KR101732149B1 - Pharmaceutical composition comprising anti-cd25 monoclonal antibody- photosensitizer complex for preventing or treating cancer - Google Patents
Pharmaceutical composition comprising anti-cd25 monoclonal antibody- photosensitizer complex for preventing or treating cancer Download PDFInfo
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- KR101732149B1 KR101732149B1 KR1020150056138A KR20150056138A KR101732149B1 KR 101732149 B1 KR101732149 B1 KR 101732149B1 KR 1020150056138 A KR1020150056138 A KR 1020150056138A KR 20150056138 A KR20150056138 A KR 20150056138A KR 101732149 B1 KR101732149 B1 KR 101732149B1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
Abstract
The present invention relates to anti-CD25 monoclonal antibody-photosensitizer complexes and cancer prevention
And pharmaceutical compositions for therapeutic use. The ZnPC-attached anti-CD25 monoclonal antibody
Injection of tumor cells into the tumor and metastasis to tumor mass alone
T cells can be specifically removed, and the effect of immunotherapy on tumors can be enhanced
useful.
Description
The present invention relates to an anti-CD25 monoclonal antibody-photosensitizer complex and a pharmaceutical composition for preventing and treating cancer comprising the same.
Cancer is the second leading cause of mortality in the western world, after heart disease, and continues to increase despite advances in medicine. In Korea, cancer deaths have also increased steadily, leading to the nation's leading cause of deaths. According to the Ministry of Health and Welfare statistics, cancer incidence increased from 214 in 1999 to 361 in 2008, The number of students is increasing from 114 in 2009 to 141 in 2009. Currently, clinically used treatments for cancer include surgery, radiation therapy, and chemotherapy. Although radiation therapy is useful for the treatment of almost all cancer patients, radiation therapy is limited because of the problems such as the inevitable damage to the normal tissues around the cancer. Therefore, Are used in combination. In addition, existing cancer therapies have been limited in that they involve side effects such as damage to normal tissues other than cancer and immunosuppression.
In recent years, attempts have been actively made to treat cancer by using an immune mechanism, which is a human disease defense system. Cancer immunotherapy can be roughly divided into active immunization and passive immunotherapy. Active immunotherapy induces cancer-specific immune responses in patients, inducing cancer-specific immune responses using cancer antigens, and inducing immune responses such as BCG administration nonspecifically. Passive immunotherapy is the administration of antibodies, cytokines and T cells that have already been formed so that they can directly or indirectly remove cancer cells. Immunological cancer therapy is a technique to induce cancer-specific CD8 + cytotoxic T-cells to attack and remove cancer cells, and even micro-metastasis cancer cells that can not be removed by surgery can be removed and removed And that it does not give side effects to other tissues through selective treatment of cancer cells. However, the immunotherapy methods known so far have shown excellent therapeutic effects in preclinical experiments using experimental animals, and the actual clinical results in cancer patients have not been as expected.
Regulatory T cells are known as CD4 + CD25 + Foxp3 + T cells, a safety device for suppressing the autoimmune reaction that is attacked by recognizing an inflammatory response that is overly induced in vivo and self as an external intrusion. Tumor cells are abnormal cells, but they are strictly autologous, so immunological tolerance occurs when the immune response to the tumor does not exist, leading to regulatory T cells. Thus, regulatory T cells infiltrated into the tumor inhibit the immune response of the body to the tumor by inhibiting the activity of cytotoxic T cells and producing a variety of immunosuppressive cytokines. Recently, attempts have been made to increase the effectiveness of immunotherapy for tumors by injecting an anti-CD25 monoclonal antibody into the body to eliminate regulatory T cells. However, the method of eliminating regulatory T cells by injecting anti-CD25 monoclonal antibody nonspecifically eliminates regulatory T cells that play a role in suppressing excessive immune responses in the body, thereby causing side effects such as autoimmune reactions have. Therefore, it is required to develop a method capable of enhancing the immune response against tumors and minimizing side effects such as autoimmune reaction by specifically removing only the regulatory T cells infiltrated into the tumor.
Photodynamic therapy (PDT) is a technique that can treat intractable diseases such as cancer without surgery by using a photosensitizer with selectivity and photosensitivity to various tumors. As a chemotherapeutic agent, side effects Is a kind of curative law without. For example, a photosensitizer is administered to a subject by intravenous injection, and an excited photo-sensitizer activates oxygen molecules to generate singlet oxygen by irradiating the subject with appropriate light, To destroy the intracellular organelles and induce apoptosis. Zinc phthalocyanine (ZnPC), which is the most widely used photodynamic agent for photodynamic therapy, is a hydrophobic substance. Therefore, nanocarriers such as liposomes are used to intracellularly enter tissues. This method of treating cancer using ZnPC-liposomes has been used to directly induce the death of tumor cells by directly injecting ZnPC-liposome into the tumor mass and irradiating the tumor with the appropriate wavelength of light, And a method of inducing apoptosis and necrosis of tumor cells.
Therefore, the present inventors have made efforts to find a method for selectively removing regulatory T cells that inhibit the body's immune response to cancer. As a result, when the anti-CD25 monoclonal antibody with ZnPC was injected, most of the regulatory T ZnPC was introduced into the cells, and ZnClPC in the tumor-infiltrated regulatory T cells was activated by performing broad-band therapy only on the tumor mass, thereby confirming that only the regulatory T cells in the tumor could be specifically removed, thereby completing the present invention .
It is an object of the present invention to provide an anti-CD25 monoclonal antibody-photosensitizer complex and a pharmaceutical composition for preventing and treating cancer comprising the same.
In order to achieve the above object, the present invention provides an anti-CD25 monoclonal antibody-photosensitizer complex.
In another embodiment, the present invention provides a composition for inhibiting regulatory T cell activity comprising the anti-CD25 monoclonal antibody-photosensitizer complex.
In another embodiment, the present invention provides a pharmaceutical composition for preventing and treating cancer comprising the anti-CD25 monoclonal antibody-photosensitizer complex.
In the present invention, the photosensitizer may be selected from the group consisting of a phorphyrins compound, a chlorins compound, a bacteriochlorins compound, a phthalocyanine compound, a naphthalocyanines compound, (5-aminoevuline esters) compound, and the photosensitizer may be a zinc-phthalocyanine (ZnPC) compound.
In addition, the complex according to the present invention may further comprise a liposome, a lipid nanoparticle, a nanocapsule, a nano emulsion, and a nanostructure.
In the present invention, the cancer is selected from the group consisting of a brain tumor, a benign astrocytoma, a malignant pheochromocytoma, a pituitary adenoma, a meningioma, a brain lymphoma, an oliguria, Nasopharyngeal cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, hepatic cancer, gallbladder cancer, bile duct cancer, cholangiocarcinoma, cholangiocarcinoma, cholangiocarcinoma Cancer, pancreatic cancer, small intestine cancer, colon cancer, anal cancer, bladder cancer, kidney cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma and skin cancer.
The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. But is not limited thereto. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc., in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995). The pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, the composition can be administered by intravenous infusion, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration, mucosal administration, or topical administration.
The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on such factors as formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, route of administration, excretion rate, . The dosage of the pharmaceutical composition of the present invention may be 0.001-100 mg / kg (body weight), 0.01-80 mg / kg (body weight), and 0.1-60 mg / kg (body weight) per day on an adult basis. In addition, depending on the judgment of a doctor or a pharmacist, it may be administered once or several times a day at intervals of a certain time.
The pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy and biological response modifiers for the treatment of cancer.
Injection of anti-CD25 monoclonal antibody with ZnPC according to the present invention resulted in the entry of ZnPC into most regulatory T cells expressing CD25, and ZnPC in regulatory T cells infiltrated into the tumor by performing broad- Lt; RTI ID = 0.0 > T cells < / RTI > within the tumor.
FIG. 1 shows that the anti-CD25-ZnPC-liposome complex according to an embodiment of the present invention is formed through the attachment process of an antibody with ZnPC-liposome.
FIG. 2 shows a comparison of sizes of ZnPC-liposome before and after attachment of an antibody according to an embodiment of the present invention.
FIG. 3 shows that an anti-CD25-ZnPC-liposome complex according to an embodiment of the present invention is well adhered to the surface of cells expressing CD25 through flow cytometry analysis.
FIG. 4 is a fluorescence microscope image showing that the anti-CD25-DiI-liposome complex according to an embodiment of the present invention is well adhered to regulatory T cells expressing FoxP3-GFP fluorescence.
FIG. 5 shows the results of a flow cytometer analyzing the effect of laser irradiation on anti-CD25-ZnPC-liposome complex according to an embodiment of the present invention to induce destruction of regulatory T cells expressing CD25 by a photodynamic effect and cell suicide .
Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.
Example 1: Fabrication of ZnPC-liposome with anti-CD25 monoclonal antibody
In the preparation of ZnPC-liposomes, four types of lipids in Table 1 were used. Lipids dissolved in chloroform solvent at a concentration of 10 mg / ml were mixed at the indicated ratios (based on 1 μmole total lipid). At this time, 1 mg / ml ZnPC dissolved in chloroform was added. After the evaporation of the chloroform solvent, a lipid film was formed, which was hydrated with 1 ml of PBS buffer and passed through a film having a pore size of 100 nm. In the attachment of the anti-CD25 mAb, 40 μl of 0.25 M ethyl (dimethylaminopropyl) carbodiimide (EDC) and 0.25 M N-hydroxysuccinimide were added, based on 1 ml of the ZnPC- 40 μl of N-hydroxysulfosuccinimide (S-NHS) was added, and the mixture was reacted at room temperature for 15 minutes. This is to activate the carboxyl group (COOH) of the MPEG-DSPE-COOH lipid and later to attach to the amine group (NH2) of the anti-CD25 monoclonal antibody. Next, centrifugation was performed using an amicon filter (100K) to remove unreacted EDC and S-NHS. To the prepared ZnPC-liposome, 1/1000 of the antibody corresponding to 1/1000 of the phospholipid was added, followed by gentle mixing at room temperature for 2 to 8 hours (FIG. 1). As a result, the size of the liposome was significantly increased by about 20 nm on average, indicating that the antibody was effectively attached to the liposome (FIG. 2).
● HSPC: L-αphosphatidylcholine, hydrogenated
MPEG-DSPE: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy (polyethylene glycol) -2000]
DSPE-PEG (2000)
● ZnPC: Zinc phthalocyanine
Example 2: Regulation of anti-CD25 monoclonal antibody-ZnPC-liposome complexes Adherence to T cells was confirmed by flow cytometry
When FoxP3 (a transcription factor of regulatory T cells) was expressed, the spleen of transgenic mice was isolated to express GFP. The separated spleen was separated into single cells using a strainer. The cells were reacted in RBC lysis buffer for 5 minutes to remove red blood cells, and CD4 + T cells were separated using microbeads. When target cells are attached to fluorescence, target cells can be identified by flow cytometry. For this purpose, fluorescence is labeled on target cells. The target cell is firstly conjugated with an antibody with biotin attached thereto, and a second-order reaction of streptavidin-fluorochrome is carried out to measure the degree of fluorescence through biotin-streptavidin binding I can see whether or not.
The binding of anti-CD25-biotin-liposomes, isotype-biotin-liposomes and pure liposomes to the targeted cells of the prepared Example 1 can be confirmed by a flow cytometer. To this end, 2x10 5 CD4 + T cells and anti- The CD25 monoclonal antibody-liposome complex was reacted at 4 DEG C for 30 minutes to allow sufficient binding. Washed twice with PBS, and then reacted again with streptavidin-fluorescent dye at 4 ° C for 15 minutes. After all the reactions were completed, the cells were washed twice with PBS, and the antibody-liposome complex prepared using the flow cytometer was confirmed to bind well to the target cells (FIG. 1). As a result, it was confirmed by flow cytometry that the anti-CD25-biotin-liposome produced by the present inventor was effectively adhered to target cells effectively.
Example 3: Regulation of anti-CD25 monoclonal antibody-ZnPC-liposome complexes Adherence to T cells was confirmed by fluorescence microscopy
When FoxP3 (a transcription factor of regulatory T cells) was expressed, the spleen of transgenic mice was isolated to express GFP. The separated spleen was separated into single cells using a strainer. The cells were incubated in RBC lysis buffer for 5 minutes to remove red blood cells, and CD4 + T cells were separated using microbeads. When the target cells are labeled with fluorescence using fluorescence-labeled liposomes, target cells can be identified by fluorescence microscopy. For this purpose, the target cells are labeled with DiI-liposome fluorescence
The anti-CD25-DiI fluorescently labeled liposome, isotype-DIi fluorescently labeled liposome of the prepared Example 1 was confirmed by fluorescence microscopy to confirm that the liposome was well adhered to the target cells. 2x10 < 5 > CD4 + T cells and anti-CD25 monoclonal antibody-liposome complex were allowed to react for 30 minutes at 4 < 0 > C to allow sufficient binding. Washed twice with PBS and cells were attached to cover slides using a cytospin. Fluorescence microscopy was used to confirm whether the antibody liposome complex binds well to the target cells (FIG. 4). As a result, it was confirmed by fluorescence microscopy that the anti-CD25-DiI-liposome produced by the present inventor was efficiently and specifically attached to the target cell.
Example 4: Regulatory T cell removal through the effect of the photodynamic effect using the anti-CD25 monoclonal antibody-ZnPC-liposome complex
When FoxP3 (a transcription factor of regulatory T cells) was expressed, the spleen of transgenic mice was isolated to express GFP. The separated spleen was separated into single cells using a strainer. The cells were incubated in RBC lysis buffer for 5 minutes to remove red blood cells, and CD4 + T cells were separated using microbeads. Subsequently, only regulatory T cells expressing GFP were isolated using a cell separator. When an anti-CD25 monoclonal antibody-ZnPC-liposome complex is attached to a target cell and irradiated with a laser at a wavelength of 660 nm, it is possible to effectively remove regulatory cells expressing CD25, which is the most regulatory cell through a photodynamic effect.
The production example of the embodiment, wherein 1 -CD25-ZnPC- liposomes, wherein the liposomes are -CD25-ZnPC- to ensure that can selectively remove the targeted cells, 3x10 4 CD4 + FoxP3 + T cells and the anti -CD25 mAb- The ZnPC-liposome complex was reacted at 4 캜 for 30 minutes to allow sufficient binding. The cells were washed twice with PBS and incubated in a cell incubator for 10 minutes to confirm the photodynamic effect. The cells were then submerged into a single layer using a centrifuge at the bottom of the plate to which the laser was irradiated. Then, the laser of 660 nm wavelength was irradiated for 5 minutes. The extent of cell apoptosis and degree of cell destruction caused by the photodynamic effect after irradiation were analyzed by flow cytometry. In the cells where apoptosis occurred, phosphatidylserine was present on the surface, and the extent of apoptosis was measured using Annexin V, which specifically binds to phosphatidylserine. The degree of destruction of the cells was measured by using 7AAD to bind to DNA (FIG. 5). As a result, it can be seen that the anti-CD25-ZnPC-liposome produced by the inventor effectively destroys the target cells and induces apoptosis and cell destruction.
While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (13)
Wherein said lipid is hydrogenated phosphatidylcholine (HSPC) and DSPE-PEG carboxylic acid.
Ethyl (dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysulfosuccinimide (S-NHS) were added to the ZnPC-liposome to form a carboxyl group of the lipid Activating; And
Comprising the step of attaching an anti-CD25 antibody to the amine group of the antibody and the carboxyl group,
Wherein the lipid is a hydrogenated phosphatidylcholine and a DSPE-PEG carboxylic acid, and the anti-CD25 monoclonal antibody is conjugated with zinc-phthalocyanine (ZnPC) and lipid.
Wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, prostate cancer, melanoma, non-small cell lung cancer, renal cell cancer, metastatic melanoma, metastatic breast cancer, metastatic breast cancer and metastatic renal cell cancer Or a pharmaceutically acceptable salt thereof.
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| KR20220057883A (en) * | 2020-10-30 | 2022-05-09 | 전남대학교산학협력단 | Immunocyte-nanoliposome complex and method for producing the same |
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| US20120010558A1 (en) * | 2010-07-09 | 2012-01-12 | Services, National Institutes of Health | Photosensitizing antibody-fluorophore conjugates |
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| US20120010558A1 (en) * | 2010-07-09 | 2012-01-12 | Services, National Institutes of Health | Photosensitizing antibody-fluorophore conjugates |
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| KR20220057883A (en) * | 2020-10-30 | 2022-05-09 | 전남대학교산학협력단 | Immunocyte-nanoliposome complex and method for producing the same |
| KR102540728B1 (en) | 2020-10-30 | 2023-06-12 | 전남대학교산학협력단 | Immunocyte-nanoliposome complex and method for producing the same |
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