CN103755888B - A kind of amphipathic nature polyalcohol and preparation, magnetic hollow nano-medicament carrier and its preparation method - Google Patents
A kind of amphipathic nature polyalcohol and preparation, magnetic hollow nano-medicament carrier and its preparation method Download PDFInfo
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Abstract
The invention discloses a kind of amphipathic nature polyalcohol containing near infrared sensitive group and preparation method thereof and comprise the near infrared light of this amphipathic nature polyalcohol and the magnetic hollow nano-medicament carrier of pH double-response and preparation method thereof.The hollow porous ferroferric oxide nanoparticle that pre-synthesis multi-functional amphipathic nature polyalcohol to be wrapped in load medicine by the method for self-assembly by contriver is outer, form hud typed high capacity amount pharmaceutical carrier, the method compares that conventional to carry out chemically modified on ferriferrous oxide nano-particle surface more simple and convenient, simultaneously first carrying medicament wrap up polymkeric substance again method also than after chemically modified again carrying medicament there is higher drug loading; By controlling the release of medicine as direct light source to the strong near infrared light of human body Low Damage, penetration into tissue, can accurately Co ntrolled release position and time of releasing, reduce Normocellular injury.
Description
Technical field
The invention belongs to technical field of polymer materials, relate to a kind of amphipathic nature polyalcohol containing near infrared sensitive group and preparation method thereof and comprise the near infrared light of this amphipathic nature polyalcohol and the magnetic hollow nano-medicament carrier of pH double-response and preparation method thereof.
Background technology
Hollow porous ferroferric oxide nanoparticle (HPFe
3o
4) be prepared from pentacarbonyl iron thermolysis oxidation, there is nuclear magnetic resonance (MRI) effect that particle diameter little (10 ~ 20nm), superparamagnetism are strong and good.Due to its Stability Analysis of Structures, and hollow kernel can improve the Drug loading capacity of ferriferrous oxide nano-particle to a great extent.In addition, the ferriferrous oxide nano-particle of porous is stable existence under neutral or basic conditions, but under slightly acidic condition, the duct of ferriferrous oxide nano-particle can corrode by acid and cause larger aperture and rate of release faster, therefore hollow porous ferroferric oxide nanoparticle can be used to some hydrophobicity tumour medicines of load.But inornate hollow porous ferroferric oxide nanoparticle is due to its surface hydrophobicity, cannot realize separately in water medium physiological environment the targeted drug delivery of tumour cell or lesions position and the Co ntrolled release after entering cell thereof.Therefore, carrying out finishing by the method for physics or chemistry to hollow porous ferroferric oxide, give this nano-carrier with tumor-targeting, controllable release performance and cell fluorescence imaging function etc., is the main path solving this class problem.
The structure designability of amphipathic nature polyalcohol (referring to simultaneously contain in molecular structure the polymkeric substance of hydrophilic radical and hydrophobic grouping) is utilized can more easily to realize the integrated of polymkeric substance several functions by the method for chemosynthesis.
In order to reach the object of controllable release, the amphipathic nature polyalcohol of environmental response type can be used to carry out controlled drug transmission usually.Environmental response type refers under outside environmental stimulus (as pH, light, heat, enzyme etc.), and fracture occurs polymkeric substance or hydrophilic-hydrophobic balance transforms.Wherein light activated polymkeric substance can in tumour external control, and can accurately controlled light position and light application time, has more advantage.The polymkeric substance (as azo polymer) of current light activated polymkeric substance mainly visible ray and ultraviolet-sensitive, their can absorb by tissue and significantly reduce light intensity, and UV-light also can have infringement to human normal cell and tissue, therefore this base polymer is restricted clinically.The near infrared light utilizing energy lower then can effectively solve this problem as direct light source.The wavelength region of near infrared light is at 700 ~ 1000nm, very little to human injury, and has good penetration into tissue, is therefore more suitable for the direct light source being used as light-operated drug delivery system.
Summary of the invention
In view of this, an object of the present invention is to provide a kind of amphipathic nature polyalcohol containing near infrared sensitive group.
Amphipathic nature polyalcohol containing near infrared sensitive group provided by the invention, has the structure shown in formula (I):
Wherein, R
1, R
2independently for carbonatoms is more than or equal to 8, is less than or equal to the straight chained alkyl of 20;
FA is folic acid;
N is the natural number of 10 ~ 20;
X, y and z are natural number, and 10≤x≤30,30≤y≤150,1≤z≤5.
Present invention provides a kind of method preparing the above-mentioned amphipathic nature polyalcohol containing near infrared sensitive group, specifically comprise the steps:
(1) photosensitive monomer of structure formula (II) Suo Shi and methoxypolyethylene glycol methacrylic ester (PEG), N-hydroxy-succinamide acrylate (NSA) and initiator are dissolved in solvent a; 60 ~ 80 DEG C of reaction 6 ~ 10h under inactive gas protection; separate out in solvent b; obtain the polymkeric substance of structure shown in formula (III); wherein, R
1, R
2independently for carbonatoms is more than or equal to 8, is less than or equal to the straight chained alkyl of 20; N is the natural number of 10 ~ 20; X, y and z are natural number, and 10≤x≤30,30≤y≤150,1≤z≤5;
(2) polymkeric substance that step (1) is obtained is dissolved in solvent c, adds the folic acid of 1 ~ 5wt%, stir 24 ~ 48h under normal temperature, separate out in solvent b, obtain the amphipathic nature polyalcohol of structure shown in formula (I).
In technique scheme, described initiator is azo-initiator.
Preferably, described initiator is Diisopropyl azodicarboxylate or 2,2'-Azobis(2,4-dimethylvaleronitrile).
In technique scheme, described inactive gas is nitrogen or argon gas.
In technique scheme, described solvent a is pimelinketone, DMF or dimethyl sulfoxide (DMSO).
In technique scheme, described solvent b is low polar solvent.
Preferably, described solvent b is the sherwood oil of boiling point 60 ~ 90 DEG C, normal hexane or ether.
In technique scheme, described solvent c is DMF or dimethyl sulfoxide (DMSO).
In technique scheme, described photosensitive monomer, the molar feed ratio of PEG, NSA are 1:(3 ~ 6): (0.1 ~ 0.5).
Two of object of the present invention be to provide a kind of drug loading high, there is Targeting Effect and can fluorescence and magnetic resonance radiography be carried out, and the nano combined pharmaceutical carrier of Co ntrolled release cancer therapy drug under near infrared light and under tumor locus acidity, i.e. a kind of magnetic hollow nano-medicament carrier comprising the above-mentioned amphipathic nature polyalcohol containing near infrared sensitive group.
Magnetic hollow nano-medicament carrier provided by the invention, there is nucleocapsid structure, its kernel is hollow porous ferroferric oxide nanoparticle, shell is the above-mentioned amphipathic nature polyalcohol containing near infrared sensitive group, and described amphipathic nature polyalcohol is wrapped in the skin of hollow porous ferroferric oxide nanoparticle.
Preferably, described hollow porous ferroferric oxide nano particle diameter is 10 ~ 30nm.
Present invention provides a kind of method preparing above-mentioned magnetic hollow nano-medicament carrier, specifically comprise the steps:
1, the preparation of hollow porous ferroferric oxide nanoparticle
(preparation method is at J.Am.Chem.Soc.2009, and on the basis of 131,10637, improvement forms)
Inject pentacarbonyl iron in 1-octadecylene under oleyl amine and inactive gas protection, be warming up to 100 ~ 150 DEG C, reaction 20 ~ 40min, obtains Fe/Fe
3o
4nanometer bead, oxidizer oxidation Fe wherein, reaction 1 ~ 2h, obtains hollow Fe
3o
4nanometer bead, is warming up to 250 ~ 300 DEG C of perforates, obtains hollow porous ferroferric oxide nanoparticle;
In technique scheme, described inactive gas is nitrogen or argon gas.
In technique scheme, described oxygenant is oxygen or trimethylamine-N-oxide.
In technique scheme, the volume ratio that feeds intake of described oleyl amine and pentacarbonyl iron is 1:(0.2 ~ 5.0).
In technique scheme, by regulating and controlling the ratio control Fe of oleyl amine and pentacarbonyl iron
3o
4the size (10 ~ 30nm) of nanometer bead.
In technique scheme, within the scope of 250 ~ 300 DEG C, raised temperature or prolongation can expand Fe in the reaction times (1 ~ 4h) of high temperature
3o
4the aperture of nanometer bead.
The synthesis of the amphipathic nature polyalcohol 2, containing near infrared sensitive group
The method containing the amphipathic nature polyalcohol of near infrared sensitive group according to above-mentioned preparation prepares the amphipathic nature polyalcohol containing near infrared sensitive group;
3, the self-assembly of hollow porous ferroferric oxide nanoparticle and amphipathic nature polyalcohol
The amphipathic nature polyalcohol that step 2 is obtained is dissolved in tetrahydrofuran (THF), ultrasonic disperse is even, the hollow porous ferroferric oxide nanoparticle sonic oscillation that step 1 is obtained is scattered in wherein, while stirring water droplet is added in mixing solutions, continue to stir until tetrahydrofuran (THF) volatilization is clean, obtain the magnetic hollow nano-medicament carrier of target product.
Preferably, the feed ratio of described amphipathic nature polyalcohol, tetrahydrofuran (THF), hollow porous ferroferric oxide nanoparticle and water is 20 ~ 30mg:1 ~ 2mL:5 ~ 10mg:5 ~ 10mL.
Preferably, after preparing described hollow porous ferroferric oxide nanoparticle, first carry out the load of medicine, then carry out self-assembly with described amphipathic nature polyalcohol.
The hollow porous ferroferric oxide nanoparticle that pre-synthesis multi-functional amphipathic nature polyalcohol to be wrapped in load medicine by the method for self-assembly by contriver is outer, form hud typed high capacity amount pharmaceutical carrier, the method compares that conventional to carry out chemically modified on ferriferrous oxide nano-particle surface more simple and convenient, simultaneously first carrying medicament wrap up polymkeric substance again method also than after chemically modified again carrying medicament there is higher drug loading.
The magnetic hollow nano-medicament carrier of near infrared light disclosed by the invention (800nm) and pH Dual Sensitive can be used for targeted and the Co ntrolled release of medicine, has fluorescence and magnetic resonance radiography function concurrently simultaneously.This magnetic hollow nano-medicament carrier with hollow porous ferroferric oxide nanoparticle for core, after carrying medicament, realize self-assembly by the oleophylic section in the oleic acid moieties of Z 250 particle surface and amphipathic nature polyalcohol, amphipathic nature polyalcohol that is responsive containing near infrared and target function is wrapped in the skin of ferriferrous oxide nano-particle.This magnetic hollow nano-medicament carrier can be enriched to tumor locus by carrying medicament with folate-targeted group because of surface.By the near infrared light of outside, the polymer layer on nano-carrier surface is disintegrated, and discharges the medicine of inner institute load.Now, ferriferrous oxide nano-particle is completely exposed under the sour environment of inside tumor, and its duct is slowly corroded, thus accelerates the process of drug release.All the distribution of nano-medicament carrier in tumour cell and the release conditions of medicine can be observed by fluoroscopic visualization or magnetic resonance radiography in above process.
The advantage of magnetic hollow nano-medicament carrier of the present invention is, by controlling the release of medicine as direct light source to the strong near infrared light of human body Low Damage, penetration into tissue, can accurately Co ntrolled release position and time of releasing, reduce Normocellular injury.The nanostructure of hollow porous that simultaneously ferriferrous oxide nano-particle has can improve drug loading largely.And the Z 250 kernel comprised in this core-shell type nano mixture and polymeric shell layer with coumarin fluorescent group be respectively magnetic resonance radiography and cell fluorescence radiography provides approach.
Accompanying drawing explanation
In order to be illustrated more clearly in the technical scheme in the embodiment of the present invention, below the accompanying drawing used required in describing embodiment is briefly described, apparently, accompanying drawing for the present invention in the following describes is only some embodiments of the present invention, for those of ordinary skill in the art, under the prerequisite not paying creative work, other accompanying drawing can also be obtained according to these accompanying drawings.
Fig. 1 is HPFe prepared by embodiment 1
3o
4x-ray diffractogram (XRD);
Fig. 2 is Fe in embodiment 1 and embodiment 6
3o
4the transmission electron microscope picture (TEM) of different synthesis phase, wherein a is Fe/Fe
3o
4, b is HFe
3o
4, c is HPFe
3o
4, d is the HPFe of parcel amphipathic nature polyalcohol
3o
4;
Fig. 3 is the release conditions graphic representation of nano combined pharmaceutical carrier at different light and pH Imitating medicine of embodiment 7;
Fig. 4 is the HPFe of embodiment 8
3o
4the cytotoxicity situation histogram of nanoparticle in KB cell.
Embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, be described in detail the technical scheme in the embodiment of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skill in the art obtain under the prerequisite not making creative work, all belongs to the scope of protection of the invention.
The present invention's each raw material used all can be buied by market.
Embodiment 1
Synthesis hollow porous ferroferric oxide (HPFe
3o
4), concrete steps are as follows:
0.15mL oleyl amine is added in 20mL1-octadecylene, at 120 DEG C, logical argon-degassed 2h; after be warming up to 180 DEG C; add the pentacarbonyl iron (argon shield) of 1.4mL immediately, constantly stir 30min, be then cooled to room temperature; incline supernatant liquid; add the mixed solution dispersion of normal hexane and oleyl amine, add isopropanol precipitating, after centrifugal; again wash 2 times with the mixed solution of normal hexane and oleyl amine, the nanoparticle dispersion finally obtained is in the mixed solution of 15mL normal hexane and 0.01mL oleyl amine.The nanoparticle obtained is Fe/Fe
3o
4core-shell nanospheres.
Add 30mg trimethylamine-N-oxide in 20mL1-octadecylene, at 130 DEG C, logical argon-degassed 2h, adds the above-mentioned Fe/Fe containing 80mg
3o
4hexane solution, keep 130 DEG C continue stir removing normal hexanes, after at 130 DEG C, keep 12h, be warming up to 250 DEG C, keep 1h, be cooled to room temperature, add 40mL ethanol, be dispersed in after centrifugal in the mixing solutions of normal hexane and oleyl amine, then the ethanol adding 40mL centrifugal after be dispersed in normal hexane.The nanoparticle obtained is the Fe of hollow
3o
4(HFe
3o
4).
20mL dibenzyl ether mixed solution containing 0.17mL and 0.16mL oleic acid, at 120 DEG C of logical degas with nitrogen 2h, adds the above-mentioned HFe containing 50mg
3o
4hexane solution, keep 30min remove normal hexane, be warming up to 300 DEG C, maintenance 30min, be cooled to room temperature, add 30mL ethanol, centrifugal rear normal hexane, ethanol wash 3 times, after be distributed in normal hexane.The nanoparticle obtained is the Fe of hollow porous
3o
4(HPFe
3o
4).
Embodiment 2 and embodiment 3 are the synthesis of hydrophobic monomer
Embodiment 2
Two dodecylamino-4-hydroxymethylcoumarin methacrylic ester (DDACMM) of synthesis 7-:
22g Ortho-Aminophenol adds 150mL and contains in the ethyl acetate of 25g saleratus and 10mL water, after under ice bath, continuous stirring dropwise adds 18mL methyl-chloroformate, reaction 1h, add 50mL water and stir 3h, after separatory, organic phase uses the sulphuric acid soln of water, 1mol/L, water and saturated common salt water washing respectively, after revolving steaming after dried over mgso, use benzene recrystallization, obtain compound 1.
23g compound 1 adds in the mixed solution of 25mL methyl aceto acetate and the 60mL vitriol oil, adds the frozen water of 250mL after stirring 2h, and continue to be stirred to crystallization and stop, filter, filter cake obtains compound 2 with drying after water, methyl alcohol, washed with diethylether respectively.
The compound 2 of 28g adds in the potassium hydroxide solution of 60mL45%, formation solution is constantly stirred at 85 DEG C, filter after adding 200mL water after cooling, add alkali lye add hydrochloric acid tune pH to 5 ~ 6 under ice bath after and be adjusted to 8, be stirred to stopping crystallization, after filtration, with water, methyl alcohol, washed with diethylether, drying obtains compound 3.Compound 3 proton nmr spectra result is as follows:
1hNMR (DMSO, 400MHz): δ 7.42 (d, J=8.0Hz, 1H, Ar-H), 6.58 (d, J=8.0Hz, 1H, Ar-H), 6.42 (s, 1H, Ar-H), 6.11 (s, 2H, NH
2), 5.92 (s, 1H, Ar-H), 2.32 (s, 3H, CH
3).
2.66g compound 3 and 38.46g lauryl bromide are dissolved in the N of 250mL, in dinethylformamide, add 7.4g cesium carbonate, back flow reaction 12h, underpressure distillation DMF, add water and ethyl acetate separatory, after organic phase washed with water and saturated common salt water washing, anhydrous magnesium sulfate drying, with ethyl acetate after revolving steaming: sherwood oil=1:4 crosses post, obtains compound 4.Compound 4 proton nmr spectra result is as follows:
1hNMR (CDCl
3, 400MHz): δ 7.36 (d, J=8.0Hz, 1H, Ar-H), 6.55 (d, J=8.0Hz, 1H, Ar-H), 6.49 (s, 1H, Ar-H), 5.99 (s, 1H, Ar-H), 3.64 (t, J=12.0Hz, 1H, N-CH
2cH
2), 3.16 (t, J=12.0HZ, 3H, N-CH
2cH
2), 2.34 (s, 3H, CH
3), 1.72-1.47 (m, 4H, N-CH
2), 1.45-1.15 (m, 36H, CH
2), 0.88 (t, J=16Hz, 6H, CH
3).
8.9g compound 4 is dissolved in 150mL dimethylbenzene, adds 13.4g tin anhydride back flow reaction 24h, crosses and filters tin anhydride, boil off dimethylbenzene, add 150mL methyl alcohol/tetrahydrofuran (THF) (1:1, V:V) solution, 3.86g sodium borohydride is progressively added in above-mentioned solution, stirring at normal temperature 4h, after add hydrochloric acid and be neutralized to neutrality, revolve steaming, raffinate dichloromethane extraction, with anhydrous magnesium sulfate drying after saturated common salt water washing, be spin-dried for rear methylene dichloride: acetone=5:1 crosses post, obtain compound 5.Compound 5 proton nmr spectra result is as follows:
1hNMR (DMSO, 400MHz): δ 10.14 (s, 1H, Ar-H), 7.61 (t, J=19.6Hz, 2H, Ar-H), 7.39 (d, J=10.4Hz, 1H, Ar-H), 6.33 (s, 1H, N-CH
2cH
2), 5.64 (t, J=11.2Hz, 1H, OH), 4.73 (d, J=4.8Hz, 3H, N-CH
2cH
2), 4.13 (t, J=13.2,2H, OCH
2), 1.63-1.66 (m, 4H, N-CH
2), 1.25 (s, 36H, CH
2), 0.86 (t, J=13.2, CH
3).
527mg compound 5 is dissolved in 50mL anhydrous tetrahydro furan, add the triethylamine of 4mL, after under ice bath, constantly drip 1.5mL methacrylic chloride, stirring at normal temperature 4h, revolve steaming after filtration, add methylene dichloride and dissolve, with anhydrous magnesium sulfate drying after salt of wormwood and saturated common salt water washing, evaporate to dryness normal hexane recrystallization, obtains Compound D DACMM.Compound D DACMM proton nmr spectra result is as follows:
1hNMR (CDCl
3, 400MHz): δ 7.29 (s, 1H, Ar-H), 6.52 (t, J=18.8Hz, 3H, Ar-H), 6.25 (s, 1H, CCH
2), 6.19 (s, 1H, CCH
2), 5.69 (s, 1H, N-CH
2cH
2), 5.28 (d, J=32.4,3H, N-CH
2cH
2), 3.17 (t, J=14.4,2H, CH
2), 2.02 (s, 3H, CH
3), 1.67-1.63 (m, 4H, N-CH
2), 1.47-1.26 (m, 36H, CH
2), 0.88 (t, J=12.8,6H, CH
3).
Embodiment 3
Synthesis 7-double hexadecyl amino-4-hydroxymethylcoumarin methacrylic ester (DHACMM)
With reference to the 2-in-1 one-tenth compound 3 of embodiment.
Get 2.66g compound 3 and be dissolved in 250mLN with 47.12g hexadecyl bromine, in dinethylformamide, add 7.4g cesium carbonate, back flow reaction 12h, underpressure distillation DMF, add water and ethyl acetate separatory, after organic phase washed with water and saturated common salt water washing, anhydrous magnesium sulfate drying, with ethyl acetate after revolving steaming: sherwood oil=1:4 crosses post, obtains compound 6.Compound 6 proton nmr spectra result is as follows:
1hNMR (CDCl
3, 400MHz): δ 7.36 (d, J=8.0Hz, 1H, Ar-H), 6.55 (d, J=8.0Hz, 1H, Ar-H), 6.49 (s, 1H, Ar-H), 5.99 (s, 1H, Ar-H), 3.64 (t, J=12.0Hz, 1H, N-CH
2cH
2), 3.14 (t, J=12.0HZ, 3H, N-CH
2cH
2), 2.34 (s, 3H, CH
3), 1.72-1.47 (m, 4H, N-CH
2), 1.45-1.05 (m, 44H, CH
2), 0.88 (t, J=16Hz, 6H, CH
3).
9.86g compound 6 is dissolved in 150mL dimethylbenzene, adds 13.4g tin anhydride back flow reaction 24h, crosses and filters tin anhydride, boil off dimethylbenzene, add 150mL methyl alcohol/tetrahydrofuran (THF) (1:1, V:V) solution, 3.86g sodium borohydride is progressively added in above-mentioned solution, stirring at normal temperature 4h, after add hydrochloric acid and be neutralized to neutrality, revolve steaming, raffinate dichloromethane extraction, with anhydrous magnesium sulfate drying after saturated common salt water washing, be spin-dried for rear methylene dichloride: acetone=6:1 crosses post, obtain compound 7.Compound 7 proton nmr spectra result is as follows:
1hNMR (DMSO, 400MHz): δ 10.14 (s, 1H, Ar-H), 7.61 (t, J=19.6Hz, 2H, Ar-H), 7.39 (d, J=10.4Hz, 1H, Ar-H), 6.33 (s, 1H, N-CH
2cH
2), 5.64 (t, J=11.2Hz, 1H, OH), 4.73 (d, J=4.8Hz, 3H, N-CH
2cH
2), 4.13 (t, J=13.2,2H, OCH
2), 1.63-1.66 (m, 4H, N-CH
2), 1.25 (s, 44H, CH
2), 0.86 (t, J=13.2, CH
3).
583mg compound 7 is dissolved in 50mL anhydrous tetrahydro furan, add the triethylamine of 4mL, after under ice bath, constantly drip 1.5mL methacrylic chloride, stirring at normal temperature 4h, revolve steaming after filtration, add methylene dichloride and dissolve, with anhydrous magnesium sulfate drying after salt of wormwood and saturated common salt water washing, evaporate to dryness normal hexane recrystallization, obtains Compound D HACMM.Compound D HACMM proton nmr spectra result is as follows:
1hNMR (CDCl
3, 400MHz): δ 7.27 (s, 1H, Ar-H), 6.50 (t, J=18.8Hz, 3H, Ar-H), 6.25 (s, 1H, CCH
2), 6.19 (s, 1H, CCH
2), 5.69 (s, 1H, N-CH
2cH
2), 5.28 (d, J=32.4,3H, N-CH
2cH
2), 3.16 (t, J=14.4,2H, CH
2), 2.12 (s, 3H, CH
3), 1.66-1.63 (m, 4H, N-CH
2), 1.47-1.26 (m, 44H, CH
2), 0.88 (t, J=12.8,6H, CH
3).
Embodiment 4 and embodiment 5 are the synthesis of amphipathic nature polyalcohol.
Embodiment 4
By gained monomer DDACMM synthetic polymer DDACMM-PEG-FA in embodiment 2
168mgDDACMM, 1.6gPEG, 23mgNSA, 3.4mgAIBN are dissolved in refining pimelinketone, under argon shield, 70 DEG C of reaction 8h, separate out and obtain polymkeric substance DDACMM-PEG in sherwood oil.Proton nmr spectra result is as follows:
1hNMR (CDCl
3, 400MHz), δ (ppm): 4.08 (COOCH
2cH
2), 3.89-3.14 (CH
2oCH
2), 1.24 (CH
2), 0.85 (CH
3).
Getting 180mgDDACMM-PEG is dissolved in DMSO, adds 4mg folic acid, separates out after stirring at normal temperature 48h in sherwood oil, obtains polymkeric substance DDACMM-PEG-FA.Proton nmr spectra result is as follows:
1hNMR (d6-DMSO, 400MHz), δ (ppm): 8.64-6.65 (folicacid), 4.00 (COOCH
2cH
2), 3.85-2.99 (CH
2oCH
2), 1.24 (CH
2), 0.84 (CH
3).
Embodiment 5
By gained monomer DHACMM synthetic polymer DHACMM-PEG-FA in embodiment 3
182mgDHACMM, 1.6gPEG, 23mgNSA, 3.4mgAIBN are dissolved in refining pimelinketone, under argon shield, 70 DEG C of reaction 8h, separate out and obtain polymkeric substance DHACMM-PEG in sherwood oil.Proton nmr spectra result is as follows:
1hNMR (CDCl
3, 400MHz), δ (ppm): 4.09 (COOCH
2cH
2), 3.88-3.14 (CH
2oCH
2), 1.24 (CH
2), 0.82 (CH
3).
Getting 180mgDHACMM-PEG is dissolved in DMSO, adds 4mg folic acid, separates out after stirring at normal temperature 48h in sherwood oil, obtains polymkeric substance DHACMM-PEG-FA.Proton nmr spectra result is as follows:
1hNMR (d6-DMSO, 400MHz), δ (ppm): 8.65-6.65 (folicacid), 4.02 (COOCH
2cH
2), 3.85-3.02 (CH
2oCH
2), 1.24 (CH
2), 0.86 (CH
3).
Embodiment 6
By 5mgHPFe
3o
4be dissolved in 1mL tetrahydrofuran (THF) with 30mg polymkeric substance DDACMM-PEG-FA, under constantly stirring, tetrahydrofuran (THF) constantly volatilizees, and the oleic acid outside Z 250 is connected by Intermolecular Forces with the oleophylic chain in polymkeric substance, finally forms a polymer layer outward at Z 250.
Accompanying drawing 2 is transmission electron microscope pictures (TEM) of nano combined carrier, and figure c is HPFe
3o
4, obviously can see nano pore, figure d is the HPFe having wrapped up polymkeric substance
3o
4, can obviously see outer field polymer layer, also can see that particle diameter is approximately 18nm simultaneously.
Embodiment 7
Zorubicin is used for the drug loading of Study of Support and load efficiency as aids drug.Z 250 is scattered in the solution being dissolved with a certain amount of Zorubicin, stirs after spending the night, by centrifugal, supernatant liquor is taken out.The concentration of the Zorubicin of original solution and centrifuged supernatant is by the fluorescence intensity (λ in solution
ex=475nm and λ
em=592nm) contrast can calculate drug loading with pharmaceutical standards curve values.Table 1 lists drug loading and the medicine carrying efficiency of nano-carrier.
Drug loading and load efficiency can be drawn by following formula:
Drug loading (wt.%)=(carrying medicament quality/carrier quality) × 100%;
Medicine carrying efficiency (%)=(carrying medicament quality/original solution drug quality) × 100%.
Table 1
By the Z 250 after carrying medicament and amphipathic nature polyalcohol self-assembly, by the nanoparticle dispersion after self-assembly in SBF, and under different outside atmosphere stimulates the concentration of Zorubicin in test soln, thus determine the release conditions of Zorubicin.
Accompanying drawing 3 is the release conditions that different outside atmosphere stimulates lower medicine.As pH=5.0, under not having suitable outside atmosphere to stimulate, medicine is only having and is seldom discharging from carrier.In addition, under suitable illumination, there is fracture and come off from Z 250 surface in polymkeric substance, medicine can discharge timely in carrier, illustrates that this medicament nano carrier has very high susceptibility near infrared light.Simultaneously when pH=5.0 compares at pH=7.4, the release amount of medicine of 24h exceeds 13%, illustrates that this nanoparticle can accelerate release efficiency under sour environment.
Embodiment 8
By the HPFe prepared
3o
4nanoparticle is used for the cytotoxicity of test to human oral cavity epithelial cancer cells (KB).Accompanying drawing 4 shows, and the survival rate of the nanoparticle cultured cells of pure near infrared light and non-illumination is all higher than 90%, and the nanoparticle of non-carrying medicament also demonstrates quite high cell survival rate after illumination.After load aids drug (DOX), after illumination 30min, cell survival rate is only 55%, this shows that this nanoparticle is not before carrying out illumination, substantially harmless to cell, cancer therapy drug release after illumination, thus kills cancer cells.
To those skilled in the art, obviously the invention is not restricted to the details of above-mentioned one exemplary embodiment, and when not deviating from spirit of the present invention or essential characteristic, the present invention can be realized in other specific forms.Therefore, no matter from which point, all should embodiment be regarded as exemplary, and be nonrestrictive, scope of the present invention is limited by claims instead of above-mentioned explanation, and all changes be therefore intended in the implication of the equivalency by dropping on claim and scope are included in the present invention.
In addition, be to be understood that, although this specification sheets is described according to embodiment, but not each embodiment only comprises an independently technical scheme, this narrating mode of specification sheets is only for clarity sake, those skilled in the art should by specification sheets integrally, and the technical scheme in each embodiment also through appropriately combined, can form other embodiments that it will be appreciated by those skilled in the art that.
Claims (19)
1. the amphipathic nature polyalcohol containing near infrared sensitive group, has the structure shown in formula (I):
Wherein, R
1, R
2independently for carbonatoms is more than or equal to 8, is less than or equal to the straight chained alkyl of 20;
FA is folic acid;
N is the natural number of 10 ~ 20;
X, y and z are natural number, and 10≤x≤30,30≤y≤150,1≤z≤5.
2. prepare a method for the amphipathic nature polyalcohol containing near infrared sensitive group according to claim 1, it is characterized in that, comprise the steps:
(1) photosensitive monomer of structure formula (II) Suo Shi and methoxypolyethylene glycol methacrylic ester, N-hydroxy-succinamide acrylate and initiator are dissolved in solvent a, 60 ~ 80 DEG C of reaction 6 ~ 10h under inactive gas protection, separate out in solvent b, obtain the polymkeric substance of structure shown in formula (III);
Wherein, R
1, R
2independently for carbonatoms is more than or equal to 8, is less than or equal to the straight chained alkyl of 20; N is the natural number of 10 ~ 20; X, y and z are natural number, and 10≤x≤30,30≤y≤150,1≤z≤5;
(2) polymkeric substance that step (1) is obtained is dissolved in solvent c, adds the folic acid of 1 ~ 5wt%, stir 24 ~ 48h under normal temperature, separate out in solvent b, obtain the amphipathic nature polyalcohol of structure shown in formula (I).
3. method according to claim 2, is characterized in that: described initiator is azo-initiator.
4. method according to claim 3, is characterized in that: described initiator is Diisopropyl azodicarboxylate or 2,2'-Azobis(2,4-dimethylvaleronitrile).
5. method according to claim 2, is characterized in that: described inactive gas is nitrogen or argon gas.
6. method according to claim 2, is characterized in that: described solvent a is pimelinketone, DMF or dimethyl sulfoxide (DMSO).
7. method according to claim 2, is characterized in that: described solvent b is low polar solvent.
8. method according to claim 7, is characterized in that: described solvent b is the sherwood oil of boiling point 60 ~ 90 DEG C, normal hexane or ether.
9. method according to claim 2, is characterized in that: described solvent c is DMF or dimethyl sulfoxide (DMSO).
10. method according to claim 2, is characterized in that: the molar feed ratio of described photosensitive monomer, methoxypolyethylene glycol methacrylic ester, N-hydroxy-succinamide acrylate is 1:(3 ~ 6): (0.1 ~ 0.5).
11. 1 kinds of magnetic hollow nano-medicament carriers, it is characterized in that: there is nucleocapsid structure, kernel is hollow porous ferroferric oxide nanoparticle, shell is the amphipathic nature polyalcohol containing near infrared sensitive group according to claim 1, and described amphipathic nature polyalcohol is wrapped in the skin of hollow porous ferroferric oxide nanoparticle.
12. magnetic hollow nano-medicament carriers according to claim 11, is characterized in that: described hollow porous ferroferric oxide nano particle diameter is 10 ~ 30nm.
13. 1 kinds of methods preparing the magnetic hollow nano-medicament carrier described in claim 11 or 12, is characterized in that, comprise the steps:
(1) preparation of hollow porous ferroferric oxide nanoparticle
Inject pentacarbonyl iron in 1-octadecylene under oleyl amine and inactive gas protection, be warming up to 100 ~ 150 DEG C, reaction 20 ~ 40min, obtains Fe/Fe
3o
4nanometer bead, oxidizer oxidation Fe wherein, reaction 1 ~ 2h, obtains hollow Fe
3o
4nanometer bead, is warming up to 250 ~ 300 DEG C of perforates, obtains hollow porous ferroferric oxide nanoparticle;
(2) synthesis of the amphipathic nature polyalcohol containing near infrared sensitive group
Method according to any one of claim 2 ~ 10 prepares the amphipathic nature polyalcohol containing near infrared sensitive group;
(3) self-assembly of hollow porous ferroferric oxide nanoparticle and amphipathic nature polyalcohol
The amphipathic nature polyalcohol that step (2) is obtained is dissolved in tetrahydrofuran (THF), ultrasonic disperse is even, the hollow porous ferroferric oxide nanoparticle sonic oscillation that step (1) is obtained is scattered in wherein, while stirring water droplet is added in mixing solutions, continue to stir until tetrahydrofuran (THF) volatilization is clean, obtain the magnetic hollow nano-medicament carrier of target product.
14. methods according to claim 13, is characterized in that: in step (1), and described inactive gas is nitrogen or argon gas.
15. methods according to claim 13, is characterized in that: described oxygenant is oxygen or trimethylamine-N-oxide.
16. methods according to claim 13, is characterized in that: the volume ratio that feeds intake of described oleyl amine and pentacarbonyl iron is 1:(0.2 ~ 5.0).
17. methods according to claim 13, is characterized in that: in step (1), obtain hollow Fe
3o
4after nanometer bead, be warming up to 250 ~ 300 DEG C of perforate 1 ~ 4h.
18. methods according to claim 13, it is characterized in that: in step (3), the feed ratio of described amphipathic nature polyalcohol, tetrahydrofuran (THF), hollow porous ferroferric oxide nanoparticle and water is 20 ~ 30mg:1 ~ 2mL:5 ~ 10mg:5 ~ 10mL.
19. methods according to claim 13, is characterized in that: after preparing described hollow porous ferroferric oxide nanoparticle, first carry out the load of medicine, then carry out self-assembly with described amphipathic nature polyalcohol.
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