CN107998404A - A kind of folate-targeted carrier for loading cancer therapy drug and its preparation method and application - Google Patents
A kind of folate-targeted carrier for loading cancer therapy drug and its preparation method and application Download PDFInfo
- Publication number
- CN107998404A CN107998404A CN201711314545.XA CN201711314545A CN107998404A CN 107998404 A CN107998404 A CN 107998404A CN 201711314545 A CN201711314545 A CN 201711314545A CN 107998404 A CN107998404 A CN 107998404A
- Authority
- CN
- China
- Prior art keywords
- cancer therapy
- therapy drug
- carrier
- folate
- zif
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of folate-targeted carrier for loading cancer therapy drug and its preparation method and application.It is encapsulated in carrier first using zinc nitrate and 2 methylimidazoles as carrier material, by cancer therapy drug by original flavor investment, and synthesis obtains cancer therapy drug zeolite imidazole skeleton carrier；Folic acid in coordination key connection is formed by the zinc ion in cancer therapy drug zeolite imidazole skeleton carrier and folic acid polyethylene glycol again, the folate-targeted carrier of load cancer therapy drug is successfully prepared.The target medicine carrier good biocompatibility, synthetic method is simple, has targeting, and can reduce poisonous side effect of medicine.Meanwhile the drugloading rate of chloroquine diphosphate is up to 18% in the carrier, the utilization rate and drug effect of medicine are improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of folate-targeted carrier for loading cancer therapy drug and its preparation
Methods and applications.
Background technology
The harm of cancer in the world constantly aggravates, it has also become threatens No.1 " killer " of human body health.Mesh
Before, it is clinical in most commonly used treatment method be that operation, chemotherapy also have radiotherapy.Chemotherapy can cause a series of urgency
Property and Chronic organ's toxicity.Since many chemotherapeutics and its metabolin are drained by renal cells, kidney is easy to
Damaged by chemotherapeutic agent.Therefore, the use of chemotherapeutics is limited be subject to its renal toxicity side effect sometimes.Chemotherapy is related
Kidney injury typically result in treatment of cancer deficiency because renal dysfunction need clinician reduce chemotherapy doses to avoid into
The injury of kidney of one step.Kidney damage can also cause other unfavorable complication, such as water and nitrogenouz wastes retention, electrolyte disturbance,
Immunity degradation etc..
Effective pharmaceutical carrier is developed, reduces the inherent adverse reaction of chemotherapeutics, improves therapeutic effect, it has also become treatment
One of key issue of cancer.At present, in order to which the permeability and reserve effects of enhancing, medicament nano carrier are developed to change
Kind medicine is in the accumulation of tumor region, and the nano-carrier includes polymer vesicle, micella, and polymer nano granules are inorganic to receive
Rice grain and hybridization porous solid.Wherein, nano metal organic frame（MOFs）Carried as the medicament nano with high drug load
Body, its high pore volume, high surface area and in frame have adjustable pore size and cause concern.In MOFs, zeolite miaow
Azoles skeleton ZIF-8 especially has prospect as pharmaceutical carrier because ZIF-8 be by zinc ion and 2-methylimidazole salt foundation it is nontoxic
And the MOF of bio-compatible, it stablizes and is decomposed in the relatively low tumor locus of pH value in physiological conditions.
Chloroquine has carried out as a kind of new antitumor drug or some ongoing clinical tests has been shown
The effect of profit.Although exact mechanism waits to determine, the antitumaous effect of chloroquine is probably the inhibitory action due to it to autophagy.
Autophagy is the one of which physiology course influenced by chloroquine.Chloroquine suppresses lysosome activity, then prevents the latter step of autophagy
Suddenly, i.e. the degraded of autophagy lysosome, leads to not provide energy by autophagy approach.Since autophagy is considered as cell in cancer
The approach of survival, therefore chloroquine is used in combination with Treated with Chemotherapeutic Drugs thing and radiotherapy, has been demonstrated that killing can be strengthened
Tumour cell acts on, chloroquine diphosphate（CQ）For one kind of chloroquine.
Folic acid has been widely studied as the targeting ligand for delivering medicine, what it can be overexpressed on cancer cell surfaces
Folacin receptor Selective recognition and the encytosis of costimulatory receptor mediation, so as to increase intake of the tumour to medicine, are reduced at the same time
Systemic toxicity.Polyethylene glycol（PEG）It is considered as best biocompatible substance, extends circulation time.Therefore, folic acid-
Polyethylene glycol is considered as to improve one of the promising stabilizer of drug delivery system to realize satisfied neoplasm targeted therapy.
The content of the invention
For the above-mentioned problems in the prior art, it is an object of the invention to provide a kind of leaf for loading cancer therapy drug
Sour targeting vector and its preparation method and application.
The folate-targeted carrier of a kind of load cancer therapy drug, it is characterised in that first by zinc nitrate, 2-methylimidazole
With cancer therapy drug cancer therapy drug-zeolite imidazole skeleton carrier is obtained by being chemically synthesized；Cancer therapy drug-zeolite imidazole skeleton
Carrier forms folic acid in coordination key connection by zinc ion and folic acid-polyethylene glycol again, obtains the folic acid target of load cancer therapy drug
To carrier.
The folate-targeted carrier of a kind of load cancer therapy drug, it is characterised in that cancer therapy drug is chloroquine diphosphate.
The folate-targeted carrier of a kind of load cancer therapy drug, it is characterised in that chemical method is embedding in situ method.
The folate-targeted carrier of a kind of load cancer therapy drug, it is characterised in that cancer therapy drug uses embedding in situ method
It is encapsulated in the zeolite imidazole skeleton synthesized by zinc nitrate and 2-methylimidazole.
The preparation method of the folate-targeted carrier of the load cancer therapy drug, it is characterised in that include the following steps：
1）Complex is formed first with the zinc ion and cancer therapy drug of zinc nitrate, then 2- methyl is added into complex
The zinc ion of imidazoles and complex forms ZIF-8, and cancer therapy drug is embedded in ZIF-8 by embedding in situ method, is obtained
Cancer therapy drug-zeolite imidazole skeleton carrier；
2）By step 1）Zinc ion and folic acid-polyethylene glycol on obtained cancer therapy drug-zeolite imidazole skeleton carrier, which is formed, matches somebody with somebody
Position key, is connected to zeolite imidazole skeleton carrier surface by folic acid, obtains the folate-targeted carrier of carried anticancer medicine thing chloroquine diphosphate.
The preparation method of the folate-targeted carrier of the load cancer therapy drug, it is characterised in that comprise the following steps that：
1）Cancer therapy drug is dissolved in deionized water, is mixed with the zinc nitrate in water, 1-5min is stirred at room temperature and obtains coordinationization
Compound system, then absolute methanol, 2-methylimidazole are added in the coordination complex system, continue to stir 15-20min at room temperature
Mixed system is obtained, which is transferred in centrifuge 10-20min is centrifuged with 10000-12000rmp/min, obtained
Solid is washed with absolute methanol and deionization wash away unreacted reagent respectively, and vacuum drying, that is, obtain cancer therapy drug-ZIF-8
Carrier, it is preferable that absolute methanol and deionization washing times are 3 times；
2）Folic acid-polyethylene glycol and deionized water ultrasonic vibration is uniform, add step 1）Obtained cancer therapy drug-ZIF-8 is carried
Ultrasonic vibration is uniform again for body, stirs 35-50h at room temperature, centrifuge washing removes unreacted folic acid-polyethylene glycol, and vacuum is done
It is dry, that is, obtain the folate-targeted carrier of load cancer therapy drug.
The preparation method of the folate-targeted carrier of the load cancer therapy drug, it is characterised in that step 1）In anticarcinogen
The mass ratio of thing, zinc nitrate and deionized water is 35-55:1-2：4-6, preferably each 55:1:5；2-methylimidazole and absolute methanol
Mass volume ratio be 2-5g：10ml, is preferably 4g：8ml；2min is stirred at room temperature in cancer therapy drug after being mixed with zinc nitrate, coordination
Continue to stir 16min at room temperature after adding absolute methanol, 2-methylimidazole in chemical combination objects system；Centrifugal rotational speed is 11000rmp/
Min, centrifugation time 10min.
The preparation method of the folate-targeted carrier of the load cancer therapy drug, it is characterised in that step 2）In folic acid-
The mass volume ratio 8-10g of polyethylene glycol and deionized water：5ml, is preferably 10g：1ml.
The preparation method of the folate-targeted carrier of the load cancer therapy drug, it is characterised in that step 2）In folic acid-
The mass ratio of polyethylene glycol and cancer therapy drug-ZIF-8 carriers is 2:2-3, is preferably 1:1.
Application of the folate-targeted carrier of the load cancer therapy drug in cancer therapy drug is prepared.
By using above-mentioned technology, compared with prior art, beneficial effects of the present invention are as follows：
1）The present invention is by cancer therapy drug（Chloroquine diphosphate）It is encapsulated in using chemical reaction in ZIF-8, while CQ-ZIF-8 carriers are again
Connect folic acid-polyethylene glycol structure target medicine carrier（FA-PEG/CQ-ZIF-8）, and material characterization is carried out, the characterization of use
Method has：FTIR spectrum（FTIR）, X-ray diffraction（XRD）, scanning electron microscope etc., it was demonstrated that vector construction success, together
When, chloroquine diphosphate and FA-PEG/CQ-ZIF-8 carriers are investigated to the toxicity of cancer cell and normal cell, are contrasted using MTT
Method have detected survival rate of the carrier in cancer cell and normal cell, it was demonstrated that ZIF-8 is for cancer therapy drug in the carrier medicament
Also a kind of protective effect, can reach lesion, and release chloroquine diphosphate carrys out treating cancer, can target enhancing to cancer cell
Toxicity, and the toxicity to normal cell can be reduced；To improve the carrying drug ratio of chloroquine diphosphate, the targeting conveying of cancer therapy drug is established
System and reduction organ toxicity lay a solid foundation, and have not only solved the problems, such as that cancer therapy drug chloroquine diphosphate profit utilization rate is low but also subtracts
Lacked the toxic side effect for the treatment of cancer, and made the treatment of medicine that there is targeting, for cancer treatment opened up it is a kind of newly
Approach；
2）Zeolite imidazole skeleton ZIF-8 used in the present invention, for the first time applied to medicament carrier system, a diameter of 10- of ZIF-8
500 nanometers, cell can be entered by the endocytosis of cell membrane, because of stable structure, can be excluded by body metabolism, therefore
No cytotoxicity；ZIF-8 has huge specific surface area and pore volume, so as to have larger drugloading rate, special pore passage structure
Drug slow release function is made it have again；
3）The present invention passes through inhibiting tumor cell verification experimental verification, the results show that the present invention is successfully prepared load cancer therapy drug p chloromethylbenzoic acid
The folate-targeted carrier of quinoline, carries cancer therapy drug chloroquine diphosphate and reaches lesion, additionally it is possible to play reduction medicine in which can not only target
The effect of thing cytotoxicity, and effect of the cancer therapy drug chloroquine diphosphate to cancer cell has been successfully reserved, have very to cancer cell
Good inhibitory action and curative effect.
Brief description of the drawings
Fig. 1 is the canonical plotting of chloroquine diphosphate；
Fig. 2A is the infared spectrum spectrogram of ZIF-8；
Fig. 2 B are the infared spectrum spectrogram of FA-PEG；
Fig. 2 C are the infared spectrum spectrogram of CQ；
Fig. 2 D are the infared spectrum spectrogram of FA-PEG/CQ-ZIF-8；
Fig. 3 A are zeolite imidazole class skeleton（ZIF-8）Transmission electron microscope picture；
Fig. 3 B are the zeolite imidazole class skeleton of load chloroquine diphosphate（CQ-ZIF-8）Transmission electron microscope picture；
Fig. 3 C are folic acid-polyethylene glycol/chloroquine diphosphate-zeolite imidazole skeleton carrier（FA-PEG/CQ-ZIF-8）Transmission electron microscope
Figure；
The Ultraluminescence detection figure that Fig. 4 is CQ-ZIF-8；
Fig. 5 A are the cytotoxicity result figure of folic acid-polyethylene glycol；
Fig. 5 B are the cytotoxicity result figure of ZIF-8；
Fig. 5 C are the cytotoxicity result figure of chloroquine diphosphate；
Fig. 5 D are the cytotoxicity result figure of CQ-ZIF-8 and FA-PEG/CQ-ZIF-8.
Embodiment
Embodiment 1 loads the preparation of the folate-targeted carrier of cancer therapy drug chloroquine diphosphate
1st, chloroquine diphosphate-zeolite imidazole skeleton carrier（CQ-ZIF-8）Preparation
Cancer therapy drug chloroquine diphosphate is encapsulated in zeolite imidazole skeleton by embedding in situ method, synthesis obtains chloroquine diphosphate-boiling
Stone imidazoles skeleton carrier（CQ-ZIF-8）, it is specific to react as follows：
（1）50mg chloroquine diphosphates are dissolved in 5ml deionized waters, is mixed with zinc nitrate, stirs 1min at room temperature, utilize zinc nitrate
Zinc ion and cancer therapy drug form complex；
（2）8ml absolute methanols, 4g2- methylimidazoles are added, continues to stir 15min, 2-methylimidazole and ligand compound at room temperature
The zinc ion of thing forms ZIF-8；
（3）10min is centrifuged under the rotating speed of 10000rmp/min, then washs three times with absolute methanol and deionization respectively and washes away not
The reagent of reaction, vacuum drying, that is, obtain CQ-ZIF-8 carriers；
2nd, folic acid-polyethylene glycol/chloroquine diphosphate-zeolite imidazole skeleton carrier（FA-PEG/CQ-ZIF-8）Preparation
Zinc ion in zeolite imidazole skeleton forms coordinate bond with folic acid-polyethylene glycol, and the upper folic acid of connection, it is specifically reacted such as
Under：
（1）50mg folic acid-polyethylene glycol and 5ml deionized water ultrasonic vibrations is uniform；
（2）50mgCQ-ZIF-8 carriers are added, ultrasonic vibration is uniform, stirs 35h at room temperature；
（3）Centrifuge washing removes unreacted folic acid-polyethylene glycol, and is dried in vacuo, that is, obtains FA-PEG/CQ-ZIF-8 loads
Body.
The characterization of 2 carrier FA-PEG/CQ-ZIF-8 of embodiment
1st, the standard curve of chloroquine diphosphate is as shown in Figure 1
The chloroquine diphosphate solution light absorption value of various concentrations is measured at 257nm by ultraviolet spectrophotometry, so as to draw Fig. 1
Standard curve, the R of Fig. 12=0.9988 has reached more than 0.99 grade, therefore this standard can be used.But standard curve
Use scope be 10-40 μ g/ml.
2nd, infrared spectrum detects
（1）By FA-PEG, CQ, ZIF-8, processing is dried in FA-PEG/CQ-ZIF-8, is then placed in mortar, adds certain
Amount（It is more a small amount of）KBr, grinding uniformly makes mixture be ground to granularity less than 2 μm, in order to avoid stray light effects, are put into drying afterwards
Processing is dried in machine, mixture is pressed into transparent sheet, upper machine measure with the pressure of 40MPa or so on hydraulic press；
（2）Infared spectrum（FTIR）As shown in attached drawing 2A, Fig. 2 B, Fig. 2 C and Fig. 2 D, Fig. 2A is zeolite imidazole class skeleton（ZIF-
8）, Fig. 2 B are folic acid-polyethylene glycol（FA-PEG）, Fig. 2 C are chloroquine diphosphate（CQ）, Fig. 2 D are folic acid-polyethylene glycol/p chloromethylbenzoic acid
Quinoline-zeolite imidazole skeleton carrier（FA-PEG/CQ-ZIF-8）, Fig. 2A has absworption peak representative-C=C- at 1570；Have at 1420
There should be these groups in stronger absworption peak representative-N=C-, ZIF-8；Fig. 2 B have absworption peak generation at 3570,1650,1600
Table has-COOH；There is characteristic absorption peak 1090 on Fig. 2 C, represent the absworption peak of chlorobenzene class；Fig. 2 D after synthesis, there is suction at 3570
Receipts peak represents the-H on folic acid carboxylic acid, and folic acid-polyethylene glycol has been connected on carrier；Having absworption peak to represent at 1420 has ZIF-8
- N=C-；Loseing has the characteristic absorption peak of Fig. 2 C, is because medicine is to be encapsulated in carrier inside.
3rd, ZIF-8, CQ-ZIF-8 and FA-PEG/CQ-ZIF-8 transmission electron microscope picture are as shown in attached drawing 3A, Fig. 3 B, Fig. 3 C, figure
3A is zeolite imidazole class skeleton（ZIF-8）, Fig. 3 B are the zeolite imidazole class skeleton of load chloroquine diphosphate（CQ-ZIF-8）, Fig. 3 C are
Folic acid-polyethylene glycol/chloroquine diphosphate-zeolite imidazole skeleton carrier（FA-PEG/CQ-ZIF-8）.
It is octahedron from transmission electron microscope it can be seen from the figure that zeolite imidazole class skeleton, and size is in Nano grade；Fig. 3 A and
Compared to knowable to, separately synthesized ZIF-8 becomes apparent Fig. 3 B with the ZIF-8 after carrying medicament, octahedra crystal form, and particle diameter reduces,
And no longer it is adhered.It is relatively more steady compared to figure B and figure C as it can be seen that the CQ-ZIF-8 size crystal forms before and after connecing folic acid are held essentially constant
It is fixed.
The CQ charging ratios that ZIF-8 is loaded in 3 carrier FA-PEG/CQ-ZIF-8 of embodiment
1st, the measure of the CQ charging ratios of ZIF-8 loads
UV spectrophotometer measuring：Consulting literatures learn that the characteristic absorption peak of chloroquine diphosphate is 254nm
（1）The standard curve for drawing chloroquine diphosphate comprises the following steps that：
1. the preparation of curcumin storing solution
Accurately weigh chloroquine diphosphate 1mg to be placed in beaker, after adding appropriate amount of deionized water to dissolve, be transferred in the volumetric flask of 10mL,
Scale is settled to deionized water again, it is spare as chloroquine diphosphate storing solution；
2. measurement 1.0,1.5,2.0,2.5,3.0,3.5,4.0mL are respectively placed in 7 10mL volumetric flasks from storing solution respectively,
Scale is settled to deionized water, is shaken up.Using deionized water as blank control, absorbance is measured at 257nm, and with each dense
Spend the average value of absorbance three times（A）For ordinate, concentration（c）For abscissa, calibration curve is drawn；
（2）The measure of the CQ charging ratios of ZIF-8 loads
1. the CQ-ZIF-8 being prepared, adds 0.9% hydrochloric acid solution, dissolving ZIF-8 by chloroquine diphosphate so that be dissolved in solution
In；
2. its light absorption value at 257nm will can be measured after CQ-ZIF-8 hydrochloric acid solutions, solution is calculated according to standard curve
The charging ratio of middle chloroquine diphosphate；
The Ultraluminescence detection of CQ-ZIF-8 as shown in Figure 4, can obtain its drug loading efficiency according to absworption peak at its 257nm and reach
18%。
4 cytotoxicity of example detects
CQ, CQ-ZIF-8, FA-PEG/CQ-ZIF-8 are carried out ultraviolet lamp sterilization treatment, be dissolved in ultra-pure water respectively, and constant volume is in 50
In mL volumetric flasks, the solution that concentration is 200 μ g/mL is configured to.Using concentration gradient, dilution method will with DMEM culture mediums step by step
CQ, CQ-ZIF-8, FA-PEG/CQ-ZIF-8 solution are diluted to required concentration（0.1,0.5,1,2,5,10,15,20 μ g/ml）,
（1）Take the logarithm the phase growth HeLa cells, single cell suspension is made with 0.25% Trypsin Induced cell monolayer（Training
Support base：DMEM+10%FCS）, add 200 μ L cell suspensions in the cell tests hole of 96 orifice plates, 1 × 104Cells/well, will
Cell is put into CO2Incubator（37 DEG C, 5% CO2）Middle culture 16-18h, reaches completely adherent；
（2）The culture medium in 96 orifice plates is suctioned out with liquid-transfering gun, 200 μ L are contained into various concentrations CQ or CQ-ZIF-8 or FA-PEG/
The culture medium of CQ-ZIF-8 is added in instrument connection, and blank control group is separately added into corresponding culture medium and sterile water.All controls
Group and to be detected group it is 5 times parallel.Continue cell culture in CO2Incubator（37 DEG C, 5% CO2）Middle 4h；
（3）Culture medium is discarded, the MTT solution of 100 μ L, 5 mg/mL is separately added into per hole, is continued in CO2Incubator（37 DEG C,
5% CO2）Cultivate 4 h；
（4）Turnover panel abandoning supernatant, 100 μ L DMSO are added per hole.After 5 min are shaken on earthquake device, using microplate reader in
Solution absorbance OD values are surveyed at 570nm wavelength；
Survival rate of the cell in different surfaces activator solution is calculated according to the following formula（V）：
V=（A-A0）/（AC-A0）
Wherein：
V is the survival rate of cell（%）；
A is the OD values of the cell after 3-MA@ZIF-8 hydroponics；
A0It is the OD values that cell after CQ or CQ-ZIF-8 or FA-PEG/CQ-ZIF-8 is substituted with aqua sterilisa, cell growth rate at this time
For 0；
Ac is the OD values of cell when CQ or CQ-ZIF-8 or FA-PEG/CQ-ZIF-8 is not added with nutrient solution, at this time cell growth rate
For 100 %.
（5）For cytotoxicity experiment result figure as shown in Fig. 5 A, Fig. 5 B, Fig. 5 C and Fig. 5 D, Fig. 5 A are folic acid-polyethylene glycol
Cytotoxicity result figure, Fig. 5 B are the cytotoxicity result figure of ZIF-8, and Fig. 5 C are the cytotoxicity result figure of chloroquine diphosphate, are schemed
In 5D, a is the cytotoxicity result figure of CQ-ZIF-8, and b is the cytotoxicity result figure of FA-PEG/CQ-ZIF-8.
It is very small that the cytotoxicity of FA-PEG can be obtained according to Fig. 5 A, cell survival rate is in 50% corresponding reagent concentration
（IC50Value）For 10g/ml；Fig. 5 A can be ignored compared to the cytotoxicity of Fig. 5 B and Fig. 5 C, FA-PEG, and the IC of CQ50
It is worth the substantially IC than ZIF-850Value is big, it is seen that medicine is bigger than carrier toxicity；, can be with from the comparison of a and b in Fig. 5 D
It was observed that the IC of b50Value 18 micrograms per millilitre smaller than a in figure, this shows that the carrier for having connect folic acid makes medicine have certain target
Tropism.
Claims (10)
1. a kind of folate-targeted carrier for loading cancer therapy drug, it is characterised in that first by zinc nitrate, 2-methylimidazole and anticarcinogen
Thing obtains cancer therapy drug-zeolite imidazole skeleton carrier by being chemically synthesized；Cancer therapy drug-zeolite imidazole skeleton carrier leads to again
Cross zinc ion and form folic acid in coordination key connection with folic acid-polyethylene glycol, obtain the folate-targeted carrier of load cancer therapy drug.
2. a kind of folate-targeted carrier for loading cancer therapy drug according to claim 1, it is characterised in that cancer therapy drug is
Chloroquine diphosphate.
3. a kind of folate-targeted carrier for loading cancer therapy drug according to claim 1, it is characterised in that chemical method is
Embedding in situ method.
4. a kind of folate-targeted carrier for loading cancer therapy drug according to claim 1, it is characterised in that cancer therapy drug is adopted
It is encapsulated in embedding in situ method in the zeolite imidazole skeleton synthesized by zinc nitrate and 2-methylimidazole.
A kind of 5. preparation method of the folate-targeted carrier of load cancer therapy drug according to claim 1, it is characterised in that
Include the following steps：
1）Complex is formed first with the zinc ion and cancer therapy drug of zinc nitrate, then 2- methyl is added into complex
The zinc ion of imidazoles and complex forms ZIF-8, and cancer therapy drug is embedded in ZIF-8 by embedding in situ method, is obtained
Cancer therapy drug-zeolite imidazole skeleton carrier；
2）By step 1）Zinc ion and folic acid-polyethylene glycol on obtained cancer therapy drug-zeolite imidazole skeleton carrier, which is formed, matches somebody with somebody
Position key, is connected to zeolite imidazole skeleton carrier surface by folic acid, obtains the folate-targeted carrier of carried anticancer medicine thing chloroquine diphosphate.
6. the preparation method of the folate-targeted carrier of load cancer therapy drug according to claim 5, it is characterised in that specific
Step is as follows：
1）Cancer therapy drug is dissolved in deionized water, is mixed with the zinc nitrate in water, 1-5min is stirred at room temperature and obtains coordinationization
Compound system, then absolute methanol, 2-methylimidazole are added in the coordination complex system, continue to stir 15-20min at room temperature
Mixed system is obtained, which is transferred in centrifuge 10-20min is centrifuged with 10000-12000rmp/min, obtained
Solid is washed with absolute methanol and deionization wash away unreacted reagent respectively, and vacuum drying, that is, obtain cancer therapy drug-ZIF-8
Carrier；
2）Folic acid-polyethylene glycol and deionized water ultrasonic vibration is uniform, add step 1）Obtained cancer therapy drug-ZIF-8 is carried
Ultrasonic vibration is uniform again for body, stirs 35-50h at room temperature, centrifuge washing removes unreacted folic acid-polyethylene glycol, and vacuum is done
It is dry, that is, obtain the folate-targeted carrier of load cancer therapy drug.
7. the preparation method of the folate-targeted carrier of the load cancer therapy drug according to claim 5 or 6, it is characterised in that step
Rapid 1）In cancer therapy drug, the mass ratio of zinc nitrate and deionized water be 35-55:1-2：4-6, preferably each 55:1:5；2- methyl
The mass volume ratio of imidazoles and absolute methanol is 2-5g：10ml, is preferably 4g：8ml；Room temperature after cancer therapy drug is mixed with zinc nitrate
2min is stirred, continues to stir 16min at room temperature after absolute methanol, 2-methylimidazole are added in coordination complex system；Centrifugation turns
Speed is 11000rmp/min, centrifugation time 10min.
8. the preparation method of the folate-targeted carrier of the load cancer therapy drug according to claim 5 or 6, it is characterised in that step
Rapid 2）In folic acid-polyethylene glycol and deionized water mass volume ratio 8-10g：5ml, is preferably 10g：1ml.
9. the preparation method of the folate-targeted carrier of the load cancer therapy drug according to claim 5 or 6, it is characterised in that step
Rapid 2）In folic acid-polyethylene glycol and cancer therapy drug-ZIF-8 carriers mass ratio be 2:2-3, is preferably 1:1.
10. a kind of folate-targeted carrier of load cancer therapy drug according to claim 1 or 6 or 7 is preparing cancer therapy drug
In application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711314545.XA CN107998404B (en) | 2017-12-09 | 2017-12-09 | Folic acid targeting vector loaded with anticancer drug and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711314545.XA CN107998404B (en) | 2017-12-09 | 2017-12-09 | Folic acid targeting vector loaded with anticancer drug and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107998404A true CN107998404A (en) | 2018-05-08 |
| CN107998404B CN107998404B (en) | 2021-05-04 |
Family
ID=62058185
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711314545.XA Active CN107998404B (en) | 2017-12-09 | 2017-12-09 | Folic acid targeting vector loaded with anticancer drug and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107998404B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108837159A (en) * | 2018-07-17 | 2018-11-20 | 西北农林科技大学 | A kind of nano antibacterial agent and preparation method thereof |
| CN109266636A (en) * | 2018-09-25 | 2019-01-25 | 江苏大学 | A kind of nano enzyme and its preparation method and application |
| CN111418596A (en) * | 2020-05-29 | 2020-07-17 | 中国农业科学院植物保护研究所 | Thiofuramide-loaded folic acid/zinc nitrate gel system and preparation method and application thereof |
| WO2021103232A1 (en) * | 2019-11-25 | 2021-06-03 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method for core-shell nanoparticles based on lipid membrane and metal organic framework |
| WO2022007298A1 (en) * | 2020-07-08 | 2022-01-13 | 中国科学院深圳先进技术研究院 | Composite nanosphere having fast mucus penetration, preparation method therefor and use thereof |
| WO2022261191A1 (en) * | 2021-06-08 | 2022-12-15 | University Of Georgia Research Foundation, Inc. | Nanoparticles for treating prostate cancer |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101432070A (en) * | 2006-02-28 | 2009-05-13 | 密歇根大学董事会 | Preparation of functionalized zeolitic frameworks |
| CN102579353A (en) * | 2012-03-30 | 2012-07-18 | 吉林大学 | Pegylated liposome of folate-targeted anticancer drug and preparation method |
| CN102276813B (en) * | 2011-08-19 | 2013-01-16 | 江西科技师范学院 | Targeting polymer drug carrier containing folic acid and preparation method thereof |
| EP3006474A1 (en) * | 2014-10-08 | 2016-04-13 | Commissariat à l'Énergie Atomique et aux Énergies Alternatives | Porous solid with outer surface grafted with a polymer |
| CN105816883A (en) * | 2016-02-03 | 2016-08-03 | 华南师范大学 | Probiotics folic acid targeting carrier carrying anti-cancer medicament curcumin and preparation method thereof |
-
2017
- 2017-12-09 CN CN201711314545.XA patent/CN107998404B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101432070A (en) * | 2006-02-28 | 2009-05-13 | 密歇根大学董事会 | Preparation of functionalized zeolitic frameworks |
| CN102276813B (en) * | 2011-08-19 | 2013-01-16 | 江西科技师范学院 | Targeting polymer drug carrier containing folic acid and preparation method thereof |
| CN102579353A (en) * | 2012-03-30 | 2012-07-18 | 吉林大学 | Pegylated liposome of folate-targeted anticancer drug and preparation method |
| CN102579353B (en) * | 2012-03-30 | 2013-12-04 | 吉林大学 | Pegylated liposome of folate-targeted anticancer drug and preparation method |
| EP3006474A1 (en) * | 2014-10-08 | 2016-04-13 | Commissariat à l'Énergie Atomique et aux Énergies Alternatives | Porous solid with outer surface grafted with a polymer |
| CN105816883A (en) * | 2016-02-03 | 2016-08-03 | 华南师范大学 | Probiotics folic acid targeting carrier carrying anti-cancer medicament curcumin and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| HUIYUAN ZHANG ET AL: ""Rational Design of Metal Organic Framework Nanocarrier-Based Codelivery System of Doxorubicin Hydrochloride/Verapamil Hydrochloride for Overcoming Multidrug Resistance with Efficient Targeted Cancer Therapy"", 《ACS APPL. MATER. INTERFACES》 * |
| XIAOYAN XU，ET AL: ""Folate-Functionalized Mesoporous Silica Nanoparticles as a Liver Tumor-Targeted Drug Delivery System to Improve the Antitumor Effect of Paclitaxel"", 《JOURNAL OF NANOMATERIALS》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108837159A (en) * | 2018-07-17 | 2018-11-20 | 西北农林科技大学 | A kind of nano antibacterial agent and preparation method thereof |
| CN108837159B (en) * | 2018-07-17 | 2021-03-30 | 西北农林科技大学 | Nano antibacterial agent and preparation method thereof |
| CN109266636A (en) * | 2018-09-25 | 2019-01-25 | 江苏大学 | A kind of nano enzyme and its preparation method and application |
| WO2021103232A1 (en) * | 2019-11-25 | 2021-06-03 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method for core-shell nanoparticles based on lipid membrane and metal organic framework |
| CN111418596A (en) * | 2020-05-29 | 2020-07-17 | 中国农业科学院植物保护研究所 | Thiofuramide-loaded folic acid/zinc nitrate gel system and preparation method and application thereof |
| CN111418596B (en) * | 2020-05-29 | 2021-01-15 | 中国农业科学院植物保护研究所 | Thiofuramide-loaded folic acid/zinc nitrate gel system and preparation method and application thereof |
| WO2022007298A1 (en) * | 2020-07-08 | 2022-01-13 | 中国科学院深圳先进技术研究院 | Composite nanosphere having fast mucus penetration, preparation method therefor and use thereof |
| WO2022261191A1 (en) * | 2021-06-08 | 2022-12-15 | University Of Georgia Research Foundation, Inc. | Nanoparticles for treating prostate cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107998404B (en) | 2021-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107998404A (en) | A kind of folate-targeted carrier for loading cancer therapy drug and its preparation method and application | |
| Ding et al. | A multimodal Metal-Organic framework based on unsaturated metal site for enhancing antitumor cytotoxicity through Chemo-Photodynamic therapy | |
| Chen et al. | Catalase-like metal–organic framework nanoparticles to enhance radiotherapy in hypoxic cancer and prevent cancer recurrence | |
| Zeng et al. | A drug‐self‐gated mesoporous antitumor nanoplatform based on pH‐sensitive dynamic covalent bond | |
| CN107095859B (en) | Drug-loaded nanocapsule with tumor cell bioreductive microenvironment sensitivity and preparation method thereof | |
| CN106806344A (en) | Poly-dopamine and the mesoporous silicon dioxide nano particle of TPGS modification and preparation method and application | |
| CN105030795B (en) | A kind of nano medicament carrying system and its preparation method and application | |
| CN105017445B (en) | PH response star polymer and micella and composite based on beta cyclodextrin | |
| CN110408047B (en) | Nano coordination polymer and preparation method and application thereof | |
| CN109771659A (en) | A kind of weary oxygen responsive nano pharmaceutical carrier and its preparation method and application | |
| CN101879427B (en) | Doxorubicin hydrochloride-carrying natural polymer-poly(3-benzene acid acrylamide) composite nanospheres, manufacturing method and application thereof | |
| CN105106970B (en) | The nanometer diamond medicine preparation and application of high capacity and pH controlled release adriamycins | |
| CN108403641A (en) | A kind of medicament-carried nano material and preparation method thereof | |
| CN108273068A (en) | Load the folate-targeted carrier and its preparation method and application of Epigallo-catechin gallate (EGCG) | |
| CN102784397B (en) | Method for loading doxorubicine (DOX) anti-cancer medicine by laponite (LAP) clay nanoparticles | |
| CN104368000A (en) | Targeting modified gold nanorod targeted drug delivery compound and application of delivery compound to anti-tumor photothermal therapy | |
| CN112972423A (en) | Cascade reaction-based nano enzyme and chemotherapeutic drug co-loaded bionic nano drug carrier and preparation method and application thereof | |
| Xing et al. | Mitochondria-targeting zeolitic imidazole frameworks to overcome platinum-resistant ovarian cancer | |
| CN101077418A (en) | Bacteria nano magnetosome loaded with primary amino medicine and preparation method thereof | |
| Liu et al. | Integration of a porous coordination network and black phosphorus nanosheets for improved photodynamic therapy of tumor | |
| CN108329404B (en) | IR-780 iodide-chitosan stearic acid graft and preparation and application thereof | |
| Solomevich et al. | Chitosan–dextran phosphate carbamate hydrogels for locally controlled co-delivery of doxorubicin and indomethacin: From computation study to in vivo pharmacokinetics | |
| CN108888775A (en) | A kind of hyaluronic acid-methotrexate (MTX) self-assembled nano micelle and preparation method thereof | |
| CN105106176A (en) | Degradable organic silicon nanocapsule drug carrier as well as preparation method and application thereof | |
| CN104398504B (en) | A kind of pharmaceutical composition of deoxypodophyllotoxin class medicine and preparation method thereof and preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |