CN109528688A - Novel heatproof nano medicament carrying system - Google Patents
Novel heatproof nano medicament carrying system Download PDFInfo
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- CN109528688A CN109528688A CN201811582584.2A CN201811582584A CN109528688A CN 109528688 A CN109528688 A CN 109528688A CN 201811582584 A CN201811582584 A CN 201811582584A CN 109528688 A CN109528688 A CN 109528688A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5176—Compounds of unknown constitution, e.g. material from plants or animals
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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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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Abstract
The invention belongs to nano drug-carrying fields, and in particular to a kind of novel heatproof nano medicament carrying system, the lipid microbubble including deriving from milk.A kind of heatproof nano medicament carrying system of the invention, using be originated from raising in milk cow in lactation period milk extract size 150nm or so lipid microbubble as carrier, combine the chemotherapeutic being wrapped in the lipid microbubble, so that chemotherapeutics is more acted on tumour cell, while reducing chemotherapeutics to the toxic side effect of body.
Description
Technical field
The invention belongs to nano drug-carrying fields, and in particular to a kind of novel heatproof nano medicament carrying system.
Background technique
Nano medicament carrying system is due to EPR effect, can be improved tumor-targeting, enhancing chemotherapeutical medicine curative effect and reducing
Toxic side effect and be widely used in oncotherapy.It has been reported that chemotherapeutics can be carried out package carry out target administration nanometer
Material includes: polyethylene glycol-cephalin copolymer (PEG-PE), poly- lactic aldehyde ethanol copolymer (PLGA) etc., and having proven to can be with
For wrapping up chemotherapeutics, and chemotherapeutics can be transported to tumor locus, improve chemotherapeutics and tumour cell is killed
Wound effect.Anti-tumor nano drug-loading system need to pass through internal multiple physiological barrier when reaching target area by intravenous injection, be prominent
Break these physiologic barriers, ideal nano medicament carrying system must have long circulating in blood, tumor locus be effectively enriched with, tumour deep
It penetrates, effectively absorbed by tumour cell and ability etc. of responsiveness intracellular release drug.Since nano material is exogenous material,
To living organism, there are certain toxic side effects for itself, while the grain size specification of the nano material of clinical use also leads to the material
Expect the chemotherapeutics carried to the toxic side effect of body.Although there is many strategies to be used to improve Nano medication antineoplaston at present
Effect, but these strategies are not able to satisfy all conditions mostly to overcome intracorporal multiple physiological barrier.In addition, many nanometer materials
The production of material and technique require height, and cost is big, is unfavorable for clinical application.
The nano material of biological source can overcome traditional nano materials as drug-loading system as drug-loading system
It is insufficient.Existing research confirms that the vesica that biofilm structure is formed can conduct drugs to organism lesions position as carrier, and
And there is targeting.It is unstable in vitro since the vesica partial size of cell origin is larger (400-1000nm), and to heat intolerant to
By；Meanwhile some use the vesica in tumour cell source as pharmaceutical carrier, there is the wind that tumour is formed to induction in organism
Danger；The vesica of cell origin is more demanding in preparation, and cost is big, once can not largely obtain.
Therefore, how to find it is a kind of can largely obtain, and there is high-temperature stability, while also biologically active nanometer
Carrier, it has also become urgent need to solve the problem in therapeutic treatment.
Summary of the invention
The purpose of the present invention is to provide a kind of novel heatproof nano medicament carrying systems.
The present invention to achieve the above object, using following technical scheme:
A kind of novel heatproof nano medicament carrying system, the lipid microbubble including deriving from milk.
The average grain diameter of the lipid microbubble is 150nm, and particle size range is 100-200nm.
The milk colostrum or the milk of other different lactations secretion.
The lipid microbubble can use following step to prepare: by the milk with the centrifugal force of 13000-20000g
Centrifuge separation removal fat globule, casein and fragment, take supernatant with centrifugal force 0.5-2 hours of 20000g, collection obtains
The precipitating obtained is lipid microbubble.
The lipid microbubble can also be prepared using following step: use membrane filtration, filter sizes are 10 microns；It will
For the supernatant obtained after filtering with centrifugal force 0.5-2 hours of 20000g, the precipitating for collecting acquisition was lipid microbubble.
Centrifuge separation condition is room temperature or 0-10 degree cryogenic conditions.Room temperature refers to 30 degree or less.
Within thermo-chemotherapy 6 hours of lipid microbubble tolerance no more than 42 degree.
It further include medicine；The lipid microbubble and chemotherapeutic is incubated for 0.5-2 hours in mixed at room temperature.
It can be applied to treatment oophoroma, lung cancer, gastric cancer, colon cancer, liver cancer, bladder cancer or the carcinoma of the rectum.
Compared with prior art, the beneficial effects of the present invention are:
1, a kind of heatproof nano medicament carrying system of the invention, to be originated from the ruler that milk of the raising in milk cow in lactation period extracts
The very little lipid microbubble in 150nm or so is carrier, combines the chemotherapeutic being wrapped in the lipid microbubble, keeps chemotherapeutics more
Effect tumour cell, while reducing chemotherapeutics to the toxic side effect of body.
2, when lipid microbubble vector administration of the invention is to tumour cell, more tumour cells can be targeted, simultaneously because
Its lesser nano-scale can improve the chemotherapeutics as effective component in the release of tumour, enhance tumour cell to package
The intake of chemotherapeutic can reduce dosage in the treatment, almost can be with while reducing chemotherapeutic to the injury of human body
Avoid harm of the foreign carrier to body.
3, milk is very easy to, and extracting method is mature, and the scheme recorded according to the present invention can be obtained from milk
A large amount of lipid microbubble is used to prepare pharmaceutical preparation of the invention, and cost is very small, easy to operate.
Detailed description of the invention
Fig. 1 is the SEM figure for the lipid microbubble that milk extracts.
Fig. 2 is the phenogram of lipid microbubble of the invention, including particle diameter distribution and surface potential.
Fig. 3 is the characterization of lipid microbubble of the invention different time under the conditions of 42 degree, including partial size and surface potential.
Fig. 4 shows the figure after the lipid microbubble observed under Electronic Speculum is incubated for 6 hours under the conditions of 42 degree.
Heatproof nano medicament carrying system Fig. 5 of the invention has lethal effect to tumour cell.
Heatproof nano medicament carrying system Fig. 6 of the invention inhibits tumour growth, extends the time-to-live of tumor-bearing mice.
The toxic side effect of heatproof nano medicament carrying system Fig. 7 of the invention to body.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, with reference to the accompanying drawing and most
The present invention is described in further detail for good embodiment.
Milk used in the embodiment, tumour cell, drug and experimental animal: H22 murine hepatocarcinoma cell system
It is bought from ATCC company, the U.S. or Chinese Typical Representative object collection CCTCC.BALB/C mice is purchased from Wuhan University's medical experiment
Animal center, week old was at 5-6 weeks, 18 grams of weight；The fresh colostrum that milk is produced from the milk cow that pasture is raised.
Embodiment 1: the preparation of lipid microbubble in milk: milk is dispensed into centrifuge tube, by the way that above-mentioned rouge is collected by centrifugation
Matter microvesicle, comprising: first with the centrifugal force of 13000g, under conditions of 4 degree, be centrifuged 30 minutes, remove fat globule, casein and broken
The supernatant of acquisition is centrifuged 1 hour by piece in 20000g, and the precipitating for collecting acquisition is lipid microbubble.
Embodiment 2: the preparation of lipid microbubble in milk: milk polypropylene filter is filtered, and filter sizes are 10 microns.It will
For the supernatant obtained after filtering with centrifugal force 1 hour of 20000g, the precipitating for collecting acquisition was lipid microbubble.It is centrifuged item
Part can be between 0.5-2 hours, and obtained lipid microbubble is substantially similar.
The lipid microbubble effect that embodiment 1-2 is prepared is similar, effect explanation:
1, it is observed under transmission electron microscope after the lipid microbubble being collected into being resuspended with 0.9% (g/ml) physiological saline, from Fig. 1
As can be seen that the particle size range of lipid microbubble is in 150 rans, and uniformity is higher, at blister.
2, after the lipid microbubble being collected into being resuspended with 0.9% (g/ml) physiological saline, the lipid microbubble after resuspension is existed
It is observed under transmission electron microscope again after being incubated for 6 hours in 42 DEG C of water-baths.From fig. 4, it can be seen that the particle size range of lipid microbubble is 150
Ran, and uniformity is higher, at blister.Confirm the lipid microbubble of milk extraction of the invention 6 hours under 42 DEG C of environment
Afterwards, the biological structure of lipid microbubble is not destroyed, and also there is no aggregations.Suitable for clinical thermo-chemotherapy
3, by the lipid microbubble being collected into 0.9% (g/ml) physiological saline be resuspended after with laser particle analyzer detect granularity and
Current potential., from figure 2 it can be seen that 150 ran of partial size average grain diameter for the lipid microbubble that milk extracts, and partial size point
Cloth is very narrow, illustrates material than more uniform (Fig. 2A)；Surface potential is at -10mV (Fig. 2 B).
4, the lipid microbubble being collected into is incubated for 1,2 in 42 DEG C of water-baths after being resuspended with 0.9% (g/ml) physiological saline respectively,
4,6 hours.The granularity and current potential of lipid microbubble after detecting different incubation times with laser particle analyzer.The results show that milk extracts
Lipid microbubble in 42 DEG C of environment, into the incubation for crossing different time, partial size (Fig. 3 A, 3C, 3E, 3G) and current potential (Fig. 3 B,
3D, 3F, 3H) do not significantly change, and its particle diameter distribution is relatively narrow, illustrating lipid microbubble, there is no groups in an environment of high temperature
It is poly-.It confirms that the lipid microbubble of milk extraction of the invention is resistant to 42 DEG C of temperature, is applicable in clinical thermo-chemotherapy.
Embodiment 3: heatproof nano medicament carrying system has lethal effect to tumour cell.
1, experimental material and reagent: H22 murine hepatocarcinoma cell system, chemotherapeutic adriamycin is commercially available, and milk is commercially available.
2, experimental procedure:
1) preparation of lipid microbubble.The preparation method is the same as that of Example 1.
2) lipid microbubble of preparation and Doxorubicin solution (1mg/ml) are incubated for 1 hour at room temperature, then
20000g is centrifuged 1 hour, and precipitating is to wrap up the load medicine lipid microbubble of adriamycin.
3) H22 tumor cells of hepatocellular carcinoma is cultivated in RPMI medium1640 cell culture fluid, by tumour cell kind in 96 holes
Plate kind, 1 × 104A/hole.
By the load medicine lipid microbubble of acquisition with the equivalent of adriamycin, respectively with the amount and tumour of 0.5,2,4ug/ml adriamycin
Cell incubation is incubated for 24 hours, as experimental group；The tumour cell of free adriamycin will be added as a control group.After 24 hours
The survival condition of cell is observed by MTT.
3, experimental result: as shown in Figure 5, load medicine lipid microbubble of the invention has lethal effect to tumour cell.With chemotherapy
The control group of drug direct killing tumour cell is compared, and the apoptosis rate for carrying the experimental group tumour cell of medicine lipid microbubble is higher, is said
Bright load medicine lipid microbubble of the invention can kill more tumour cells.
Embodiment 4: heatproof nano medicament carrying system of the invention inhibits tumour growth, extends the time-to-live of tumor-bearing mice.
1, experimental material and reagent: for the H22 murine hepatocarcinoma cell used with embodiment 3, chemotherapeutic adriamycin is commercially available,
Milk be it is commercially available, BALB/C mice be purchased from Wuhan University's medical faunae center.
2, experimental procedure:
1) preparation of lipid microbubble.The preparation method is the same as that of Example 1.
2) preparation of medicine lipid microbubble is carried with embodiment 3.
3) H22 tumor cells of hepatocellular carcinoma is cultivated in RPMI medium1640 cell culture fluid.
4) foundation of rat liver cancer H22 Ascites Model: 1 × 10 is taken from the cell of above-mentioned culture5H22 murine hepatocarcinoma cell
Intraperitoneal inoculation co-injection mouse 56, obtains the BALB/C mice for suffering from H22 liver cancer cells ascites to BALB/C mice, random to divide
It is equal number of 4 groups.
5) by the lipid microbubble of prepared package chemotherapeutic with the dosage of 4mg (adriamycin equivalent)/kg, 200 μ l
BALB/C mice is injected intraperitoneally as experimental group in dosage respectively, by lipid microbubble with 25mg albumen/kg dosage, 200 μ l
Dosage distinguishes abdominal vein injection BALB/C mice as a control group 1；Identical dose is injected respectively to other BALB/C mice simultaneously
The physiological saline of the adriamycin of amount and 0.9% (g/ml), respectively as control group 2,3.Once a day, from continuous 7 days, the 8th day
Normal raising.
3, the BALB/C mice in experimental group and control group all experimental result: is divided into equal number of two groups, in experimental group
First group of BALB/C mice and control group in first group of BALB/C mice respectively at the 10th day put to death, measure ascites volume (Fig. 6
In 6A), the in experimental group, second group of BALB/C mice is respectively used to observation survival in two groups of BALB/C mices and control group
Time.The result shows that load medicine lipid microbubble significantly inhibits the liver cancer cells of BALB/C mice in experimental group compared to control group
Growth, and extend the time-to-live (6B in Fig. 6) of BALB/C mice.
Embodiment 7: the micro- toxic side effect to body of chemotherapeutic is wrapped up.
1, experimental material and reagent: the H22 murine hepatocarcinoma cell used is quotient with embodiment 1, chemotherapeutic adriamycin, milk
Purchase, BALB/C mice are purchased from Wuhan University's medical faunae center.
2, experimental procedure:
1) preparation of lipid microbubble.The preparation method is the same as that of Example 1.
2) preparation of medicine lipid microbubble is carried with embodiment 3.
3) H22 tumor cells of hepatocellular carcinoma is cultivated in RPMI medium1640 cell culture fluid.
4) foundation of rat liver cancer H22 Ascites Model: with embodiment 4.
5) BALB/C mice for suffering from H22 liver cancer cells ascites will be obtained, is randomly divided into equal number of 4 groups.It will be prepared
BALB/ is injected intraperitoneally with the dosage of the dosage of 4mg (adriamycin equivalent)/kg, 200 μ l in the lipid microbubble of package chemotherapeutic respectively
C mice is as experimental group, by lipid microbubble with the dosage difference abdominal vein injection of 25mg albumen/kg dosage, 200 μ l
BALB/C mice as a control group 1；Inject the adriamycin and 0.9% (g/ of same dose respectively to other BALB/C mice simultaneously
Ml physiological saline), respectively as control group 2,3.Once a day, normal raising from continuous 7 days, the 8th day.
6) the 10th day, respectively to experimental group, control group mice extracting vein blood was detected in serum about heart, kidney and liver
Dirty toxicity index.
3, experimental result: as seen from Figure 7, compared to control group mice, the lipid microbubble group of injection package chemotherapeutic
All xicity related indexs of mouse will be substantially less than control group.As it can be seen that wrapping up chemotherapy with the lipid microbubble that milk extracts
The pharmaceutical preparation that medicine obtains is to body substantially without toxic side effect.
The above is only a preferred embodiment of the present invention, for those of ordinary skill in the art, according to the present invention
Thought, there will be changes in the specific implementation manner and application range, and the content of the present specification should not be construed as to the present invention
Limitation.
Claims (9)
1. a kind of novel heatproof nano medicament carrying system, which is characterized in that the lipid microbubble including deriving from milk.
2. novel heatproof nano medicament carrying system according to claim 1, which is characterized in that the lipid microbubble is averaged
Partial size is 150nm.
3. novel heatproof nano medicament carrying system according to claim 1, which is characterized in that the milk colostrum or
The milk of other different lactations secretion.
4. novel heatproof nano medicament carrying system according to claim 1, which is characterized in that under the lipid microbubble uses
It states step preparation: the milk is separated with the centrifugal force of 13000-20000g except fat globule, casein and fragment,
Take supernatant with centrifugal force 0.5-2 hours of 20000g, the precipitating for collecting acquisition is lipid microbubble.
5. novel heatproof nano medicament carrying system according to claim 1, which is characterized in that under the lipid microbubble uses
State step preparation: using membrane filtration, filter sizes are 10 microns；By the supernatant obtained after filtering with the centrifugal force of 20000g
Centrifugation 0.5-2 hours, the precipitating for collecting acquisition is lipid microbubble.
6. according to novel heatproof nano medicament carrying system described in claim 4-5, which is characterized in that centrifuge separation condition is room temperature
Or 0-10 degree cryogenic conditions.
7. novel heatproof nano medicament carrying system according to claim 1, which is characterized in that the lipid microbubble tolerance is not
Within thermo-chemotherapy 6 hours more than 42 degree.
8. novel heatproof nano medicament carrying system according to claim 1, which is characterized in that further include medicine；Described
Lipid microbubble and chemotherapeutic are incubated for 0.5-2 hours in mixed at room temperature.
9. novel heatproof nano medicament carrying system according to claim 8, which is characterized in that can be applied to treatment ovary
Cancer, lung cancer, gastric cancer, colon cancer, liver cancer, bladder cancer or the carcinoma of the rectum.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| WO2018102397A1 (en) * | 2016-11-29 | 2018-06-07 | PureTech Health LLC | Exosomes for delivery of therapeutic agents |
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- 2018-12-24 CN CN201811582584.2A patent/CN109528688A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018102397A1 (en) * | 2016-11-29 | 2018-06-07 | PureTech Health LLC | Exosomes for delivery of therapeutic agents |
| CN107375944A (en) * | 2017-08-02 | 2017-11-24 | 上海市皮肤病医院 | A kind of Dacarbazine for targetting anti-malignant mela noma and miR 205 carry excretion body and its preparation method and application altogether |
Non-Patent Citations (3)
| Title |
|---|
| 《中国肿瘤临床年鉴》编辑委员会: "《中国肿瘤临床年鉴》", 30 September 2016, 中国协和医科大学出版社 * |
| RADHA MUNAGALA，等: "Bovine milk-derived exosomes for drug delivery", 《CANCER LETT.》 * |
| TAKETOSHI HATA，等: "Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
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Application publication date: 20190329 |