CN108434456A - A kind of nano-medicament carrier and the preparation method and application thereof - Google Patents
A kind of nano-medicament carrier and the preparation method and application thereof Download PDFInfo
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- 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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Abstract
The present invention relates to a kind of nano-medicament carriers and the preparation method and application thereof, belong to accurate Clinics and Practices technical field.The nano-medicament carrier of the present invention has the structural formula as shown in following formula (I), wherein x：Y=(50~800):1, y 2；Application the present invention also provides the nano-medicament carrier as carrier in being used to prepare antitumor nanometer medicine-carried system.The nano-medicament carrier of the present invention can be with carrying medicament body, drug can be discharged when its carrying medicament under radioactive ray irradiation, the chemicals that it is loaded can assist reducing the radioresistance of tumour cell and improve radiation sensitivity, the collaboration of radiotherapy simultaneously overcomes the serious toxic side effect and multi-drug resistant of chemotherapeutics, to realize radiotherapy and chemotherapy synergistic treatment tumour, have complementary advantages, it is synergistic, to improve oncotherapy effect to the maximum extent.
Description
Technical field
The present invention relates to a kind of nano-medicament carriers and the preparation method and application thereof, belong to accurate Clinics and Practices technology neck
Domain.
Background technology
Malignant tumour is one of main lethal factor in current world wide, and has become China city dweller first
The cause of death.The means for treating malignant tumour are mainly surgical operation therapy, radiotherapy, chemotherapy.It is individually outer
Surgical treatment is difficult to effect a radical cure tumour；Radiotherapy leads to DNA of tumor cell irreversible damage by radioactive ray irradiation and lures
Apoptosis of tumor cells is led, but the radioresistance of tumour cell and the Esophageal carcinoma of normal cell frequently result in radiotherapeutic effect
It is bad；Chemotherapy can kill tumour cell, inhibit growth of tumour cell breeding, but poor specificity, toxic side effect it is big and
It is also easy to produce drug resistance.Improve tumor radio-sensitivity, prepare targeting chemicals will be to the toxic side effect of body to reduce it
For the inexorable trend of future therapeutic tumor development.
With the continuous development of nanotechnology, nano particle is widely used in medical diagnosis on disease, in-vivo imaging and tumour and controls
In treatment, wherein nano-medicament carrier plays an important role in neoplasm targeted therapy.Nano-medicament carrier is a kind of nano level
Submicron drug delivery system, general grain size can contain a variety of drug molecules in 10-200nm, including protein, siRNA,
DNA and small molecule chemotherapeutic medicine etc..Nano-medicament carrier can be solved by covalent bond, absorption or package action carrying medicament
It has determined the problems of dissolution of drug, has protected pharmaceutical activity, avoid being degraded by vivo environment；It can be overcome by dimensional effect more in vivo
Weight biological barrier improves the distribution of drug vivo biodistribution；Using targeting is passively or actively, enhance the targeting of drug, improves tumour
The drug-rich of tissue reduces the toxic side effect of normal tissue；The material and technology that can also be synthesized by controlling nano-carrier,
Drug controlled release speed realizes the long-acting slow-release of drug in vivo.The targeting turn-over capacity of nano particle makes it possess thoroughly
Change the potentiality of oncotherapy mode, and the defect of classic chemotherapy can be overcome, such as undesirable bio distribution, tumour medicine support
Anti-, serious systemic side reaction etc..
Nano-medicament carrier can be divided into passive target nano-medicament carrier, active targeting nano-medicament carrier and intelligent receive
Rice pharmaceutical carrier.Passive target nano-medicament carrier relies primarily on the dimensional effect of nano particle, using tumor tissues and normally
The physiological differences of tissue realize targeting；The disadvantage is that excessively relying on tumor neovasculature formation and hyperplasia degree, tumour
The hyperosmosis of interstitial is unfavorable for diffusion of nanometer delivery vector in tumor tissues.Active targeting nano material mainly will be various
Targeted molecular is special using targeted molecular and tumor cell surface acceptor molecule by being either physically or chemically coupled to carrier surface
It is anisotropic in conjunction with and realize active targeting；The disadvantage is that the tumor ligand molecular amounts found are less, the individual difference of oncotherapy
Property is big.Intelligent nano-medicament carrier is based on poor existing for tumour cell and normal cell, tumor microenvironment and physiological environment
It is different, such as pH, temperature, redox potential, outside stimulus, such as magnetic field, ultrasound and light are added, the physical of carrier is changed
The change of matter such as configuration, fracture, dispersion or the aggregation of special groups etc., to reach Drug controlled release, enhancing tumour enrichment,
Improve the purpose of cellular uptake.
Currently, the difference based on tumour cell Yu normal cell internal and external environment, domestic and international seminar devises a series of intelligence
The stimuli responsive type pharmaceutical carrier of energy, mainly there is pH responsive types, redox potential responsive type, enzyme responsive type, temperature sensitive, magnetic
Property responsive type, ultrasonic sensitive type and photaesthesia type.These response properties can make pharmaceutical carrier become by the environment in the interior external world
Change to control the rate of release of drug, so as to reduce the toxic action to internal normal cell and tissue.Existing stimulation
The physical chemistry stimuli responsive type that response type pharmaceutical carrier is relied on has：Magnetic guidance, light excitation, supersound process, temperature change,
Enzymatic activity size, oxidation-reduction potential variation and difference pH, the disadvantage is that the interior environmental stimuli that these pharmaceutical carriers are responded is only
Can Drug controlled release rate, to the treatment of tumour without collaboration booster action, final play therapeutic effect is still chemicals sheet
Body.Also, the toxic side effect of single chemotherapy is big, to utterly destroy the primary lesion and transfer stove of tumour, ensures patient's treatment
Life quality afterwards realizes that the effect that tumour is thoroughly cured, single chemotherapy are often difficult to reach.
Why there are these disadvantages in the prior art, be that when designing preparation, emphasis is poly- because of current intellectual drug carrier
Coke is in the controlled release for how realizing by interior extraneous environmental change drug, and these variations hardly play oncotherapy auxiliary and make
With.At this stage, more stimulus main still temperature, pH and oxidation-reduction potential these " internal stimulus sources " are studied.It
Be all based on tumour existence microenvironment it is different from normal cell, i.e. the drug resistance of tumour cell is weak, distinctive acidic environment
The reductive glutathione of high concentration around, therefore can only realize chemicals single therapy." outside stimulus source " such as magnetic lures
Lead, light excitation, be ultrasonically treated can not equally play the role of cooperate with adjuvant therapy of tumors, return make a thorough investigation of bottom be also to rely only on unification
It treats.
Invention content
One is provided it is an object of the invention to overcome the shortcoming of above-mentioned existing stimuli responsive type nano-medicament carrier
Kind can radioactive ray irradiation under release drug and can realize radiotherapy and chemotherapy synergistic treatment tumour new nano-medicament carrier and its
Preparation method and application.
To achieve the above object, the technical solution that the present invention takes is：A kind of nano-medicament carrier has such as following formula
(I) structural formula shown in：
Wherein, x：Y=(50~800):1, y 2.
The nano-medicament carrier of the present invention can be with carrying medicament body, and when carrying medicament can discharge medicine under radioactive ray irradiation
Object, the chemicals that it is loaded can assist reducing the radioresistance of tumour cell and improve radiation sensitivity, while radiotherapy
Collaboration overcomes the serious toxic side effect and multi-drug resistant of chemotherapeutics, excellent to realize radiotherapy and chemotherapy synergistic treatment tumour
Gesture is complementary, synergistic, to improve oncotherapy effect to the maximum extent.
As the preferred embodiment of nano-medicament carrier of the present invention, the ratio of the x and y are x：Y=(190~
210):1。
As the preferred embodiment of nano-medicament carrier of the present invention, the ratio of the x and y are x：Y=200:1.
As the preferred embodiment of nano-medicament carrier of the present invention, the grain size of the nano-medicament carrier is 100
~200nm.
In addition, the present invention also provides the preparation methods of above-mentioned nano-medicament carrier comprising following steps：
(1) lactide is prepared by raw material of lactic acid；
(2) catalyst is added into lactide made from step (1), carries out polymerisation, polylactic acid is made；
(3) polylactic acid is reacted under vacuum with polyethylene glycol, obtains the nano-medicament carrier as shown in formula (I).
The preferred embodiment of preparation method as nano-medicament carrier of the present invention, in the step (2), catalysis
Agent is stannous chloride.
The preferred embodiment of preparation method as nano-medicament carrier of the present invention, in the step (3), poly- second
Glycol is PEG-1000.
In addition, the present invention also provides above-mentioned nano-medicament carriers as carrier is being used to prepare antitumor nano drug-carrying
Application in system.
Finally, the present invention provides a kind of nanometer medicine-carried systems comprising above-mentioned nano-medicament carrier and anticancer drug.
As the preferred embodiment of above-mentioned nanometer medicine-carried system, the anticancer drug be taxol, the taxol with
The nano-medicament carrier is connected by disulfide bond.Branch containing amino and carboxyl in taxane molecule prepares the present invention and receives
When the paclitaxel nano medicine-carried system of rice pharmaceutical carrier load, the mode for generating peptide bond can be first passed through to taxol progress pyridine mercapto
Base is modified, and is then prepared into the drug and carrier conjugates that are connected with disulfide bond by disulfide bond exchange reaction.
Compared with prior art, beneficial effects of the present invention are：The present invention has synthesized a kind of new stimuli responsive type nanometer
Pharmaceutical carrier can be radiated at specific with carrying medicament body, the drug that nano-medicament carrier of the present invention loads by radioactive ray
Position discharges.
The new drug carrier that the present invention synthesizes is made different from what existing intelligent nano carrier was relied on without auxiliary treatment
Inside and outside stimulates, the pharmaceutical carrier that the present invention researches and develops can artificial Drug controlled release position, pass through radioactive ray irradiation release
While the chemicals of killing tumor cell, radioactive ray itself have powerful DNA damage to the tumour cell of irradiated site
It acts on and inducing apoptosis of tumour cell, so that tumour cell generates the same of DNA damage and Apoptosis in radiation
When, it is final to realize that radiotherapy is combined treatment with chemotherapy since the carrying medicament of radiotherapy position release plays curative effect and mortality
Tumour achievees the effect that drug and radioactive ray double treatment tumour.In addition, local treatment and the chemicals collaboration of radioactive ray
Enhanced sensitivity is also further reduced the injury effect of single therapy normal tissue cell, really realizes the maximization of therapeutic effect.Therefore
Compared with existing stimuli responsive type nano-medicament carrier, what the present invention researched and developed irradiates controllable release drug based on radioactive ray
Organic Nano-Scale Pharmaceutical Carrier have can artificially control the targeting to tumour cell, overcome single toxic and side and
The advantages of drug resistance, secondary combined radiation cure, and the present invention can improve oncotherapy effect to greatest extent, ensure patient
Life quality after treatment.
In addition, when nano-medicament carrier carrying medicament using the present invention, radioactive ray can both be used as Drug controlled release
Outside stimulus source again can to tumour cell generate radioactive damage, kill two birds with one stone, realize chemicotherapy have complementary advantages, make the best use of the advantages and keep away
It is short, cooperative gain.
Description of the drawings
Fig. 1 is SEM figure of the nano-medicament carrier of the present invention after radioactive ray pre-irradiation；
Fig. 2 is the curve graph that number of viable cells counts in effect example 3 of the present invention.
Specific implementation mode
For the object, technical solutions and advantages of the present invention are better described, below in conjunction with the drawings and specific embodiments pair
The present invention is described further.
Embodiment 1
A kind of embodiment of nano-medicament carrier of the present invention, the structural formula such as formula of nano-medicament carrier described in the present embodiment
(I) shown in：
Wherein, x：Y=200:1, y=2；The grain size of nano-medicament carrier described in the present embodiment is 200nm.
The preparation method of nano-medicament carrier described in the present embodiment is：
(1) preparation of lactide (two molecule lactic acid polycondensations dehydration generates lactide)：It is loaded onto on the three-necked flask of 250mL
Suitable D, Pfansteihl are added into three-necked flask for reflux condensing tube, and a small amount of zeolite is added prevents bumping；Lactic acid is heated to open
Begin to boil, decompression makes the moisture to dissociate in lactic acid and the water generated in reaction process be steamed out, and is continuously heating to 80 degrees Celsius simultaneously
Isothermal reaction 2 hours, when dehydrating amount reaches theoretical value 90% or so, replacement receiving flask continues to be evaporated under reduced pressure；Gradually rise temperature
To 190 degrees Celsius, lactide is set to be steamed out at reduced pressure conditions, it is seen that have yellow crystals precipitation in conical flask, obtained yellow
Crystal is crude lactide, subsequently carries out recrystallization purifying with ethyl acetate, obtains white needle-like crystals, true in 50 degrees Celsius
It is preserved after sky is dry.
(2) preparation (lactide ring-opening polymerisation) of polylactic acid：Take refined lactide made from a certain amount of above-mentioned steps in
In 250mL three-necked flasks, appropriate SnCl is added2(stannous chloride) is used as catalyst, decompression pumping to form vacuum state, heat；
After lactide crystal and catalyst mix well, it is continuously heating to steady temperature, heat preservation polymerisation 30 minutes, Temperature fall
To room temperature, mixture CHCl after reaction is taken out3(chloroform) dissolves, and the solution that mass fraction is 8%, object to be mixed is made
After being completely dissolved, be added in the methanol of 10 times of volumes, be precipitated white flocculent polymer, then with a certain amount of methanol wash 2-3 all over to get
Polylactic acid preserves after 50 degrees Celsius of vacuum drying；
(3) polylactic acid-polyglycol copolyreaction：D, Pfansteihl is taken to add by dehydration-condition polylactic acid obtained by the reaction
Enter in beaker, is 160 degrees Celsius, initial depression 80KPa in temperature, under conditions of being stirred continuously, after reacting about 7 hours,
Polyethylene glycol-1000 (PEG-1000) after purification is added, up to PLA-PEG copolymers after the reaction was continued 10 hours.
The nanometer medicine-carried system of the present embodiment comprising the nano-medicament carrier and anticancer drug of the present embodiment, it is described anti-
Cancer drug is taxol, and the taxol is connect with the nano-medicament carrier by disulfide bond.
The preparation method of the present embodiment nanometer medicine-carried system is：Branch containing amino and carboxyl in taxane molecule, first
Pyridine sulfydryl modification is carried out to drug molecule by way of generating peptide bond, is then prepared into two by disulfide bond exchange reaction
The drug and carrier conjugates of sulfide linkage connection.
Embodiment 2
A kind of embodiment of nano-medicament carrier of the present invention, the structural formula such as formula of nano-medicament carrier described in the present embodiment
(I) shown in：
Wherein, x：Y=190:1, y=2；The grain size of nano-medicament carrier described in the present embodiment is 200nm.
The nanometer medicine-carried system of the present embodiment comprising the nano-medicament carrier and anticancer drug of the present embodiment, it is described anti-
Cancer drug is taxol, and the taxol is connect with the nano-medicament carrier by disulfide bond.
The preparation method of the present embodiment nano-medicament carrier and nanometer medicine-carried system is the same as embodiment 1.
Embodiment 3
A kind of embodiment of nano-medicament carrier of the present invention, the structural formula such as formula of nano-medicament carrier described in the present embodiment
(I) shown in：
Wherein, x：Y=210:1, y=2；The grain size of nano-medicament carrier described in the present embodiment is 200nm.
The nanometer medicine-carried system of the present embodiment comprising the nano-medicament carrier and anticancer drug of the present embodiment, it is described anti-
Cancer drug is taxol, and the taxol is connect with the nano-medicament carrier by disulfide bond.
The preparation method of the present embodiment nano-medicament carrier and nanometer medicine-carried system is the same as embodiment 1.
Embodiment 4
A kind of embodiment of nano-medicament carrier of the present invention, nano-medicament carrier described in the present embodiment with described in embodiment 1
Nano-medicament carrier the difference is that only：In the present embodiment, the grain size of nano-medicament carrier is 100nm.
The nanometer medicine-carried system of the present embodiment comprising the nano-medicament carrier and anticancer drug of the present embodiment, it is described anti-
Cancer drug is taxol, and the taxol is connect with the nano-medicament carrier by disulfide bond.
The preparation method of the present embodiment nano-medicament carrier and nanometer medicine-carried system is the same as embodiment 1.
Embodiment 5
A kind of embodiment of nano-medicament carrier of the present invention, nano-medicament carrier described in the present embodiment with described in embodiment 1
Nano-medicament carrier the difference is that only：In the present embodiment, the grain size of nano-medicament carrier is 150nm.
The nanometer medicine-carried system of the present embodiment comprising the nano-medicament carrier and anticancer drug of the present embodiment, it is described anti-
Cancer drug is taxol, and the taxol is connect with the nano-medicament carrier by disulfide bond.
The preparation method of the present embodiment nano-medicament carrier and nanometer medicine-carried system is the same as embodiment 1.
Embodiment 6
A kind of embodiment of nano-medicament carrier of the present invention, the structural formula such as formula of nano-medicament carrier described in the present embodiment
(I) shown in：
Wherein, x：Y=50:1, y=2；The grain size of nano-medicament carrier described in the present embodiment is 200nm.
The nanometer medicine-carried system of the present embodiment comprising the nano-medicament carrier and anticancer drug of the present embodiment, it is described anti-
Cancer drug is taxol, and the taxol is connect with the nano-medicament carrier by disulfide bond.
The preparation method of the present embodiment nano-medicament carrier and nanometer medicine-carried system is the same as embodiment 1.
Embodiment 7
A kind of embodiment of nano-medicament carrier of the present invention, the structural formula such as formula of nano-medicament carrier described in the present embodiment
(I) shown in：
Wherein, x：Y=800:1, y=2；The grain size of nano-medicament carrier described in the present embodiment is 200nm.
The nanometer medicine-carried system of the present embodiment comprising the nano-medicament carrier and anticancer drug of the present embodiment, it is described anti-
Cancer drug is taxol, and the taxol is connect with the nano-medicament carrier by disulfide bond.
The preparation method of the present embodiment nano-medicament carrier and nanometer medicine-carried system is the same as embodiment 1.
Effect example 1 detects the release conditions of nanometer medicine-carried system of the present invention drug after radioactive ray irradiation
This effect example has been investigated by scanning electron microscope (SEM) described in Examples 1 to 3, embodiment 6 and embodiment 7
Nanometer medicine-carried system its pattern after radioactive ray pre-irradiation changes.In radioactive ray pre-irradiation, nanometer medicine-carried system is that grain size is
The particle of 200nm (as shown in A in Fig. 1)；After receiving radioactive ray irradiation, nanometer medicine-carried system becomes fragment shape from graininess
(as shown in B in Fig. 1).Thus illustrate, nanometer medicine-carried system of the present invention can destroy under radioactive ray irradiation and discharge drug.
2 Study of cytotoxicity of effect example
This effect example is carried with the nanometer medicine-carried system of present invention package taxol, the Nano medication without package taxol respectively
Body handles HCT116 cells, while being compared with the HCT116 cells for not making any processing.This effect example Beyotime (green clouds
It) absorbance OD values under CCK-8 kits detection 450nm wavelength, the cell viabilities of three groups of cells is characterized with this and is become whether there is or not apparent
Change, to study the physiological security of nano-medicament carrier.Experimental result is as shown in table 1 below.
Table 1
In table 1, OD values are higher to show that cell viability is higher, as can be seen from Table 1, blank Nano medication of the invention
Carrier is without apparent cytotoxicity.
Effect example 3 detects the radio therapy sensitization effect of nanometer medicine-carried system of the present invention
This effect example carries out the cell of package Examples 1 to 7 nanometer medicine-carried system using Human colorectal cancer cells HCT116
Experiment, detects the variation of the cell viability in the case where there is no radiation irradiation, and then reflects the radio therapy sensitization effect of nanometer medicine-carried system.
This effect example is divided into 8 test groups according to following table 2, and each test group is quantitatively inoculated with the cell of identical quantity in 12
In orifice plate.With inoculating cell for the 0th day, the processing of the corresponding radioactive ray of different group cells is given on day 2, respectively the 3rd, 5,
It carries out viable count within 7,9 days, count each group number of viable cells and makes corresponding curve graph, the results are shown in Figure 2.
Table 2
According to fig. 2 as it can be seen that the cell number of group 4 and group 8 is in normal growth trend, the cell number relatively group 4,8 of group 1,2,3
In different degrees of reduction, the cell number of group 5,6,7 is presented has significant different degrees of reduction than group 1,2,3, illustrates to wrap
The nanometer medicine-carried system for wrapping up in taxol has radio therapy sensitization effect and to cytotoxic side effect.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than is protected to the present invention
The limitation of range is protected, although being explained in detail to the present invention with reference to preferred embodiment, those skilled in the art should
Understand, technical scheme of the present invention can be modified or replaced equivalently, without departing from the essence of technical solution of the present invention
And range.
Claims (10)
1. a kind of nano-medicament carrier, which is characterized in that the nano-medicament carrier has the structure as shown in following formula (I)
Formula：
Wherein, x：Y=(50~800):1, y 2.
2. nano-medicament carrier as described in claim 1, which is characterized in that the ratio of the x and y is x：Y=(190~
210):1。
3. nano-medicament carrier as claimed in claim 2, which is characterized in that the ratio of the x and y is x：Y=200:1.
4. such as claims 1 to 3 any one of them nano-medicament carrier, which is characterized in that the grain of the nano-medicament carrier
Diameter is 100~200nm.
5. the preparation method of nano-medicament carrier as described in claim 1, which is characterized in that include the following steps：
(1) lactide is prepared by raw material of lactic acid；
(2) catalyst is added into lactide made from step (1), carries out polymerisation, polylactic acid is made；
(3) polylactic acid is reacted under vacuum with polyethylene glycol, obtains the nano-medicament carrier as shown in formula (I).
6. the preparation method of nano-medicament carrier as claimed in claim 5, which is characterized in that in the step (2), catalyst
For stannous chloride.
7. the preparation method of nano-medicament carrier as claimed in claim 5, which is characterized in that in the step (3), poly- second two
Alcohol is PEG-1000.
8. as Claims 1 to 4 any one of them nano-medicament carrier is being used to prepare antitumor nanometer load as carrier
Application in medicine body system.
9. a kind of nanometer medicine-carried system, which is characterized in that including Claims 1 to 4 any one of them nano-medicament carrier and
Anticancer drug.
10. nanometer medicine-carried system as claimed in claim 9, which is characterized in that the anticancer drug is taxol, the Japanese yew
Alcohol is connect with the nano-medicament carrier by disulfide bond.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101007868A (en) * | 2007-01-25 | 2007-08-01 | 复旦大学 | Preparation method of biodegradable nano micelle controlled release formulation |
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| WO2016201378A1 (en) * | 2015-06-12 | 2016-12-15 | Wisconsin Alumni Research Foundation | Multi-drug combinations that act as potent radiosensitizers |
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