mouse PD-1 (CD 279), purchased from BioXcell company, cat#BE0273; the reaction species: a Mouse; clone number: 29f.1a12; isotype: rat IgG2a; immunogens: recombinant PD-1-Ig fusion protein; the IgG antibody used was InVivoMAb rat IgG2a isotype control, purchased from BioXcell company, cat#be0089; clone number: 2A3, isotype: rat IgG2a, κ.
The above detailed description is intended to illustrate the present invention by way of example only and not to limit the invention to the particular embodiments disclosed, but to limit the invention to the precise embodiments disclosed, and any modifications, equivalents, improvements, etc. that fall within the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. The application of indole-3-propionic acid in preparing medicine for sensitization tumor immunotherapy.
2. The use according to claim 1, wherein said indole-3-propionic acid is capable of significantly increasing the number of CD8 + T cells in a tumor.
3. The use according to claim 1, wherein the tumor is colorectal cancer, breast cancer or melanoma.
4. The use according to claim 1, wherein the medicament comprises indole-3-propionic acid and/or a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof or a metabolite thereof.
5. The use according to claim 1, wherein the medicament further comprises a pharmaceutical carrier and/or pharmaceutically acceptable excipients.
6. A pharmaceutical composition for the therapeutic effect of a sensitized anti-PD-1 antibody, comprising indole-3-propionic acid and one or more pharmaceutically acceptable carriers, or a pharmaceutical composition comprising indole-3-propionic acid and one or more therapeutic effects of a sensitized anti-PD-1 antibody.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable carrier comprises one or more of solvents, solubilizers, co-solvents, emulsifiers, flavoring agents, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, pH regulators, stabilizers, surfactants, preservatives.
8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a solid formulation, a semi-solid formulation, or a liquid formulation.
9. The pharmaceutical composition of claim 6, wherein the solid formulation is a tablet, capsule, granule, or pill; the semisolid preparation is gel, suppository or ointment; the liquid preparation is emulsion, mixture, suspension or solution.
10. The use according to claim 1 and the pharmaceutical composition according to claim 6, wherein the medicament or pharmaceutical composition is administered by intraperitoneal injection, oral lavage or intratumoral injection, wherein the amount of indole-3-propionic acid administered is: intraperitoneal injection or oral lavage is 60 mg/kg/day; intratumoral injection is 5-50 mu m, 50 mu L/day.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1292693A (en) * | 1998-02-23 | 2001-04-25 | 南亚拉巴马州医学科学基金会 | Indole-3-propionic acids, salts and esters thereof used as medicaments |
| WO2021222309A1 (en) * | 2020-04-27 | 2021-11-04 | Ixcela, Inc. | Detection and modification of gut microbial population |
| CN114558007A (en) * | 2021-12-06 | 2022-05-31 | 南京医科大学 | Application of indole-3-lactic acid in preparation of anti-colorectal cancer drugs |
| KR20230111841A (en) * | 2022-01-19 | 2023-07-26 | 한국과학기술원 | Composition for preventing and treating cancer, containing tryptophan metabolite as an active ingredient |
-
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- 2024-03-06 CN CN202410254831.5A patent/CN118141804A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1292693A (en) * | 1998-02-23 | 2001-04-25 | 南亚拉巴马州医学科学基金会 | Indole-3-propionic acids, salts and esters thereof used as medicaments |
| WO2021222309A1 (en) * | 2020-04-27 | 2021-11-04 | Ixcela, Inc. | Detection and modification of gut microbial population |
| CN114558007A (en) * | 2021-12-06 | 2022-05-31 | 南京医科大学 | Application of indole-3-lactic acid in preparation of anti-colorectal cancer drugs |
| KR20230111841A (en) * | 2022-01-19 | 2023-07-26 | 한국과학기술원 | Composition for preventing and treating cancer, containing tryptophan metabolite as an active ingredient |
Non-Patent Citations (1)
| Title |
|---|
| ETHAN SHELKEY等: "Immuno‑reactive cancer organoid model to assess effects of the microbiome on cancer immunotherapy", SCIENTIFIC REPORTS, vol. 12, 15 June 2022 (2022-06-15), pages 1 - 13 * |
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