CN110876803B - Pharmaceutical composition containing milk protein and oleic acid - Google Patents
Pharmaceutical composition containing milk protein and oleic acid Download PDFInfo
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- CN110876803B CN110876803B CN201911193771.6A CN201911193771A CN110876803B CN 110876803 B CN110876803 B CN 110876803B CN 201911193771 A CN201911193771 A CN 201911193771A CN 110876803 B CN110876803 B CN 110876803B
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- oleic acid
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- lactoferrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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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
Abstract
The invention belongs to the technical field of medicaments for treating colon cancer, and particularly relates to a pharmaceutical composition containing lactoprotein and oleic acid. The active protein and the unsaturated fatty acid in the pharmaceutical composition are both derived from food, have small toxic and side effects, can effectively inhibit the survival rate of colon cancer cells at multiple targets and multiple mechanisms, can play the activities of sensitization and attenuation when being applied in combination with the chemotherapeutic drug taxol, and the pharmaceutical composition containing two or three active ingredients can be used for treating and assisting in treating colon cancer clinically. The pharmaceutical composition comprises natural components of milk protein and oleic acid, and the milk protein and the oleic acid are stable in properties and rich in sources.
Description
Technical Field
The invention belongs to the technical field of medicaments for treating colon cancer, and particularly relates to a pharmaceutical composition containing lactoprotein and oleic acid.
Background
Colon cancer is a common malignant tumor of the digestive tract in the colon, mostly occurs at the junction of the rectum and the sigmoid colon, and has a polypoid, ulcer and the like in general morphology. Colon cancer can circulate along the intestinal wall, spread up and down along the longitudinal diameter of the intestinal canal or infiltrate deeply into the intestinal wall, can be planted in the abdominal cavity or spread and transferred along the suture line and the incision surface besides lymphatic vessel and blood flow transfer and local invasion, and belongs to a cancer species with higher malignancy degree (Klaver CE, et al.J.Nation.Comple.Can.Net.2017.; Weisburger JH, et al.Semin.Oncol.1991.).
At present, the colon cancer is clinically treated by a common method through an operation, but the method has the problems of large trauma, easy residual and relapse of cancer cells and the like. Therefore, the drug therapy is common, and the drug therapy mainly comprises chemotherapy drugs. The common colon cancer clinical chemotherapy drugs are in various types, and comprise fluorouracil, capecitabine, oxaliplatin, irinotecan, cetuximab, bevacizumab and the like. The medicines are mostly administrated by intravenous drip, and the disease deterioration can be controlled rapidly basically (Huabin, etc. Chinese medicine 2011; girl, etc. Chinese new medicine journal 2007). However, these chemotherapeutic agents have some drawbacks. First, these drugs have certain requirements on the constitution and immunity of the patient, and patients with weak constitution and low resistance are not recommended to use the therapy. In addition, chemotherapy drugs have large side effects, which may cause nausea, vomiting, inappetence and other gastrointestinal reactions of patients, and may cause rare and serious symptoms such as ketonuria, heart disease, liver disease, renal failure and the like (Dingshou, China general Ex. J.Clin 2016; Song Xiujin. J.Utility and technology 2006); secondly, the chemotherapy drug lacks certain selectivity on normal cells and cancer cells, has the defects of 'enemy and my friend', 'drinking 40489and thirst' and the like, and generates serious toxic and side effects on patients. For example, the content of leukocytes and platelets in chemotherapy intermediates of most patients is seriously reduced, infection and bleeding are caused, and even life is endangered (Wanglian et al, J. China tumor prevention and treatment, 1999; Wangze. asking for medical questions, 2012; Belgium et al, J. clinical rational medicine, 2018); finally, chemotherapy drugs cannot transform the living environment of cancer foci, so that the problem of temporary solution and permanent solution exists, the long-term treatment effect is poor, and the patients are difficult to be helped to recover thoroughly.
Because colon cancer onset involves each link of human metabolism, the onset causes are widely described as < 32429and the action targets are rich, the optimal therapeutic drug is difficult to be regulated by a single mechanism and a single method.
Disclosure of Invention
In order to improve the technical problems, the invention firstly provides a pharmaceutical composition which comprises milk protein and oleic acid or pharmaceutically acceptable salts and polymorphs thereof.
According to an embodiment of the invention, the milk protein is selected from one or more of alpha-lactalbumin, alpha-casein, beta-casein, kappa-casein, lactoferrin, and beta-lactoglobulin, preferably lactoferrin.
According to an embodiment of the invention, the mass ratio of milk protein to oleic acid or a pharmaceutically acceptable salt, polymorph thereof in the pharmaceutical composition is 10: 1.
according to an embodiment of the invention, the pharmaceutical composition further comprises other anticancer active ingredients, such as paclitaxel.
According to an embodiment of the present invention, when the pharmaceutical composition further includes paclitaxel, the mass ratio of milk protein, oleic acid and paclitaxel in the pharmaceutical composition is 10: 1: (0.1 to 0.5), for example, 10: 1: 0.2.
according to an embodiment of the invention, the pharmaceutical composition is for the treatment of colon cancer, e.g. inhibition of HT29 cells.
The invention also provides application of the pharmaceutical composition in preparing a medicine for treating colon cancer.
According to an embodiment of the invention, the medicament is an oral formulation, e.g. various dosage forms including oral administration.
According to an embodiment of the invention, the medicament is an injection.
According to an embodiment of the present invention, the injection is an intravenous injection, an intraperitoneal injection, or a subcutaneous injection.
The present invention also provides a method of treating colon cancer comprising administering to an individual in need thereof the above-described pharmaceutical composition.
Advantageous effects
The invention provides a pharmaceutical composition (milk protein combined with oleic acid, in a mass ratio of 10:1) for treating colon cancer, wherein active protein and unsaturated fatty acid in the pharmaceutical composition are both derived from food, have small toxic and side effects, can effectively inhibit the survival rate of colon cancer cells at multiple targets and multiple mechanisms, can play the roles of sensitization and attenuation when being applied in combination with a chemotherapeutic drug taxol, and the pharmaceutical composition containing two or three active ingredients can be used for treating and assisting in treating colon cancer clinically.
The pharmaceutical composition comprises natural components of milk protein and oleic acid, and the milk protein and the oleic acid are stable in properties and rich in sources.
Drawings
FIG. 1 shows the results of the control group, lactoferrin and oleic acid at various concentrations, in example 1 of the present invention, on the survival rate of colon cancer cells (HT 29).
FIG. 2 shows the results of the examination of the effects of the control group, lactoferrin and oleic acid in combination at different mass ratios on the survival rate of colon cancer cells (HT29) in example 1 of the present invention.
FIG. 3 shows the results of the measurement of the effect of the control group, lactoferrin, oleic acid, lactoferrin combined with oleic acid group (10:1 mass ratio) on the growth of colon-loaded tumor (HT29) in nude mice in example 2 of the present invention.
FIG. 4 shows the effect of paclitaxel, the combination of lactoferrin and oleic acid (10:1 by mass), and the combination of lactoferrin and oleic acid (10:1 by mass) with the chemotherapeutic drug paclitaxel on the growth of a colon-bearing tumor (HT29) in nude mice in example 3.
FIG. 5 shows the attenuation of liver and kidney tissues in nude mice by paclitaxel, lactoferrin and oleic acid combined group (10:1 mass ratio), lactoferrin and oleic acid (10:1 mass ratio) in combination with paclitaxel in example 3.
Detailed Description
Lactoferrin used in the following examples consisted of a single polypeptide chain and multiple polysaccharide side chains, with a molecular weight of 80 kDa. Oleic acid of formula C18H34O2And the molecular weight is 282.47. The structural formulas of the two are as follows:
in the application of the invention, the treatment of colon cancer refers to inhibition of occurrence and development of colon cancer.
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1 Effect of inhibiting Colon cancer cell survival
In order to verify that the mass ratio of the invention is 10:1 and the influence of the pharmaceutical composition of lactoferrin and oleic acid and other pharmaceutical compositions in mass ratio on the survival of colon cancer cells HT29, the following in vitro experiments were carried out.
HT29 cells were seeded in 96-well culture dishes (10)5100mL of culture medium per well), after 24h of culture, cells were treated with lactoferrin and oleic acid at concentrations of 10mg/L, 50mg/L, 100mg/L, 500mg/L and 1g/L, respectively [ each experiment was given the same volume (10. mu.L) of lactoferrin or oleic acid]In addition, a control group is set, namely, the drug is not added and acts for 24 hours. Then, the culture medium is discarded, MTT (final concentration is 5g/L) is added for acting for 4 hours, and an enzyme-labeling instrument detects the absorbance (OD) value and calculates the cell survival rate.
In addition, a combined administration group is also provided, and the combined administration group is set as follows: combining 200mg/L dose of lactoferrin with 10mg/L dose of oleic acid (mass ratio is 20:1), combining 100mg/L dose of lactoferrin with 10mg/L dose of oleic acid (mass ratio is 10:1), combining 100mg/L dose of lactoferrin with 100mg/L dose of oleic acid (mass ratio is 1:1), combining 10mg/L dose of lactoferrin with 100mg/L dose of oleic acid (mass ratio is 1:10), combining 10mg/L dose of lactoferrin with 200mg/L dose of oleic acid (mass ratio is 1:20), and setting a control group, namely not adding any medicament. Each group was dosed with the same volume of drug (20 microliters total per group, i.e., 10 microliters of each drug in the combination group) for 24 hours. Then, the culture medium is discarded, MTT (final concentration is 5g/L) is added for acting for 4 hours, and an enzyme-labeling instrument detects the absorbance (OD) value and calculates the cell survival rate.
The results of the experiments with lactoferrin or oleic acid alone are shown in figure 1.
The results of the combined administration of lactoferrin and oleic acid are shown in FIG. 2.
As shown in FIG. 1, after the lactoferrin in a dose of 100mg/L-1g/L and the oleic acid in a dose of 10mg/L-1g/L respectively act on the colon cancer HT29 cells for 24 hours, the cell survival rate is reduced (compared with a control group, P is less than 0.05, and the statistical difference is significant).
As shown in FIG. 2, the cell survival rate of the group with 100mg/L lactoferrin combined with 10mg/L oleic acid was 55.4. + -. 3.6% and the inhibitory effect on HT29 cells was the strongest (compared with the control group, P < 0.05, with a significant statistical difference) compared to the other combined group. The cell survival rate of the lactoferrin of the 10mg/L dose and the oleic acid of the 200mg/L dose is 61.7 +/-5.9% (compared with the control group, P is less than 0.05, and has a significant statistical difference), and the cell survival rate of the lactoferrin of the 10mg/L dose and the oleic acid of the 100mg/L dose is 66.9 +/-4.2% (compared with the control group, P is less than 0.05, and has a significant statistical difference). The combined administration group has better inhibition effect than the lactoferrin or oleic acid single action group under the same dosage (compared with the single action group, P is less than 0.05, and the statistical difference is significant). The symbol in figures 1 and 2 indicates a significant statistical difference with P < 0.05 compared to the level of the control without any treatment.
EXAMPLE 2 Lactoferrin and oleic acid pharmaceutical compositions inhibit the growth of HT 29-bearing tumors in nude mice
To verify that the mass ratio of the present application is 10:1 and the pharmaceutical composition with other mass ratios can inhibit the growth of HT29 tumor in vivo, and the following groups are set for verification: untreated controls (i.e., no drug added), lactoferrin at a 50mg/kg dose, oleic acid at a 5mg/kg dose, lactoferrin at a 50mg/kg dose in combination with oleic acid at a 5mg/kg dose.
The detection process is as follows: HT29 cells were cultured in 16 10cm dishes on a large scale until the cell density reached about 90%, and the cells were collected and injected subcutaneously into the right axilla of 16 BALB/C nude mice. After about two weeks, the tumor volume reached 90-100mm3Mice were divided into 4 groups of 4 mice each. Orally irrigating 50mg/kg of lactoferrin, 5mg/kg of oleic acid and 50mg/kg of lactoferrin in combination with 5mg/kg of oleic acid to mice respectively, and performing intragastric administration every dayOnce for 28 consecutive days. On day 29, after sacrifice, the tumor was dissected out, photographed and weighed.
As shown in FIG. 3, it can be seen from FIG. 3 that the HT29 tumor-inhibiting effects are achieved by using 50mg/kg lactoferrin, 5mg/kg oleic acid, 50mg/kg lactoferrin in combination with 5mg/kg oleic acid. And the combined action group has obviously better inhibition effect than the lactoferrin or oleic acid single action group. The symbol in figure 3 indicates a significant statistical difference with P < 0.05 compared to the level of the control without any treatment; symbol # indicates that there was a significant statistical difference with the combined effect group ratio, P < 0.05.
The results show that the effect of inhibiting the growth of colon cancer tumors by combining lactoferrin at a dose of 50mg/kg and oleic acid at a dose of 5mg/kg is obviously better than that of lactoferrin at a dose of 50mg/kg and that of lactoferrin at a dose of 5mg/kg in a single administration group.
Example 3 the Effect of lactoferrin and oleic acid in combination with the chemotherapeutic agent paclitaxel in inhibiting the growth of HT29 tumor in nude mice and reducing the toxicity of paclitaxel
In order to verify the effects of lactoferrin and oleic acid in combination with the chemotherapeutic drug paclitaxel in inhibiting the growth of HT29 tumor and reducing the toxicity of paclitaxel, an in vivo experiment of mice was performed. The following dosing groups were set up separately: nude mice were tested for tumor growth by HT29 tumor load in untreated controls (i.e., no drug added), paclitaxel at a 1mg/kg dose, lactoferrin at a 50mg/kg dose in combination with oleic acid at a 5mg/kg dose, lactoferrin at a 50mg/kg dose, and oleic acid at a 5mg/kg dose in combination with paclitaxel at a 1mg/kg dose.
HT29 cells were cultured in 16 10cm dishes on a large scale until the cell density reached about 90%, and the cells were collected and injected subcutaneously into the right axilla of 16 BALB/C nude mice. After about two weeks, the tumor volume reached 90-100mm3Mice were divided into 4 groups of 4 mice each. The lactoferrin group and the oleic acid group were orally administered to the mice once a day for 28 consecutive days, and were intraperitoneally injected to the mice at a dose of 1mg/kg of paclitaxel once a day for 28 consecutive days. On day 29, after sacrifice, the tumor was dissected out, photographed and weighed.
The experimental results are shown in fig. 4, and it can be seen from fig. 4 that paclitaxel, lactoferrin combined with oleic acid, and the combined group of the three have inhibitory effect on HT29 tumor (P is less than 0.05 compared with the control group). And the combined action group of the three groups has obviously better inhibition effect than the other two groups (P is less than 0.05).
In addition, the mice are subjected to hematoxylin-eosin staining on pathological sections of liver and kidney tissues so as to observe the damage degree of the liver and the kidney of the nude mice. FIG. 5 shows the results of pathological staining of liver and kidney tissues of mice in different treatment groups. Symbol denotes the level ratio with respect to the control without any treatment, P < 0.05, with significant statistical differences; the symbol # represents the combined action group ratio of the three components, P is less than 0.05, and the statistical difference is significant. Pathological conditions of the liver and the kidney of the mouse are observed through a staining result, and the damage degree of the liver and the kidney in a combined group of the three is found to be obviously lighter than that of taxol, which is mainly shown in the aspects of less deformed cells, reduction of tissue bleeding points, reduction of edema degree and the like.
The results show that when the lactoferrin and the oleic acid are combined with the taxol, the effect of inhibiting the growth of the colon cancer tumor is optimal, and the damage of the chemotherapeutic drugs to the liver and the kidney can be relieved.
In conclusion, when the lactoferrin and the oleic acid are combined in the mass ratio of 10:1, the survival of the colon cancer HT29 cells and the growth of colon cancer tumors can be effectively inhibited. Moreover, the effect of the lactoferrin combined with the oleic acid group is remarkably stronger than that of the lactoferrin or oleic acid group alone. In addition, when the lactoferrin and the oleic acid are administrated in combination with the paclitaxel, the activity of inhibiting colon cancer HT29 cells is optimal, and the liver and kidney injuries caused by the paclitaxel can be remarkably relieved, so that the synergistic and attenuation effects of the three in combination administration are shown. Thus, the combination of lactoferrin and oleic acid, and the combination of lactoferrin and oleic acid with paclitaxel of the present application can be used as a safe and effective treatment regimen for colon cancer.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. A pharmaceutical composition, wherein the active ingredients of said pharmaceutical composition consist of lactoferrin and oleic acid; the mass ratio of the lactoferrin to the oleic acid is 10: 1.
2. A pharmaceutical composition, wherein the active ingredients of said pharmaceutical composition consist of lactoferrin, oleic acid and paclitaxel; the mass ratio of the lactoferrin to the oleic acid is 10: 1.
3. The pharmaceutical composition of claim 2, wherein the weight ratio of lactoferrin to oleic acid to paclitaxel in the pharmaceutical composition is 10: 1: (0.1-0.5).
4. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical composition is for the treatment of colon cancer.
5. Use of a pharmaceutical composition according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of colon cancer.
6. The use according to claim 5, wherein the medicament is an oral formulation or an injection.
7. The use according to claim 6, wherein the injection is an intravenous, intraperitoneal or subcutaneous injection.
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| CN103372202B (en) * | 2012-07-23 | 2015-09-16 | 任发政 | A kind of composition and method of making the same and application containing lactoprotein and fatty acid |
| CN110478475A (en) * | 2019-06-11 | 2019-11-22 | 中国农业大学 | Application of the lactoalbumin-oleic acid compound in the drug that preparation inhibits tumour cell energetic supersession |
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