CN107648619A - The composite drug-loaded systems of magnetic crust core MOFs, the preparation method and applications of a kind of post aromatic hydrocarbons nano-valve controlled release - Google Patents
The composite drug-loaded systems of magnetic crust core MOFs, the preparation method and applications of a kind of post aromatic hydrocarbons nano-valve controlled release Download PDFInfo
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Abstract
The composite drug-loaded systems of magnetic crust core MOFs, the preparation method and applications of a kind of post aromatic hydrocarbons nano-valve controlled release, belong to composite drug-loaded system technical field.It is with Fe3O4For paralinin, MOFs reaction mother liquors directly react to form magnetic crust core MOFs with the paralinin by way of growth in situ, then " connecting shaft " molecular modification is carried out to the installation for the post aromatic hydrocarbons nano-valve that follow-up host-guest interaction power mediates by rear modification mode on the magnetic crust core MOFs materials for being loaded with medicine, realize the controlled release under the stimulation of lesion environmental factor.By the type for changing post aromatic hydrocarbons nano-valve and " connecting shaft " molecule, it is possible to achieve the slow release of medicine under stimuli responsive.It is controllable that whole composite diagnostic and therapeutic system using the controllability of nano-valve is that opportunity realizes targeting drug release, insoluble drug release behavior, and supramolecular chemistry and materials chemistry organically combine the fixed point that can realize multifunctionality in the present invention, timing, positioning are treated so as to improve disease treatment efficiency.
Description
Technical field
The technology of the present invention belongs to composite drug-loaded system technical field, and in particular to a kind of big PAH-post aromatic hydrocarbons nanometer valve
Gate the composite drug-loaded systems of magnetic crust core MOFs, the preparation method and applications released.The present invention realize Magneto separate, magnetic resonance into
The controlled drug release integration of the multiple stimulation response of picture synergy, is advantageously implemented the timing of composite drug-loaded system, determines
Point, positioning treatment, improve disease treatment efficiency.
Background technology
Metal-organic framework material (MOFs) emerging is formed as a kind of by metal ion/ion cluster connection organic ligand
Hybridization porous material, by the extensive concern of researcher since synthesis.The loose structure of high-sequential, big ratio table
The good properties such as area, structural constituent adjustability, scale topography controllability, functional diversity and good biocompatibility,
MOFs materials are promoted to be exhibited one's skill to the full in terms of medicament transport and disease treatment.At present, the medicament transport system based on MOFs materials
Some achievements are had been achieved with diagnostic and therapeutic system, such as：Development of Novel MOFs as medicine-carried system (Chem.Commun., 2016,52,
3669), organic-inorganic nano particle and MOFs is compound prepares medical system (Adv.Mater.2015,27,4075), although more than
Method has promoted development of the MOFs materials in medical field, but realizes the fixed point under lesion environment, timing, positioning realizing controlled-release
Medicine and visualizing monitor treatment remain one of general orientation of MOFs medical material future developments.Therefore, development is a kind of simple
Efficient diagnostic and therapeutic system, supermolecule nano valve and functional shell core MOFs composites are combined and give full play to each several part material
Synergy it is imperative to improve therapeutic efficiency.
With the development of supramolecular chemistry and macrocyclic compound, from crown ether, cyclodextrin, calixarenes, Cucurbituril again to post virtue
Hydrocarbon, more and more the macrocyclic compound system based on host-guest interaction turn into medical field research object.Post aromatic hydrocarbons conduct
A kind of artificial synthesized macrocycle molecule of new generation, have high degree of symmetry rigid structure, unique host-guest chemistry property and
It is easy to the superior function of functionalization.Therefore, the host-guest complex pseudorotaxane molecule prepared based on post aromatic hydrocarbons can be considered as one
The controllable nano-valve of kind, can obtain the valve system of different elasticities, together by regulating and controlling the intermolecular adhesion of Subjective and Objective
When this Subjective and Objective adhesion can be stimulated factor destroy realize fixed point, timing, positioning valve opening.If will be controllable
The MOFs nano material combination collaborations of post aromatic hydrocarbons nano-valve and core-shell structure play a role, that is, say, nuclear material can be with
Realize the effect of auxiliary diagnosis or synergistic treatment, MOFs shell materials can be while controllable as " between the storage " of drug molecule
The post aromatic hydrocarbons nano-valve of unlatching can selectively unlock the drug therapy for realizing fixed point under lesion environmental stimulus, this medical
The design of platform or the realization of theory will enrich existing medical material, while by material science and the organic knot of medical science
Close, supramolecular chemistry and materials chemistry are organically combined and provide a good thinking of development for the development of disease treatment.
Modified in view of the design of the existing diagnostic and therapeutic system based on MOFs materials does not have been reported that also with supermolecule nano valve
To prepare the composite drug-loaded system of multifunction, the application is actively studied and innovated core-shell structure MOFs, has finally prepared one
The composite drug-loaded systems of MOFs of kind " intelligence ", are later intelligence in a manner of expanding the combination of supramolecular chemistry and material science
The energy compound diagnostic and therapeutic system of type develops new direction.
The content of the invention
It is an object of the invention to provide a kind of composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release, after
The preparation method and applications of synthetic modification.Described composite drug-loaded system realizes that multiple stimulation responds controllable under lesion environment
Release and sustained release, diagnosis and synergistic treatment integration, it is based on improving therapeutic efficiency on the basis of MOFs diagnostic and therapeutic systems existing, it is real
The controlled drug release and treatment of existing magnetic function synergic effect.
Technical scheme is as follows：
A kind of magnetic crust core MOFs of the post aromatic hydrocarbons nano-valve controlled release prepared by rear synthetic modification method is composite drug-loaded
System, it is with Fe3O4For paralinin, MOFs reaction mother liquors directly react to form magnetic with the paralinin by way of growth in situ
Property shell core MOFs (there is MOFs shell nuclear materials preferable porosity, pore volume and specific surface area can be used as " the goods such as drug molecule
" between the storage " of thing "), " connecting shaft " molecular modification is then being loaded with by the magnetic crust core MOFs of medicine by rear modification mode
The installation of the post aromatic hydrocarbons nano-valve of follow-up host-guest interaction power mediation is carried out on material, realize stimulates in lesion environmental factor
Under controlled release.By changing the type of post aromatic hydrocarbons nano-valve and " connecting shaft " molecule, host and guest between the two can be adjusted
Body active force, the nano-valve with different elasticities can be installed and realize slow release under stimuli responsive.Whole composite wood
The design of material diagnostic and therapeutic system has given full play to the synergy of material each several part, using the designability of magnetic crust core MOFs materials as
Divergence point, high drug load, the disease treatment of magnetic mediation are realized, targeting is realized as opportunity using the controllability of nano-valve and released
Medicine, insoluble drug release behavior are controllable, and supramolecular chemistry and materials chemistry, which organically combine, in the present invention can realize determining for multifunctionality
Point, timing, positioning are treated so as to improve disease treatment efficiency.The implementation of this design concept will be MOFs and supermolecule molecule machine
A piece of wide sky is opened up in the development and clinical practice of device composite.
Specifically, a kind of preparation method of the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release, its
Step is as follows：
1) preparation of magnetic crust core MOFs materials：
MOFs precursor solutions are added in the mixed solution of magnetropism nuclear material, polyvinylpyrrolidone and organic solvent, are surpassed
After sound is uniformly dispersed, 30~40h is reacted in 80~100 DEG C in ptfe autoclave, separates, wash, be dried to obtain magnetic
Property shell core MOFs materials；
2) the rear modification of function shell core MOFs materials
The magnetic crust core MOFs materials and " connecting shaft " molecule that step 1) is obtained are with mass ratio 1：1.5~2 ratio point
Dissipate in organic solvent, 70~80h of back flow reaction under the conditions of 80~150 DEG C, cooling, separation, washing, dry be made after synthesize and repair
The shell core MOFs composites of decorations；
3) MOFs composites carry the installation of medicine and nano-valve
The shell core MOFs composites and drug molecule for the rear synthetic modification that step 2) is obtained are with mass ratio 1：1.29~
1.5 ratio is added to the water, and shakes 20~30h at normal temperatures, then adds post aromatic hydrocarbons and continues concussion 1.5~3 days, separation,
Wash, be dried to obtain the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release；The shell core MOFs after medicine is carried to answer
The mass ratio of condensation material and post aromatic hydrocarbons is 1：1.5~5；
Preferably, magnetic nuclear material is the 10~20nm for having good magnetic resonance T2 weighted imagings ability and Magneto separate ability
The Fe of particle diameter3O4Nano-particle.
MOFs precursor solutions described in step 1) are the mixing of zirconium chloride and 2- amino terephthaldehyde's acid organic solutions, instead
Should after can obtain the UiO-66MOF (Zr MOF) that biocompatibility is good, load capacity is strong, is easy to functionalization；
Described organic solvent is N,N-dimethylformamide (DMF).
Above-mentioned " connecting shaft " molecule is the pyridine that preparation method is simple, cost is cheap, has appropriate key and ability with post aromatic hydrocarbons
Salt, quaternary ammonium salt, imidazole salts equimolecular, preferably 1- (6- bromohexanes) pyridinium bromide ".
The good water-soluble post aromatic hydrocarbons of the above-mentioned preferred biocompatibility of post aromatic hydrocarbons.
The composite drug-loaded systems of shell core MOFs of post aromatic hydrocarbons nano-valve controlled release prepared by the above method discharge in controlled drug
Had a wide range of applications with terms for the treatment of.
The effect of the composite drug-loaded systems of multi-functional MOFs of nano-valve controlled release prepared by the present invention is mainly manifested in following
Aspect：
1) the feature kernel as system, Fe3O4Nano-particle is easy to MOFs materials on growth in situ as matrix and is used for
Medicament storage simultaneously imparts the good Magneto separate performance of whole medicine-carried system, facilitates the quick processing purification of target product, together
When, realize medicament transport and the chemotherapy of the magnetic resonance imaging mediation of compound system.
2) the nano-valve system based on host-guest interaction has constructed a kind of pseudorotaxane type molecule machine, realizes
Controlled drug under multiple lesion factor stimulates discharges, it can be understood as realizes another targeted therapy effect and improves treatment
Efficiency.
3) adjustability of the host-guest interaction power of post aromatic hydrocarbons and " connecting shaft " molecule causes the tightness of nano-valve not
Together, it is variant to there is the speed of lower valve opening in different stimulus i.e. " key ", the speed for causing drug molecule to discharge
It is different.Under comparing, Subjective and Objective key is opened slowly with big valve is acted on, and drug release degree reaches the sustained release on medical demands
Effect.
To sum up, the present invention has following beneficial effect：
1st, new medicine-carried system of the invention is reasonable in design flexibly, and it is convenient to prepare, shell core MOFs structure and nano-valve
Design the function of flexibility can be carried out according to Treatment need replace, prepared for the design of following multi-functional diagnostic and therapeutic system
Thinking is expanded.
2、Fe3O4Nano inner core structure is modified after being easy to and assigns whole composite drug-loaded system good magnetic property, good
Magneto separate performance facilitates the preparative separation of material, and magnetic resonance imaging property makes whole treatment visualization, facilitates monitoring treatment.
3rd, develop that increasingly rapid MOFs material structures are flexible and changeable, designability is strong, have big medicine efficiency of loading,
The serial superiority such as good biocompatibility, causes people and more and more pays close attention to, it is excellent that the present invention takes full advantage of MOFs
Different Drug loading capacity and modifiability, application of the MOFs materials in medical field is expanded.
4th, made using the aromatic hydrocarbons sodium salt (WP5/WP6) of carboxyl post five/six as the representative of water-soluble post aromatic hydrocarbons with pyridine molecules of salt
For the representative of " connecting shaft " molecule, the representative of drug molecule is used as using 5 FU 5 fluorouracil (5-Fu), it was demonstrated that make based on Subjective and Objective
By the use of water-soluble post aromatic hydrocarbons pseudorotaxane in the present invention as controllable nano-valve can lesion factor (pH, metal ion,
Temperature) multiple stimulation response release drug molecule, while can be by adjusting the size controllable adjustment valve of host-guest interaction
Open, realize fixed point, timing, the insoluble drug release of positioning and the treatment of medicine-carried system.
5th, in the present invention, the nano-valve based on water-soluble post aromatic hydrocarbons organically combines with magnetic crust core MOFs materials, association
With playing a role, integrate Magnetic Isolation, magnetic resonance imaging, efficiently carry medicine, multiple stimulation response release, be sustained.This is new
The development of big PAH nano molecular machine and MOFs composites and using providing new direction after being designed as of system.
Brief description of the drawings
Fig. 1 (A) shows Fe prepared by embodiment 13O4The SEM of nano-particle schemes, and TEM image shows to implement in Fig. 1 (B)
Fe prepared by example 53O4@UiO-66@WP6 sizes are about 40nm, and TEM enlarged drawings therein show Fe prepared by embodiment 53O4@
Fe is implicitly present in UiO-66@WP6 materials3O4, Fig. 1 (C), which is shown, installs material before and after WP6 nano-valves in embodiment 5
XRD comparison diagrams, Fig. 1 (D) show that the modification of WP6 nano-valves is front and rear and carries the FTIR spectrograms of material after medicine in embodiment 5.
Fig. 2 shows pyridiniujm " connecting shaft " molecule Py in embodiment 31H NMR scheme.
Fig. 3 shows the Fe prepared in embodiment 53O4Before and after the non-medicine-carried system WP6 nano-valves installations of@UiO-66@WP6
Potential comparison diagram and the Fe for preparing of 5-Fu and embodiment 53O4The potential of@UiO-66@5-Fu@WP6 medicine-carried systems.
Fig. 4 shows Fe prepared by embodiment 53O4The composite drug-loaded systems of@UiO-66 5-Fu WP6 are fast under external magnetic field
Speed separation photo, wherein before figure (a) is separation；After scheming (b) for separation.
Fig. 5 shows Fe prepared by embodiment 53O4The@UiO-66@composite drug-loaded systems of 5-Fu@WP6 different pH (figure A),
Various concentrations Zn2+(figure B), various concentrations Ca2+Controllable unlatching under (figure C), different temperatures (figure D) multiple stimulation response and its
Drug release situation curve.
Fig. 6 shows Fe prepared by embodiment 53O4The@UiO-66@composite drug-loaded systems of 5-Fu@WP5 different pH (figure A),
Various concentrations Zn2+(figure B), various concentrations Ca2+Controllable unlatching under (figure C), different temperatures (figure D) multiple stimulation response and its
Drug release situation curve.
Fig. 7 shows magnetic resonance imaging figure and the T2 relaxation times of cellular level, wherein figure (A) is not add composite
Hela cell magnetic resonance imaging figures and T2 relaxation times；It is to add Fe prepared by embodiment 5 to scheme (B)3O4@UiO-66@WP6 are compound
Magnetic resonance imaging figure and its T2 relaxation time of the material in Hela cells.
Embodiment
The present invention can be further illustrated by following examples, embodiment is to illustrate the invention without limitation originally
Invention, protection scope of the present invention are not restricted to this.
Embodiment 1
Based on Fe3O4The preparation of the feature kernel of nano-particle
By FeCl in nitrogen atmosphere3·6H2O (11.68g) and FeCl2·4H2O (4.30g) is dissolved in 200mL ultra-pure waters
In, 500rpm stirs 2h under the conditions of 85 DEG C, adds the NH that 40mL volume fractions are 25% afterwards3·H2O, under the conditions of 85 DEG C
500rpm stirring reactions 1h.Room temperature, Magnetic Isolation are cooled to after the completion of reaction, washs 1 time successively with water and ethanol, be dry obtained
Fe3O4Nano-particle.SEM characterizes the Fe in explanation embodiment 13O4Nano-particles size is 10-15nm, such as Fig. 1 (A).
Embodiment 2
The preparation of magnetic MOFs materials
Fe in Example 13O4Nano-particle (50mg) is scattered in 5mL polyvinylpyrrolidones (25mg) DMF solution
In, ultrasonic reaction 1h；Zirconium chloride (25.17mg) and 2- amino terephthalic acid (TPA) (19.47mg) are dissolved in DMF (10mL) respectively
In, sequentially add in above-mentioned mixed solution, gained mixed liquor is transferred in reactor 12h is reacted at 80 DEG C, at 100 DEG C
React 24h, after the completion of reaction by sample be cooled to room temperature, Magnetic Isolation, successively with DMF and ethanol wash successively 3 times, drying obtain
Obtain magnetic MOFs materials (Fe3O4@UiO-66), quality 100mg.
Embodiment 3
Connect the preparation of molecular shaft 1- (6- bromohexanes) pyridinium bromides (Py)
10mL 1,6- bromohexanes are added to 100mL CH2Cl2In, 1mL pyridine is slowly added dropwise into above-mentioned mixed liquor,
Back flow reaction 36h at 70 DEG C, cooling, decompression distillation, dry obtained Py molecules.
(Py):1H NMR(500MHz,D2O) δ 8.86 (d, J=6.1Hz, 2H), 8.56 (t, J=7.9Hz, 1H), 8.09
(t, J=7.0Hz, 2H), 4.64 (t, J=7.3Hz, 2H), 3.51 (t, J=6.7Hz, 2H), 2.15-1.99 (m, 2H), 1.95-
1.78 (m, 2H), 1.50 (m, J=7.4Hz, 2H), 1.39 (m, J=7.9Hz, 2H)1H NMR spectras such as Fig. 2.
Embodiment 4
The rear modification of magnetic MOFs materials
The Fe that will be prepared in embodiment 23O4@UiO-66 (30mg) are dispersed in 30mL DMF, are added 50mg embodiments 3 and are made
Py, flow back at 80 DEG C 12h, and flow back 12h at 100 DEG C, and flow back 24h at 120 DEG C, after the 24h that flowed back at 150 DEG C, cooling, magnetic
Separate, washed successively 3 times with DMF and ethanol successively, is dried to obtain the magnetic MOFs composites (Fe of Py modifications3O4@UiO-66-
NH-Py)。
Embodiment 5
Post aromatic hydrocarbons nano-valve modifies Fe respectively3O4The@UiO-66-NH-Py and Fe after load medicine3O4@UiO-66-NH-Py
Fe prepared by embodiment 43O4@UiO-66-NH-Py composites (1mg), add 3mL cancer therapy drugs 5-Fu
(3.3mM) aqueous solution, shakes 24h on shaking table at room temperature, adds 5mg water-soluble post aromatic hydrocarbons nano-valve molecule WP6
(J.Am.Chem.Soc.2012,134,13248-13251) continue concussion 2 days, Magnetic Isolation, be washed with water 3 times, dry be made
Composite drug-loaded system (the Fe of nano-valve molecule controlled release3O4@UiO-66@5-Fu@WP6)。
The Fe of water-soluble post aromatic hydrocarbons nano-valve molecule WP6 controlled releases3O4@UiO-66-NH-Py do not carry medicine composite
(Fe3O4@UiO-66@WP6) preparation method be same as above, other conditions are identical, and 3mL cancer therapy drugs 5-Fu (3.3mM) aqueous solution is changed
For the 3mL aqueous solution, will not be repeated here.
WP5 (Chem.Sci., 2015,6,1640-1644) nano-valve system preparation method is same as above, simply by matter such as WP6
Amount replaces with WP5, will not be repeated here.
TEM image illustrates the Fe prepared in embodiment 53O4@UiO-66@WP6 size is about 40nm, black in TEM enlarged drawings
Line surrounds part it can be seen that Fe3O4It is clearly present the Fe prepared in embodiment 53O4In@UiO-66@WP6 materials, such as Figure 1B.
It is front and rear to Fe that XRD data illustrate to install WP6 nano-valves in embodiment 53O4With the crystal formations of UiO-66MOF materials without influence,
Such as Fig. 1 C；The FTIR spectrograms of material before and after WP6 is installed are contrasted, illustrate the Fe in embodiment 53O4@UiO-66@WP6 materials are prepared into
Work(, carry the Fe after medicine3O4The FTIR spectrograms of@UiO-66 5-Fu WP6 medicine-carried systems demonstrate medicine and loaded successfully, such as Fig. 1 D.Electricity
Fe before and after the modification of WP6 nano-valves in gesture as shown by data embodiment 53O4The surface of@UiO-66 materials is changed into negative electricity from positive potential
Gesture, prove that WP6 nano-valves are modified successfully from side, the loading of 5-Fu drug molecules causes potential smaller, illustrates in embodiment 5
Medicine-carried system preparation method it is feasible, such as Fig. 3.
The positive effect of the present invention place is shown by experimental example in detail below：
Composite drug-loaded system in the present invention, which organically combines each several part material and cooperateed with, plays maximum effect, magnetic Nano
The function core of particle assigns whole medicine-carried system good magnetic property, and first, good magnetic facilitates the preparation processing of material
Process, carry medicine after whole system can in 15s or so under external magnetic field separating-purifying, such as Fig. 4.In addition, Fe3O4Receive
Rice corpuscles realizes the diagnosis and treatment integration of magnetic resonance imaging mediation as good contrast agent.It can be seen from Fig. 7, contrast is single
The magnetic resonance imaging figure and T2 relaxation time values (Fig. 7 A) of Hela cells, the composite prepared under conditions of embodiment 5 exists
There is good magnetic resonance imaging ability (Fig. 7 B) in Hela cells, add Fe3O4It is bright to darken effect for imaging after@UiO-66@WP6
Show, and the T2 relaxation times greatly shorten, and illustrate that the T2- magnetic resonance imaging abilities of material are good.
MOFs materials receive more and more attention in terms of bio-medical, and MOFs is as drug molecule 5-Fu in the present invention
Storage between there is gratifying Drug loading capacity (0.805 μm of oL/mg).The MOFs materials prepare it is simple and be easy to modification and
Can very easily growth in situ in Fe3O4Nuclear material surface, which is formed in core-shell structure and functionalization, connects molecular shaft, after convenient
The installation of continuous nano-valve.
The presence of water-soluble post aromatic hydrocarbons nano-valve assigns present invention intelligence controllable property.Water-soluble post aromatic hydrocarbons nanometer valve
Door and connection molecular shaft Py are assembled into regulatable nano-valve by host-guest interaction and switched, in the stimulation of lesion environmental factor
Under, corresponding host-guest interaction, which weakens, causes valve to be opened, and the drug molecule for being stored in MOFs shells discharges and plays chemistry
The effect for the treatment of.Such as Fig. 5 A, when the composite drug-loaded system in embodiment 5 is under the pH environment of normal human cell, medicine in 2h
Thing is only released less than 15%, but when pH is down to the lesion environment for being equal to cancer cell, drug molecule release is accelerated, identical
Time in burst size increase 2 times.Using this property, the composite drug-loaded system in the present invention is realized under carninomatosis changing environment
Intelligent chemotherapy, improves therapeutic efficiency.Meanwhile Fig. 5 B and Fig. 5 C illustrate the Zn related to sacred disease2+Concentration abnormality or height
Ca caused by caalcemia2+Concentration rise can also turn into the stimulus that the composite drug-loaded system nano-valve is opened, and illustrate this
Invention is with a wide range of applications in terms of disease treatment.In addition, high temperature can kill cancer cell, at the same raise temperature can be with
Weakening the host-guest interaction between water-soluble post aromatic hydrocarbons and Py molecules causes valve to open insoluble drug release (Fig. 5 D), prepared by the present invention
Composite drug-loaded system can organically combine thermotherapy and chemotherapy, both act synergistically improve therapeutic efficiency.
Because the host-guest interaction power between water-soluble post aromatic hydrocarbons and connection molecular shaft Py can act on molecule by change
It is adjusted, two kinds is prepared for using WP6 and the water-soluble post aromatic hydrocarbons of two kinds of WP5 and the difference of Py host-guest interaction power in the present invention
The compound system of nano-valve modification.WP6 and Py adhesions (Ka ≈ (3.26 ± 0.28) × 105M-1) than WP5 system (Ka ≈
(2.5±0.7)×103M-1) it is big, as shown in Figure 6, the medicine-carried system based on WP5 nano-valves is in identical incentive condition
Lower rate of releasing drug is much bigger, proves that the composite drug-loaded system of WP6 modifications can not only realize fixed point, positioning, timing from side
Treatment, slow releasing function can also be played and improve diagnosis and treatment efficiency.Reach slow release treatment by regulating and controlling the tightness of nano-valve
Effect, the invention provides new thinking for the design of later nano-valve diagnostic and therapeutic system.
Claims (9)
1. a kind of preparation method of the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release, its step are as follows：
1) preparation of magnetic crust core MOFs materials
MOFs precursor solutions, ultrasound point are added in the mixed solution of magnetropism nuclear material, polyvinylpyrrolidone and organic solvent
After dissipating uniformly, 30~40h is reacted in 80~100 DEG C in ptfe autoclave, separates, wash, be dried to obtain magnetic crust
Core MOFs materials；
2) the rear modification of function shell core MOFs materials
The magnetic crust core MOFs materials and " connecting shaft " molecule that step 1) is obtained are with mass ratio 1：1.5~2 ratio is dispersed in
In organic solvent, 70~80h of back flow reaction under the conditions of 80~150 DEG C, cooling, separation, wash, dry synthetic modification after being made
Shell core MOFs composites；
3) MOFs composites carry the installation of medicine and nano-valve
The shell core MOFs composites and drug molecule for the rear synthetic modification that step 2) is obtained are with mass ratio 1：1.29~1.5
Ratio is added to the water, and shakes 20~30h at normal temperatures, then adds post aromatic hydrocarbons and continues concussion 1.5~3 days, separate, wash,
It is dried to obtain the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release；Carry the shell core MOFs composites after medicine
Mass ratio with post aromatic hydrocarbons is 1：1.5~5.
A kind of 2. preparation of the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release as claimed in claim 1
Method, it is characterised in that：Magnetic nuclear material is the Fe of 10~20nm particle diameters3O4Nano-particle.
A kind of 3. preparation of the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release as claimed in claim 1
Method, it is characterised in that：MOFs precursor solutions are the mixing of zirconium chloride and 2- amino terephthaldehyde's acid organic solutions, after reaction
Obtain the UiO-66MOF that biocompatibility is good, load capacity is strong, is easy to functionalization.
A kind of 4. preparation of the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release as claimed in claim 1
Method, it is characterised in that：Organic solvent is N,N-dimethylformamide.
A kind of 5. preparation of the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release as claimed in claim 1
Method, it is characterised in that：" connecting shaft " molecule is pyridiniujm, quaternary ammonium salt or imidazoles molecules of salt.
A kind of 6. preparation of the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release as claimed in claim 5
Method, it is characterised in that：" connecting shaft " molecule is 1- (6- bromohexanes) pyridinium bromide.
A kind of 7. preparation of the composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release as claimed in claim 1
Method, it is characterised in that：Post aromatic hydrocarbons is water-soluble post aromatic hydrocarbons.
A kind of 8. composite drug-loaded systems of magnetic crust core MOFs of post aromatic hydrocarbons nano-valve controlled release, it is characterised in that：Being will by right
1~7 any one methods described is asked to be prepared.
9. the composite drug-loaded systems of magnetic crust core MOFs of the post aromatic hydrocarbons nano-valve controlled release described in claim 8 are released in controlled drug
Put and treatment in terms of application.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108714216A (en) * | 2018-06-04 | 2018-10-30 | 吉林大学 | Chemotherapy-photo-thermal combination therapy cancer compound system of double targeting mediations, preparation method and applications |
| CN109432436A (en) * | 2018-09-10 | 2019-03-08 | 上海大学 | Polypeptide conjugate, preparation method and its application based on column aromatic hydrocarbons |
| CN113777100A (en) * | 2021-08-27 | 2021-12-10 | 厦门大学 | Quantitative substance controlled release system and method based on host-guest action |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105148852A (en) * | 2015-10-12 | 2015-12-16 | 武汉大学 | Thiohydroxy-modified magnetic MOFs adsorbent and preparation method and application thereof |
-
2017
- 2017-10-23 CN CN201710989577.3A patent/CN107648619A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105148852A (en) * | 2015-10-12 | 2015-12-16 | 武汉大学 | Thiohydroxy-modified magnetic MOFs adsorbent and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| LI-LI TAN等: ""Stimuli-responsive metal–organic frameworks gated by pillar[5]arene supramolecular switches"", 《CHEM. SCI.》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108714216A (en) * | 2018-06-04 | 2018-10-30 | 吉林大学 | Chemotherapy-photo-thermal combination therapy cancer compound system of double targeting mediations, preparation method and applications |
| CN108714216B (en) * | 2018-06-04 | 2020-12-08 | 吉林大学 | Double-targeting mediated chemotherapy-photothermal combined treatment cancer composite system, preparation method and application thereof |
| CN109432436A (en) * | 2018-09-10 | 2019-03-08 | 上海大学 | Polypeptide conjugate, preparation method and its application based on column aromatic hydrocarbons |
| CN109432436B (en) * | 2018-09-10 | 2022-07-08 | 上海大学 | Polypeptide conjugate based on pillar arene, preparation method and application thereof |
| CN113777100A (en) * | 2021-08-27 | 2021-12-10 | 厦门大学 | Quantitative substance controlled release system and method based on host-guest action |
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