CN113527115A - Anti-oral tumor pH sensitive intelligent material and application thereof - Google Patents
Anti-oral tumor pH sensitive intelligent material and application thereof Download PDFInfo
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- CN113527115A CN113527115A CN202110798559.3A CN202110798559A CN113527115A CN 113527115 A CN113527115 A CN 113527115A CN 202110798559 A CN202110798559 A CN 202110798559A CN 113527115 A CN113527115 A CN 113527115A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/08—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of an acyclic unsaturated carbon skeleton
Abstract
The invention belongs to the technical field of oral tumor resistance, and discloses an oral tumor resistance pH sensitive intelligent material and an application thereof. The invention provides an application of an anti-oral tumor pH sensitive intelligent material in drugs for inhibiting growth of oral squamous cell carcinoma cells, inhibiting tumor growth caused by the oral squamous cell carcinoma cells and preventing or treating the oral squamous cell carcinoma. The anti-oral tumor pH sensitive intelligent material provided by the invention can inhibit the proliferation of tumor oral squamous cell carcinoma cells and promote the apoptosis of oral squamous cell carcinoma under the condition of biological safety concentration; and has pH sensitive property, and has enhanced effects of inhibiting proliferation and promoting apoptosis in acidic environment, i.e. pH 6.7. Animal experiments also prove that the material has anti-tumor performance.
Description
Technical Field
The invention belongs to the technical field of oral tumor resistance, and particularly relates to an oral tumor resistance pH sensitive intelligent material and application thereof.
Background
At present: oral tumors are one of ten common cancers, seriously affect the eating, chewing, speaking and beauty of patients, seriously affect the living quality of the patients and endanger the life. Wherein, the oral squamous cell carcinoma has the highest incidence rate, and more than 90 percent of oral malignant tumors are squamous cell carcinoma. In recent years, prevention and treatment of oral squamous cell carcinoma have been studied extensively. However, the recurrence rate is high, and the five-year survival rate is only about 60%. The treatment of oral squamous carcinoma is mainly multi-mode combined treatment, and is combined with chemoradiotherapy or biological agent comprehensive treatment by surgical excision. Tumor chemotherapy is an important combined treatment means and is widely applied to tumor prevention and treatment research, however, when the tumor load is too large or the tumor itself is not sensitive to the chemotherapeutic drugs and has tolerance, the efficacy of the chemotherapeutic drugs is limited; the chemotherapy drugs have large side effects on the whole body and low local effect, have certain requirements on the basic condition of the patient, and have poor tolerance to the chemotherapy drugs if the condition of the patient is poor and the functions of important organs such as heart, liver, kidney, lung and the like are incomplete. The chemotherapy effect is limited by the above reasons. In recent years, research and development of novel oral anticancer materials and drugs are receiving wide attention. According to the development and planning of the national biological industry of thirteen five, the research and development of novel anti-tumor materials, the exploration and the innovation of an accurate medical prevention and treatment mode become the important strategic direction of the national biological industry.
The tumor microenvironment is a place for the survival of tumor cells, the physicochemical properties of the microenvironment are different from the normal internal environment of a human body, and particularly, the low pH and the unbalanced pH of the tumor can promote the proliferation, survival and metastasis of the tumor cells, and are closely related to the development of the tumor. In normal internal environment, the intracellular pH is 7.05-7.2, and the extracellular pH is about 7.4, namely extracellular is greater than intracellular. Tumor cells produce large amounts of H + due to toxic waste products from their proliferation and high glycolysis. And a plurality of ion exchangers exist on the tumor cell membrane, such as V-ATPases, which can transport H + out of the cell to cause an extracellular acidic microenvironment with a trend of 'reverse' pH gradient, namely intracellular > extracellular, extracellular pH: 6.7-7.1, intracellular pH: is greater than 7.2. The acidic microenvironment is involved in the development of oral squamous cell carcinoma: high expression of the transmembrane protein CAIX associated with extracellular H + production and formation of an acidic microenvironment is associated with low prognosis in patients with oral squamous carcinoma and lymph node metastasis; the use of V-ATPases antagonists to prevent intracellular H + transfer to the outside of the cell can induce apoptosis and anti-tumor of oral squamous cell carcinoma cells. According to the low pH characteristic of a tumor microenvironment, the design of a pH-sensitive anti-oral squamous cell carcinoma intelligent material is a new breakthrough point.
Through the above analysis, the problems and defects of the prior art are as follows: the existing anti-oral tumor drugs have large systemic side effects and low local effect.
The difficulty in solving the above problems and defects is:
the existing chemotherapy drugs for resisting oral tumors have large systemic side effects and low local effect, and do not respond to specific microenvironment of tumors.
The significance of solving the problems and the defects is as follows: the invention can respond according to the acidic microenvironment of the oral tumor to kill the tumor material, thereby improving the local effect and reducing the pain of patients caused by systemic side effects.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an anti-oral tumor pH sensitive intelligent material and an application thereof.
The invention is realized by the following steps that the anti-oral tumor pH sensitive intelligent material is a tertiary ammonium monomer;
the tertiary ammonium monomer is methyl dodecyl aminoethyl methacrylate (DMAEM), and the molecular formula is C19H37NO2The specific preparation process comprises the following steps:
1-bromododecane (25 g, 100 mmol) was added to 80 mL of a 2-methylethanolamine (32 g, 500 mmol) in isopropanol and mixed well at room temperature. And continuously stirring the reaction solution at 85 ℃, refluxing for 8-10 hours, and cooling to room temperature. Then, diethyl ether was slowly poured in, and the reaction was diluted to 150 mL. The organic phase was collected after 3 repetitions of washing with deionized water (150 mL) and saturated sodium chloride solution (150 mL). Dried over anhydrous sodium sulfate and concentrated in vacuo to afford dimethylamino dodecyl alcohol (24 g, 99%) as a colorless oil. The resulting dimethylaminododecanol and 31.8mL of methyl methacrylate were mixed and stirred at room temperature. Catalyst CAA (0.4 mol%) and polymerization inhibitor p-hydroxyanisole (2 mol%) are added into the reaction system at the same time, and are uniformly mixed at room temperature. And (2) placing the reaction system at 100-110 ℃, continuously stirring during the reaction, supplementing a catalyst CAA (0.6 mol%) after the reaction is carried out for 12 hours, continuously stirring, recovering to the room temperature after the reaction is carried out for 12 hours, removing the solvent by a rotary evaporation method, and carrying out chromatography by a silica gel column chromatography method to obtain the methyl dodecyl amino ethyl methacrylate (DMAEM, 4.2g and 14%) as a yellow transparent oily substance.
Furthermore, the anti-oral tumor intelligent material has an obvious pH sensitivity characteristic.
The invention also aims to provide application of the pH sensitive intelligent material for resisting the oral tumor in preparing a medicament for inhibiting the growth of oral squamous cell carcinoma cells.
The invention also aims to provide application of the pH sensitive intelligent material for resisting the oral tumor in preparing a medicament for inhibiting tumor growth caused by oral squamous cell carcinoma cells.
The invention also aims to provide application of the pH sensitive intelligent material for resisting the oral tumor in preparing a medicament for preventing or treating oral squamous cell carcinoma.
Further, the application includes: the safe concentration of the pH sensitive intelligent material for resisting the oral tumor in the preparation of the medicines for inhibiting the growth of oral squamous cell carcinoma cells, inhibiting the growth of tumor caused by the oral squamous cell carcinoma cells and preventing or treating the oral squamous cell carcinoma is as follows: 40. mu.g/mL.
By combining all the technical schemes, the invention has the advantages and positive effects that: the invention can respond to the acidic microenvironment of oral squamous cell carcinoma to kill tumor, and has high local effect; the oral cavity normal cells (human oral cavity keratinized epithelial cells) have no obvious cytotoxicity in a neutral environment, and the biological safety is good; due to its local use, it has less side effect on the whole body.
The invention provides an anti-oral tumor pH sensitive intelligent material. The material of the invention can inhibit the proliferation of tumor oral squamous cell carcinoma cells and promote the apoptosis of the oral squamous cell carcinoma at the biological safe concentration; and has pH sensitive property, and under acidic environment (pH 6.7), the effects of inhibiting proliferation and promoting apoptosis are enhanced. Animal experiments also prove that the material has anti-tumor performance.
Drawings
FIG. 1 is a schematic diagram of biological safety detection of tertiary ammonium provided by the embodiment of the invention.
FIG. 2 is a schematic diagram of the detection of proliferation effect of tertiary ammonium on oral squamous cell carcinoma cells at different pH values according to the embodiment of the present invention.
Fig. 3 is a schematic diagram of detection of apoptosis of oral squamous cell carcinoma cells by tertiary ammonium at different pH according to an embodiment of the present invention.
Fig. 4 is a schematic diagram of the detection of the effect of tertiary ammonium on the growth of subcutaneous squamous carcinoma provided by the embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Aiming at the problems in the prior art, the invention provides an anti-oral tumor pH sensitive intelligent material and an application thereof, and the invention is described in detail with reference to the accompanying drawings.
The pH sensitive intelligent material for resisting the oral tumor provided by the embodiment of the invention is a tertiary ammonium monomer; the tertiary ammonium monomer provided by the embodiment of the invention is methyl dodecyl amino ethyl methacrylate (DMAEM).
The pH sensitive intelligent material for resisting the oral tumor provided by the embodiment of the invention has an obvious pH sensitive characteristic.
The safe concentration of the pH sensitive intelligent material for resisting oral tumor in preparing the medicine for inhibiting the growth of oral squamous cell carcinoma cells, inhibiting the growth of tumor caused by the oral squamous cell carcinoma cells and preventing or treating the oral squamous cell carcinoma provided by the embodiment of the invention is as follows: 40. mu.g/mL.
The technical solution of the present invention is further illustrated by the following specific examples.
Example 1:
the pH sensitive intelligent material used in the invention is a tertiary ammonium monomer, namely methyl dodecyl amino ethyl methacrylate (DMAEM).
Biological safety detection of mono-and tertiary-ammonium
The cells used in this section were Human Oral keratinocyte cells (HOK) cultured in DMEM high-sugar Medium (Dulbecco's modified Eagle Medium, gibco). The biosafety of the material was evaluated based on the effect of tertiary ammonium on the growth of HOK cells.
Inoculation of 1X10 in 96 well plates4HOK cells in 5% CO2Cell incubators were incubated overnight at 37 ℃. After the cells are attached to the wall, the original culture medium is aspirated, 100 mu L of fresh DMEM culture medium containing different concentrations of tertiary ammonium (0-100 mu g/mL) is added, and the cells are incubated in a cell culture box at 37 ℃. Each group of 6 multiple wells.
After 24 h, the cell proliferation toxicity assay was performed using the CCK8 kit (APExBIO). The specific operation steps are as follows: the original medium was aspirated, washed three times with PBS, 100. mu.L of DMEM medium containing 10% CCK8 reagent was added, and incubated at 37 ℃ in a cell incubator protected from light. After 1-2 h, absorbing the supernatant, transferring the supernatant to a new 96-well plate, and reading A under an enzyme-linked immunosorbent assay (ELIASA)450And calculating the cell viability relative to the Control group.
As a result, as shown in FIG. 1, the concentration of the tertiary amine was 40. mu.g/mL, which is safe.
Detection of proliferation effect of di-or tertiary-ammonium on oral squamous cell carcinoma cells
The part uses human tongue squamous carcinoma cell line Cal-27 cells, and the cells are cultured in a DMEM high-sugar medium.
Inoculation of 1X10 in 96 well plates4Cal-27 cells were incubated overnight in a cell incubator at 37 ℃. After the cells were attached to the wall, the original medium was aspirated off, and 100. mu.L of fresh medium containing different concentrations of tertiary ammonium was addedDMEM medium (0, 10, 30, 40. mu.g/mL) was incubated in a cell culture incubator, with the pH of the medium adjusted to 7.3 and 6.7, respectively. Each group of 6 multiple wells.
After 24 h, cell proliferation assay was performed using CCK8 kit. The specific operation steps are as follows: the original medium was aspirated, washed three times with PBS, 100. mu.L of DMEM medium containing 10% CCK8 reagent was added, and incubated at 37 ℃ in a cell incubator protected from light. After 1-2 h, absorbing the supernatant, transferring the supernatant to a new 96-well plate, and reading A under an enzyme-linked immunosorbent assay (ELIASA)450And calculating the cell viability relative to the Control group.
As shown in FIG. 2, the tertiary ammonium of 40. mu.g/mL had a slight effect of inhibiting proliferation of oral squamous cell carcinoma cells (P > 0.05) in a neutral (pH 7.3) environment; under the acidic (pH 6.7) environment, the tumor inhibition effect is obviously enhanced (P is less than 0.001), and the material has pH sensitivity in the tumor inhibition effect.
Detection of apoptosis effect of tertiary ammonium on oral squamous cell carcinoma
Inoculation of 3X10 in 16-well plates5Cal-27 cells were incubated overnight in a cell incubator at 37 ℃. After the cells were attached to the wall, the original medium was aspirated, 1.5 mL of fresh DMEM medium containing tertiary ammonium (0, 40. mu.g/mL) was added, the pH of the medium was adjusted to 7.3 and 6.7, respectively, and the cells were incubated in a cell incubator. Each group of 3 multiple wells.
After 24 h, apoptosis detection was performed using an apoptosis kit (Annexin V FITC/PI, dojindo). The specific operation steps are as follows:
(1) the cells in the supernatant and the bottom of the well plate were collected and adjusted to a cell concentration of 1X106The concentration is in 1xAnnexin V Binding Buffer.
(2) The cell suspension prepared in step (1) is aspirated and added to a new flow tube.
(3) Add 5. mu.L Annexin V FITC conjugate to the cell suspension, add 5. mu.L PI solution, incubate 15 min at room temperature in the dark.
(4) 400 μ L of 1xANnexin V Binding Buffer was added and assayed under a flow cytometer Millipore Guava.
The results are shown in fig. 3, and the tertiary ammonium of 40 mug/mL can promote the apoptosis of oral squamous cell carcinoma cells under the neutral environment; under the acidic environment, the apoptosis promoting effect of the material is enhanced, and the material has pH sensitivity in promoting the apoptosis of tumor cells.
Detection of in vivo growth effect of tertiary amine on subcutaneous oral squamous cell carcinoma
5-6 weeks female Balb/c nude mice, subcutaneously inoculated with 5x106Cal-27 cells were randomly divided into two groups of 4 cells each. One week later, subcutaneous nodules formed. 12.5 mg of tertiary amine monomer (dissolved in 50 uL PBS) was injected around the tumor, and an equal volume of PBS was injected into the control group three times a week. Mice were sacrificed on day 8 and day 16 of treatment, and tumor volumes were recorded.
The results are shown in fig. 4, on day 8, the tertiary ammonium slightly inhibited oral squamous carcinoma growth, but the difference was not statistically significant (P > 0.05); on day 16, the tertiary amine significantly inhibited the growth of oral squamous cell carcinoma, with the difference statistically significant (P < 0.01). It is suggested that tertiary amines can inhibit the growth of oral squamous cell carcinoma in vivo.
The above description is only for the purpose of illustrating the present invention and the appended claims are not to be construed as limiting the scope of the invention, which is intended to cover all modifications, equivalents and improvements that are within the spirit and scope of the invention as defined by the appended claims.
Claims (7)
1. An anti-oral tumor pH sensitive intelligent material is characterized in that the anti-oral tumor pH sensitive intelligent material is a tertiary ammonium monomer;
the tertiary ammonium monomer is methyl dodecyl aminoethyl methacrylate (DMAEM), and the molecular formula is C19H37NO2。
2. The use of the anti-oral tumor pH sensitive smart material of claim 1 in the preparation of a medicament for inhibiting the growth of oral squamous cell carcinoma cells.
3. The use according to claim 2, wherein the application-safe concentrations are: 40. mu.g/mL.
4. The use of the anti-oral tumor pH sensitive smart material of claim 1 in the preparation of a medicament for inhibiting tumor growth caused by oral squamous cell carcinoma cells.
5. The use according to claim 4, wherein the application-safe concentrations are: 40. mu.g/mL.
6. The use of the anti-oral tumor pH sensitive smart material of claim 1 in the preparation of a medicament for preventing or treating oral squamous cell carcinoma.
7. The use according to claim 6, wherein the use-safe concentrations are: 40. mu.g/mL.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113975281A (en) * | 2021-12-03 | 2022-01-28 | 四川大学 | Application of tertiary amine monomer in preparation of medicine for inhibiting helicobacter pylori in oral cavity and stomach |
| CN114159314A (en) * | 2021-12-08 | 2022-03-11 | 四川大学 | PH sensitive permeable resin intelligent material, preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2012127981A (en) * | 2010-12-10 | 2012-07-05 | Canon Inc | Developer carrier, process cartridge and electrophotographic apparatus |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2012127981A (en) * | 2010-12-10 | 2012-07-05 | Canon Inc | Developer carrier, process cartridge and electrophotographic apparatus |
Non-Patent Citations (2)
| Title |
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| ACS: "无", 《STN REGISTRY》 * |
| QINPING YANG等: "pH-Sensitive Polycations for siRNA Delivery: Effect of Asymmetric Structures of Tertiary Amine Groups", 《MACROMOL. BIOSCI.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113975281A (en) * | 2021-12-03 | 2022-01-28 | 四川大学 | Application of tertiary amine monomer in preparation of medicine for inhibiting helicobacter pylori in oral cavity and stomach |
| CN114159314A (en) * | 2021-12-08 | 2022-03-11 | 四川大学 | PH sensitive permeable resin intelligent material, preparation method and application |
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Application publication date: 20211022 |