CN104188910B - Targeting light-operated release nitric oxide nano composite material drug system and preparation method thereof - Google Patents
Targeting light-operated release nitric oxide nano composite material drug system and preparation method thereof Download PDFInfo
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Abstract
The invention provides a class has fluorescent tracing, targeted, the intracellular light-operated preparation method delivering nitric oxide production multifunctional nano drug system.Using titanium dioxide nano-particle, carbon quantum dot or graphene quantum dot etc. as carrier, as the NO donor of external source, Folic Acid, galactose molecule etc. are targeting homing device to this nanometer system for metal Ru, manganese nitrosyl compound.This nitric oxide delivers nanometer system good bio-compatibility and stability, possesses fluorescent tracing function, and energy selectivity, to specific cancerous cell light-operated delivery nitric oxide, has potential application foreground and commercial value lacking the fields such as the disease treatment causing and photodynamic therapy (PDT) about internal NO.
Description
Technical field
The present invention relates to inorganic nano drug world.Specifically, the invention provides a class to have fluorescent tracing, targeting defeated
Give, intracellular light-operated delivery nitric oxide production multifunctional nanocomposites drug system and preparation method thereof.
Background technology
Nitric oxide (NO) is a kind of endogenic biological micromolecule, has very important in a lot physiological process
Effect, such as adjusts blood pressure, immunity and inflammatory reaction, nerve conduction and apoptosis etc..The performance of NO biological function depends on it
Site, time and the dosage discharging in vivo.Low concentration (nmolL-1) NO promote cell to increase, and high concentration (μ
molL-1-mmolL-1) then can lead to the apoptosis of cell.NO is a kind of hydroxyl radical gas, easy and oxygen reaction, extremely unstable, half
Phase of declining is short.Although NO has the biological regulation function of many, due to its unstability, limit NO clinical medical
Application.Therefore, research worker wants to find a kind of ectogenic NO donor, and it can stably preserve during storing, and
If necessary by extraneous stimulation, the NO of suitable dose can be discharged in specific position, thus the treatment reaching NO mediation is made
With.
People include organic NO donor to all kinds of ectogenic NO donors and metal nitrosyl (M-NO) donor has been carried out greatly
Quantity research (Huerta, S.et al.Intl.J.Oncology2008,33,909 927；Sortino,
S.Chem.Soc.Rev.2010,39,2903–2913；Fry,N.L.et al.Acc.Chem.Res.2011,44,289-298；
Naghavi,N.,et al.Small2013,9,22–35；Kim,J.et al.J.Mater.Chem.B2014,2,341–
356.).Organic NO donor and its all kinds of delivery platforms of composition, such as organic nitrates RONO2, nitrites RONO, nitroso-group
Mercaptan RSNO etc. although NO can be discharged under certain external condition (illumination, pH value changes, temperature change etc.) stimulates, but
Such donor system is typically unstable in vivo, and the dosage of instant-free NO is uncontrollable, and lacks targeted function.And
The shortage of targeting, often leads to the killing to normal cell for the NO, thus bringing very big toxic and side effects.
Light, as a kind of Noninvasive easy-regulating means, can be accurately controlled by regulating illumination intensity and light application time
Metal nitrosyl donor discharges the dosage of NO.The metal nitrosyl donor of research mainly has metal Mn at present, the Asia such as Fe, Cr, Ru
Nitryl compound.Early stage research metal nitrosyl donor can only under the exciting of the ultraviolet light of high-energy release NO, then grind
Study carefully personnel to pass through to change the part of metal and connect some chromophores (as fluorescein, resorufin, red sulphonyl) or born
It is loaded in the surface (upper converting material, quantum dot) of some functional materials and then can discharge under visible ray, near infrared light
NO, be so conducive to application in living things system for these compounds (Rose, M.J.et al.Coord.Chem.Rev.2008,
252,2093–2114；Tfouni,E.et al.Coord.Chem.Rev.2010,254,353–371；Ford,P.C.Nitric
Oxide2013,34,56–64.).Above-mentioned metal nitrosyl donor is capable of NO in vivo by ambient light according to controlling
Release, but it is how that selectivity discharges the NO of suitable concentration and still suffers from specific region or specific cell
Challenge.
Therefore, research a kind of can pinpoint, regularly, the medicine (or system) of quantitative release NO particularly important.
Content of the invention
It is an object of the invention to provide a kind of there is targeting guiding, visible ray controlled release puts the nano composite material medicine body of NO
System and preparation method thereof.
A kind of a first aspect of the present invention, there is provided nano composite material drug system, described drug system includes：
Carrier, described carrier is nanoparticle；
The exogenous NO gas donor being linked with described carrier；With
The targeting homing device being linked with described carrier.
In another preference, described carrier is selected from the group：Titanium dioxide nano-particle, carbon quantum dot, Graphene amount
Sub- point, up-conversion nanoparticles, magnetic nano-particle or a combination thereof.
In another preference, described carrier is the carrier of surface amination.
In another preference, described exogenous NO gas donor is metal nitrosyl compounds；It is preferred that described metal is sub-
Nitryl compound has the structure shown in following formula I：
[(tpy′)M(R1)(NO)](PF6)3(I)
Wherein, tpy ' is three tooth containing n-donor ligands, is preferably selected from：4'- formic acid -2,2':6', 2 "-terpyridyl or its spread out
Biological, 2,2':6', 2 "-terpyridyl or derivatives thereof or a combination thereof；
R1For two tooth containing n-donor ligands, preferably it is selected from：DAMBO (boron two pyrrolylmethyl derivant), o-phenylenediamine class derive
Thing, diaminourea fluorescein derivative, diaminourea Rhodamine Derivatives or 3- formic acid-o-phenylenediamine or a combination thereof；
M is metal.
In another preference, tpy ' and R1In at least one contains hydroxy-acid group.
In another preference, M is selected from the group：Ru、Mn.
In another preference, described metal nitrosyl compounds are selected from the group：Metal Ru nitrosyl compound, or gold
Belong to manganese nitrosyl compound.
In another preference, described metal Ru nitrosyl compound is [(tpy ') Ru (R1)(NO)](PF6)3, wherein
Tpy ' is 4'- formic acid -2,2':6', 2 "-terpyridyl, R1For DAMBO and/or o-phenylenediamine.
In another preference, described manganese metal nitrosyl compound is [(tpy ') Mn (R1)(NO)](PF6)3, wherein
Tpy ' is 4'- formic acid -2,2':6', 2 "-terpyridyl, R1For DAMBO and/or o-phenylenediamine.
In another preference, described targeting homing device is selected from the group：Folate molecule, galactose molecule, biotin,
Or a combination thereof.
In another preference, described carrier is linked with described exogenous NO gas donor by covalent bond；And/or
In another preference, described carrier is linked with described targeting homing device by covalent bond.
In another preference, the radius of described nano composite material drug system is 3-200nm, preferably 5-
100nm.
In a second aspect of the present invention, there is provided a kind of nano composite material medicine prepared described in first aspect present invention
The method of system, methods described includes step：
(1) exogenous NO gas donor, targeting homing device and carrier nanoparticle are provided；
(2) described exogenous NO gas donor, described targeting homing device and described carrier nanoparticle are covalently loaded,
Thus forming the drug system described in first aspect present invention.
In another preference, in step (1), described exogenous NO gas donor includes metal nitrosyl compounds
[(tpy′)M(R1)(NO)](PF6)3, tpy ' is 4'- formic acid -2,2':6', 2 "-terpyridyl, M is metal Ru (Ru) or metal
Manganese (Mn), R1For DAMBO (boron two pyrrolylmethyl derivant) or o-phenylenediamine.
In another preference, described carrier nanoparticle is the nanoparticle of surface amination.
In another preference, in described step (2), first described targeting homing device is carried with described surface amination
Body nanoparticle carries out amidation process, then by described metal nitrosyl compounds and described is loaded with receiving of targeting homing device
Grain of rice subcarrier carries out amidation process, thus described nano composite material drug system is obtained.
In another preference, described exogenous NO gas donor includes metal nitrosyl compounds.
In another preference, described method also included preparing before step (1) described exogenous NO gas donor with
Lower step：
(a1) provide formula A compound,
M(tpy′)Cl3(A)
Wherein, M is metal, is preferably selected from the group：Ru、Mn；
Tpy ' is three tooth containing n-donor ligands；
(a2) in an inert atmosphere, with described M (tpy ') Cl3With R1And NH4PF6Reaction, forms [(tpy ') M (R1)
Cl](PF6)3；Wherein, R1It is selected from the group：DAMBO (boron two pyrrolylmethyl derivant) or o-phenylenediamine；
(a3) in suitable solvent, by described [(tpy ') M (R1)Cl](PF6)3React with nitrite, obtain
[(tpy′)M(R1)NO2](PF6)；
(a4) by [(tpy ') M (R1)NO2](PF6) and acid and NH4PF6Reaction, obtains described exogenous NO gas donor.
In another preference, acid is selected from the following group：HNO3、H2SO4、HPF6Or hydrochloric acid.
In another preference, described step (a2) is carried out in inert gas environment.
In another preference, described step (a4) is carried out under 0 DEG C～room temperature (as 25 DEG C).
In another preference, described method also included the following step preparing nanoparticulate carriers before step (1)
Suddenly：
By (4-NH2)-C6H4-PO3H is reacted with nanoparticle, obtains the nanoparticulate carriers of surface amination.
In another preference, nanoparticle is dispersed in the aqueous solution of pH9.
In another preference, in step (2), described nanoparticle is first reacted with targeting homing device, then again with
Exogenous NO gas supply precursor reactant, form described nano composite material drug system.
In another preference, the mol ratio of described targeting homing device and described exogenous NO gas donor is (1 ± 0.2)：(8
± 1.6), it is preferred that being (1 ± 0.5):(8±4).
In another preference, in described step (2), carry out in the presence of coupling agent, it is preferred that described coupling agent
It is selected from the group：EDC/NHS, wherein EDC are 1- ethyl -3- [3- dimethylaminopropyl] carbodiimides hydrochloride, and NHS is
N-hydroxy-succinamide.
In a third aspect of the present invention, there is provided the nano composite material medicine body described in a kind of first aspect present invention
System, and pharmaceutically acceptable carrier.
In another preference, described pharmaceutical composition also includes other as the medicine of active component.
In a fourth aspect of the present invention, there is provided the nano composite material drug system described in a kind of first aspect present invention
Purposes.For preparing medicine, described medicine is targeted drug and has visible ray controlled release NO.
In another preference, described medicine is used for regulation and control or adjusts the physiological process being selected from the group：Blood pressure, immunity,
Inflammation, nerve conduction or apoptosis.
In a fifth aspect of the present invention, there is provided a kind of method of release nitric oxide (NO), with radiation of visible light this
Nano composite material drug system described in bright first aspect, so that described nano composite material drug system discharges NO.
In another preference, the wavelength of described visible ray is 400-800nm.
In another preference, described method is non-therapeutic and nondiagnostic.
In another preference, described release is in vitro, carries out light to nano composite material drug system in solution
According to thus discharging NO.
In another preference, radiation modality is pulse irradiation or prolonged exposure.
In another preference, the light intensity of irradiation is 10-1000 milliwatt/square centimeter.
In a sixth aspect of the present invention, there is provided a kind of non-therapeutic by nano composite material drug system targeted
To the method for cell, including step：By the nano composite material drug system described in first aspect present invention and described cell one
Play incubation, the surface of wherein said cell carries the surface receptor matching with described targeting homing device or surface protein, from
And described nano composite material drug system is targeted and is delivered to described cell.
In another preference, described cell is the HeLa cell of folacin receptor overexpression.
In another preference, targeting cell is the MCF-7 cell of Folic Acid weak expression.
In another preference, described incubation conditions are 37 ± 2 DEG C (preferably 37 DEG C), 2 ± 1 hours, and described
Nano composite material drug system concentration be 5-500 mcg/ml.
In another preference, methods described also includes the release conditions with NO probe in detecting NO.
In another preference, NO probe is DAF-FM DA.
In another preference, it is little that targeting cell is incubated 1-24 together with nano composite material drug system and NO probe
When, then use radiation of visible light 0.5-30 minute again.
In a seventh aspect of the present invention, there is provided a kind of method of conveying NO, including step：Apply this to the object needing
Nano composite material drug system described in invention first aspect.
In another preference, described object includes mammal (such as people).
In another preference, described method also includes being irradiated with visible ray, thus light-operated release NO.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and having in below (eg embodiment)
Can be combined with each other between each technical characteristic of body description, thus constituting new or preferred technical scheme.As space is limited, exist
This no longer tires out one by one states.
Brief description
Fig. 1 shows nitric oxide nano composite material drug system structural representation.This system is with nanoparticle for carrying
Body, carrier cochain is connected to exogenous NO gas donor, and on carrier, chain is connected to targeting homing device simultaneously.
Fig. 2 shows { Ru-NO@TiO2Nano medication system sign.Wherein figure (A) is { Ru-NO@TiO2NPs } saturating
Penetrate electron microscope and particle diameter distribution；Figure (B) is { Ru-NO@TiO2NPs } diffuse-reflectance uv-vis spectra and infrared spectrum.
Fig. 3 shows { Ru-NO@TiO2NPs } Nano medication system illumination release NO in saline solution.Wherein figure (A) is
Visible light pulses are irradiated.{Ru-NO@TiO2NPs } concentration：2.0 mg/ml；Light intensity：100 milliwatts/square centimeter, λ>
400nm.Figure (B) is visible ray prolonged exposure.{Ru-NO@TiO2NPs } concentration：1.0 mg/ml；Light intensity：300 milliwatts/flat
Square centimetre, λ>400nm.
Fig. 4 shows { Ru-NO@TiO2NPs } Nano medication system targeting cell delivery.Wherein figure (A) is subject to for Folic Acid
The HeLa cell of body overexpression and { Ru-NO@TiO2NPs } (50.0 mcg/ml) laser after 37 DEG C of incubations 2 hours is altogether
Focused view；The MCF-7 cell of figure (B) folacin receptor weak expression and { Ru-NO@TiO2NPs } (50.0 mcg/ml) incubate in 37 DEG C
Educate the laser co-focusing figure after 2 hours.
Fig. 5 shows { Ru-NO@TiO2NPs } Nano medication system the intracellular NO of targeting deliver.Wherein figure (A) is leaf
The HeLa cell of acid acceptor overexpression and { Ru-NO@TiO2NPs } (50 μ g/mL) together with NO probe DAF-FM DA (5 μM)
Laser co-focusing figure after cultivating 6 hours.Figure (B) is HeLa cell and { the Ru-NO@TiO of folacin receptor overexpression2NPs}
(50 μ g/mL) cultivates 6 hours together with NO probe DAF-FM DA (5 μM), then with the laser copolymerization after radiation of visible light 1 minute
Jiao Tu.(light intensity：200 milliwatts/square centimeter, λ>400nm).
Specific embodiment
The present inventor, through extensively in-depth study, is screened and test by a large amount of, has been obtained a kind of new first
Targeting light-operated release NO nano composite material drug system, described system is included carrier and is linked (such as with described carrier
Be covalently attached) exogenous NO gas donor and targeting homing device.The system of the present invention not only can under visible light illumination can be rapid
Release NO molecule is it is possible to adjust release NO by regulating illumination time and intensity of illumination come (nM～μM) within a large range
Concentration.Additionally, the nano composite material drug system of the present invention also has targeting, good bio-compatibility and stability etc.
Advantage.Complete the present invention on this basis.
Term
As used herein, term " drug system of the present invention ", " system of the present invention ", " targeting light-operated release NO nanometer is multiple
Condensation material drug system ", " targeting light-operated release NO nano composite material medicine " and " light-operated release NO is nano combined for targeting
Material pharmaceutical composition " is used interchangeably, and refers both to nanoparticle as carrier, and carrier cochain is connected to exogenous NO gas donor, on carrier
Chain is connected to the compositionss of targeting homing device simultaneously.
Nanoparticulate carriers
The nanoparticulate carriers being applied to the present invention are not particularly limited, and can be various nanoparticles commonly used in the art
Carrier.Representational example includes but is not limited to：Titanium dioxide nano-particle, carbon quantum dot, graphene quantum dot, upper conversion
Nanoparticle, magnetic nano-particle or a combination thereof.
Typically, the particle diameter of nanoparticulate carriers is 3-200nm, preferably 5-100nm.
The preferred nanoparticulate carriers of one class are the carrier of surface amination.
Exogenous NO gas donor
The exogenous NO gas donor being applied to the present invention is not particularly limited, and the various exogenous NO gas that can be commonly used in the art supply
Body.Representational example includes but is not limited to：Metal nitrosyl compounds.
Typically, exogenous NO gas donor is metal Ru nitrosyl compound or manganese metal nitrosyl compound.
In the present invention, the weight of exogenous NO gas donor and nanoparticulate carriers is than for 0.8-10：100.
Targeting homing device
The targeting homing device being applied to the present invention is not particularly limited, and can be various targeting guiding commonly used in the art
Group.Representational example includes but is not limited to：Folate molecule, galactose molecule, biotin or a combination thereof.
In the present invention, the mol ratio of described targeting homing device and described exogenous NO gas donor is not particularly limited, typical case
The mol ratio of the described targeting homing device in ground and described exogenous NO gas donor is (1 ± 0.2)：(8 ± 1.6), more preferably for 1：8.
Composite drug system
The composite drug system of the present invention refers both to nanoparticle as carrier, and carrier cochain is connected to exogenous NO gas donor,
On carrier, chain is connected to the composite particles of targeting homing device simultaneously.A kind of schematic diagram of simplification is as shown in Figure 1.
The composite drug system of the present invention can be used for cell, tissue or object convey NO, thus for adjust or
Regulation and control physiological process, especially related to NO physiological process.
In another preference, described physiological process is selected from the group：Blood pressure, immunity, inflammation, nerve conduction or cell wither
Die.
Preparation method
Present invention also offers the preparation method of drug system of the present invention, generally include following steps：
(1) exogenous NO gas donor, targeting homing device and carrier nanoparticle are provided；
(2) described exogenous NO gas donor, described targeting homing device and described carrier nanoparticle are covalently loaded,
Thus forming described NO nano composite material drug system.
In another preference, in step (1), described exogenous NO gas donor includes metal nitrosyl compounds
[(tpy′)M(R1)(NO)](PF6)3, tpy ' is 4'- formic acid -2,2':6', 2 "-terpyridyl, M is metal Ru (Ru) or metal
Manganese (Mn), R1For DAMBO (boron two pyrrolylmethyl derivant) or o-phenylenediamine.
In another preference, described carrier nanoparticle is the nanoparticle of surface amination.
In another preference, described targeting homing device is selected from：Folate molecule, galactose molecule, biotin or its
Combination.
In another preference, in described step (2), first described targeting homing device is carried with described surface amination
Body nanoparticle carries out amidation process, then by described metal nitrosyl compounds and described is loaded with receiving of targeting homing device
Grain of rice subcarrier carries out amidation process, thus described nano composite material drug system is obtained.
Main advantages of the present invention include：
(1) provide one kind and can discharge rapidly NO molecule under visible light illumination it is possible to pass through the regulating illumination time
To adjust the nano composite material drug system of release NO concentration (nM～μM) with intensity of illumination.
(2) the nano composite material drug system of the present invention have blueness autofluorescence, can in cell spike medicine
The endocytosis situation of objects system, and the NO discharging in the cell can be by NO fluorescent probe (DAF-FM-DA) detecting.
(3) the nano composite material drug system of the present invention can be optionally to having folacin receptor (FR) overexpression
Tumor cell in convey (as HeLa cell).
(4) the nano composite material drug system of the present invention has good bio-compatibility under dark condition and stablizes
Property.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip
Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage ratio and number are percentage by weight and weight
Number.
The nitrosyl compound [(tpy of embodiment 1 metal RuCOOH)Ru(DAMBO)(NO)](PF6)3Synthesis
(1)[(tpyCOOH)Ru(DAMBO)(Cl)](PF6) synthesis (tpyCOOHFor 4'- formic acid -2,2':6', 2 "-three connection
Pyridine)：
Ru (tpy is added in the there-necked flask of 100mLCOOH)Cl3(150mg,0.31mmol)、DAMBO(117mg,
0.33mmol), LiCl (5mg, 2.0mmol) and Et3N0.4mL, evacuation and logical nitrogen three times respectively, add the EtOH/ of 40mL
H2O(3:1, v/v), in N2Flow back 8 hours in atmosphere, sucking filtration while hot, the dark red filtrate obtaining is concentrated to several milliliters, to be cooled arrives
After room temperature, add excessive saturation NH4PF6Solution, this mixture is placed on 5 DEG C of refrigerator overnight.Filter out rufous to sink
Form sediment, use H2O and Et2O washs three times respectively, vacuum drying.Obtain target product 182.3mg, yield is 64%.
(2)[(tpyCOOH)Ru(DAMBO)(NO2)](PF6) synthesis：
By [(tpyCOOH)Ru(DAMBO)(Cl)](PF6) (100mg, 0.11mmol) and excessive AgNO3(37mg,
0.22mmol) it is added in the round-bottomed flask of 100mL, add 30mL CH3CN-H2O(1:1, v/v), it is heated to reflux 2 hours, molten
Liquid color gradually becomes purple by redness, and this mixture is cooled to room temperature, filters out linen AgCl, adds in filtrate
Excessive NaNO2(103.5mg, 1.5mmol), is heated to reflux 6 hours, treats that solution is cooled to room temperature, solution is concentrated to several millis
Rise, add excessive saturation NH4PF6Solution, this mixture is placed on 5 DEG C of refrigerator overnight.Filter out red-brown precipitation,
Use H2O and Et2O washs three times respectively, vacuum drying.Obtain target product 78.2mg, yield is 77%.
(3)[(tpyCOOH)Ru(DAMBO)(NO)](PF6)3Synthesis：
At a temperature of 273K, by [(tpyCOOH) Ru (DAMBO) (NO2)](PF6) (100mg, 0.11mmol) be added to
In the round-bottomed flask of 25mL, then dropwise Deca 2mL HNO3(2mol·L-1) in above-mentioned solid, the solid of formation pasty state, stirs
After mixing 30 minutes, add excessive saturation NH4PF6Solution, this mixture is placed on 5 DEG C of refrigerator overnight.Filter out reddish brown
Color precipitates, and uses H2O and Et2O washs three times respectively, vacuum drying.Obtain target product 75.8mg, yield is 58%.
{ the Ru-NO@TiO of the present embodiment2The transmission electron microscope picture of Nano medication system and particle diameter distribution as shown in Figure 2 A, overflow
Reflection uv-vis spectra and the results of FT-IR such as Fig. 2 B.
Embodiment 2 nano composition drug system { Ru-NO@TiO2Synthesis
(1)NH2@TiO2(the TiO of surface amination2Nanoparticle) preparation
In the round-bottomed flask of 50mL, add 9.3mg (4-NH2)-C6H4-PO3Add the aqueous solution of 2mL pH9 after H, treat solid
After body dissolving, add 18mL TiO2Aqueous dispersion in above-mentioned solution, mixed liquor is stirred at room temperature overnight, and obtains
Dispersion liquid is centrifuged 10 minutes under 1000 turns, removes supernatant, washes nanoparticle with water twice, the surface amination obtaining
TiO2Nanoparticle, disperses in aqueous again, standby.
(2) nano composition drug system { Ru-NO@TiO2Preparation
By [(tpyCOOH)Ru(DAMBO)(NO)](PF6)3(100mg, 0.08mmol) and FA (Folic Acid) (5.0mg,
0.01mmol) it is dissolved in the DMF of 5mL, add EDC/NHS to activate 30 minutes, afterwards, add 50.0mg NH2@TiO2NPs, reaction
12 hours.Centrifugation, removes supernatant, with DMF and H2O washs three times respectively, finally gives { Ru-NO@TiO2NPs }, again disperse
Yu Shuizhong.
Embodiment 3 { Ru-NO@TiO2NPs } Nano medication system pulsed light photograph release NO in saline solution
{Ru-NO@TiO2NPs } concentration：2.0mg/mL；
Light intensity：100 milliwatts/square centimeter, λ>400nm.
By visible light pulses (5 seconds to the 25 seconds) irradiating sample of different time, measurement result is as shown in A in Fig. 3.
Result：The nitric oxide concentration detecting in solution is incremented by (in Fig. 3 shown in A) with the burst length.This shows, passes through
The regulation burst length can obtain immediately required suitable nitric oxide concentration.
Embodiment 4 { Ru-NO@TiO2NPs } Nano medication system continuous light release NO in saline solution
{Ru-NO@TiO2NPs } concentration：1.0mg/mL；
Light intensity：300 milliwatts/square centimeter, λ>400nm.
The nitric oxide solution of about 9 micromoles per liter can be obtained by the sample of lasting radiation of visible light 1.0mg/mL,
In the prolonged exposure of 2-3 hour, this concentration remains unchanged (in Fig. 3 shown in B).
Embodiment 5 { Ru-NO@TiO2NPs } Nano medication system targeting cell delivery
HeLa cell and { Ru-NO@TiO by folacin receptor overexpression2NPs } (50.0 μ g/mL) in 37 DEG C be incubated, 2
Carry out laser co-focusing observation after hour.
Result：Obvious blue-fluorescence can be observed in HeLa cell, this result shows { Ru-NO@TiO in a large number2NPs}
Nanometer system has been enter into cell, and major part is distributed in Cytoplasm, is also distributed (in Fig. 4 shown in A) in nucleus.If extending training
Time of educating, to 8 hours, can be observed to enter nuclear amount showed increased.
Embodiment 6 { Ru-NO@TiO2NPs } Nano medication system targeting cell delivery
MCF-7 cell and { Ru-NO@TiO by folacin receptor weak expression2NPs } (50.0 μ g/mL), in 37 DEG C of incubations, 2 is little
When after carry out laser co-focusing observation.
Result：Only observe faint blue-fluorescence in MCF-7 cell, this result shows { Ru-NO@TiO2NPs } receive
Rice system enters the amount less (in Fig. 4 shown in B) of MCF-7 cell.
Embodiment 7 { Ru-NO@TiO2NPs } Nano medication system the intracellular NO of targeting deliver
HeLa cell and { Ru-NO@TiO by folacin receptor overexpression2NPs } (50 μ g/mL) and NO probe DAF-FM
DA (5 μM) cultivates together, carries out laser co-focusing observation after 6 hours.
Result：Under the conditions of there is no light irradiation, only observe that NO probe shows that the faint green of probe itself is glimmering in the cell
Light (in Fig. 5 shown in A).
Embodiment 8 { Ru-NO@TiO2NPs } Nano medication system the intracellular NO of targeting deliver
HeLa cell and { Ru-NO@TiO by folacin receptor overexpression2NPs } (50 μ g/mL) and NO probe DAF-FM
DA (5 μM) cultivates 6 hours together, then with, after radiation of visible light 1 minute, carrying out laser co-focusing observation.(light intensity：200 milliwatts/
Square centimeter, λ>400nm).
Result：It was observed that NO probe shows very strong green fluorescence (Fig. 5 in the cell under the conditions of radiation of visible light
Shown in middle B), this result shows to can achieve the intracellular nitric oxide releasing of targeting by controlling the irradiation of light.
The all documents referring in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to like that.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, those skilled in the art can
To make various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (8)
1. a kind of nano composite material drug system is it is characterised in that described drug system includes：
Carrier, described carrier is nanoparticle；
The exogenous NO gas donor being linked with described carrier；With
The targeting homing device being linked with described carrier,
Wherein, described carrier is selected from the group：Titanium dioxide nano-particle, carbon quantum dot and/or graphene quantum dot；
Wherein, under described exogenous NO gas donor is metal nitrosyl compounds, and described metal nitrosyl compounds have
Structure shown in Formulas I：[(tpy′)M(R1)(NO)](PF6)3(I),
Wherein, tpy ' is three tooth containing n-donor ligands, is selected from：4'- formic acid -2,2':6', 2 "-terpyridyl, 2,2':6', 2 "-three connection
Pyridine or a combination thereof；
R1For two tooth containing n-donor ligands, it is selected from：DAMBO (boron two pyrrolylmethyl), o-phenylenediamine class or a combination thereof；Wherein, M is metal
Ru.
2. drug system as claimed in claim 1 is it is characterised in that described targeting homing device is selected from the group：Folic Acid is divided
Son, galactose molecule, biotin or a combination thereof.
3. drug system as claimed in claim 1 is it is characterised in that described carrier passes through covalent bond and described exogenous NO gas confession
Body phase links；And/or
Described carrier is linked with described targeting homing device by covalent bond.
4. a kind of method preparing nano composite material drug system as claimed in claim 1 is it is characterised in that methods described
Including step：
(1) exogenous NO gas donor, targeting homing device and carrier nanoparticle are provided；
(2) described exogenous NO gas donor, described targeting homing device and described carrier nanoparticle are covalently loaded, thus
Form drug system as claimed in claim 1.
5. method as claimed in claim 4 is it is characterised in that described method also included described in preparation before step (1)
Exogenous NO gas donor following steps：
(a1) provide formula A compound,
M(tpy′)Cl3(A)
Wherein, M is metal；
Tpy ' is three tooth containing n-donor ligands；
(a2) in an inert atmosphere, with described M (tpy ') Cl3With R1And NH4PF6Reaction, forms [(tpy ') M (R1)Cl]
(PF6)3；Wherein, R1It is selected from the group：DAMBO (boron two pyrrolylmethyl) or o-phenylenediamine；
(a3) in suitable solvent, by described [(tpy ') M (R1)Cl](PF6)3React with nitrite, obtain [(tpy ') M
(R1)NO2](PF6)；
(a4) by [(tpy ') M (R1)NO2](PF6) and acid and NH4PF6Reaction, obtains described exogenous NO gas donor.
6. method as claimed in claim 4, it is characterized by, described method also included preparing nanoparticle before step (1)
The following steps of subcarrier：
By (4-NH2)-C6H4-PO3H is reacted with nanoparticle, obtains the nanoparticulate carriers of surface amination.
7. a kind of pharmaceutical composition is it is characterised in that include：Described nano composite material medicine as arbitrary in claim 1-3
System, and pharmaceutically acceptable carrier.
8. the purposes of described nano composite material drug system as arbitrary in claim 1-3 is it is characterised in that be used for preparing medicine
Thing, described medicine is targeted drug and has visible ray controlled release NO.
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| TWI624269B (en) * | 2016-07-05 | 2018-05-21 | 郭文碩 | One-and two-photon photoexcited photodynamic therapy and contrast agent with graphene-based quantum dots |
| KR102373273B1 (en) * | 2017-04-18 | 2022-03-15 | 기초과학연구원 | Polymeric gel, and method of manufacturing the same, and product using the same |
| CN107961375B (en) * | 2017-10-24 | 2020-12-08 | 中国科学院高能物理研究所 | Metal sulfide nano material and preparation method and application thereof |
| CN109289052B (en) * | 2018-12-04 | 2022-02-08 | 华东理工大学 | Nitric oxide and cis-platinum targeted combined controllable drug delivery nano-drug system and preparation |
| CN110632142B (en) * | 2019-08-28 | 2022-03-15 | 江南大学 | Preparation method and application of electrochemical biosensor based on gold palladium-graphene quantum dot composite material |
| CN111481737A (en) * | 2020-05-07 | 2020-08-04 | 华东理工大学 | Magnetic temperature-sensitive hydrogel for near-infrared light-controlled release of nitric oxide, and preparation and application thereof |
| CN113082206B (en) * | 2021-04-27 | 2023-04-21 | 中国药科大学 | Macromolecule nitric oxide donor modified up-conversion nanoparticle, preparation method and application |
| CN114588272B (en) * | 2022-04-08 | 2023-05-26 | 皖西学院 | NO-loaded docetaxel nano-drug and preparation method and application thereof |
| CN115006526B (en) * | 2022-05-16 | 2022-12-16 | 中山大学附属口腔医院 | Photodynamic TiO 2 Composite nano particle and preparation method and application thereof |
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