CN103120797B - The nano-medicament carrier of reduction response, Nano medication granule and Nano medication granular preparation and preparation method thereof - Google Patents
The nano-medicament carrier of reduction response, Nano medication granule and Nano medication granular preparation and preparation method thereof Download PDFInfo
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- CN103120797B CN103120797B CN201210567031.6A CN201210567031A CN103120797B CN 103120797 B CN103120797 B CN 103120797B CN 201210567031 A CN201210567031 A CN 201210567031A CN 103120797 B CN103120797 B CN 103120797B
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Abstract
The present invention relates to a kind of reduce response nano-medicament carrier, Nano medication granule and Nano medication granular preparation and preparation method thereof.The nano-medicament carrier of this reduction response is the bi-block copolymer that Polyethylene Glycol and modified glucan are connected to form, and described modified glucan is connected to form by disulfide bond and amino by glucosan.The nano-medicament carrier positively charged of this reduction response, electronegative medicine is complexed on this carrier by electrostatic interaction, and in a reducing environment, the amino of positively charged is separated with glucosan, thus electronegative medicine is discharged fast at target spot, plays drug effect.
Description
Technical field
The present invention relates to medical art, particularly relate to a kind of reduce response nano-medicament carrier, Nano medication granule and Nano medication granular preparation and preparation method thereof.
Background technology
Nano-medicament carrier typically refers to can the system with nano-grade size of one or more medicines of load.Due to its there is quantum size effect, have concurrently specific surface area large, be easy to the advantages such as finishing, therefore in medicine transmission, controlled release, there is various advantages.Usual nano-medicament carrier has the various ways such as liposome, polymer micelle, dendritic, CNT, quantum dot.Wherein polymer micelle is subject to people because its preparation is simple, Stability Analysis of Structures, material therefor are easy to degraded etc. and pays close attention to widely.
Nano-medicament carrier, except while having good bag to medicine and carrying performance, also needs the good Co ntrolled release realizing medicine at target spot.Traditional release is generally realized by Passive diffusion, but, in order to improve the therapeutic effect of medicine, discharging rapidly after sometimes needing medicine to arrive target spot, thus improving the local concentration of medicine at target spot position.Thus, stimuli responsive delivery systme is paid close attention to widely, comprising reduction response, pH response, enzyme response and temperature-responsive etc.
Summary of the invention
Based on this, be necessary to provide a kind of nano-medicament carrier that medicine can be made to respond in the reduction that target spot discharges rapidly.
Further, the Nano medication granule that a kind of reduction of the nano-medicament carrier using this reduction to respond responds is provided.
A kind of Nano medication granular preparation and preparation method thereof reducing response is also provided.
Reduce response a nano-medicament carrier, be the bi-block copolymer that Polyethylene Glycol and modified glucan are connected to form, described modified glucan is connected to form by disulfide bond and amino by glucosan.
Wherein in an embodiment, the mass ratio of described Polyethylene Glycol and described modified glucan is 1:1 ~ 4.
Wherein in an embodiment, the molecular weight of described Polyethylene Glycol is 2000 ~ 5000, and the molecular weight of described modified glucan is 6000.
A kind of Nano medication granule responded that reduces, comprise the nano-medicament carrier of electronegative medicine and the response of the reduction as described in any one of claim 1 ~ 3, wherein, described modified glucan and described electronegative medicine form kernel, and described Polyethylene Glycol is positioned at the surface of described kernel.
Wherein in an embodiment, described electronegative medicine is selected from least one in indocyanine green and modification cisplatin.
Wherein in an embodiment, the particle diameter of the Nano medication granule of described reduction response is 100 nanometer ~ 200 nanometers.
Wherein in an embodiment, described electronegative medicine and the described mass ratio reducing the nano-medicament carrier responded are 0.05 ~ 0.2:1.
Wherein in an embodiment, also comprise the glutaraldehyde forming cross-linked network with described modified glucan.
Reduce the Nano medication granular preparation of response, comprise ultra-pure water and be scattered in the Nano medication granule of the reduction response as claimed in claim 4 in described ultra-pure water, the concentration of the Nano medication granule of described reduction response is 0.5 ~ 4mg/mL.
Reduce the preparation method of Nano medication granular preparation of response, comprise the steps:
Be dissolved in oxolane by end methoxy poly (ethylene glycol), triethylamine and p-nitrophenyl chloro-formate, react 12 hours ~ 24 hours, precipitation, collection, vacuum drying, obtains activated polyethylene glycol;
Be dissolved in dimethyl sulfoxide by glucosan and sodium cyanoborohydride, react and add ethylenediamine after 1 day, react 1 day, precipitation, collection, vacuum drying, obtains Amino End Group glucosan;
Be dissolved in dimethyl sulfoxide by described activated polyethylene glycol and described Amino End Group glucosan, react 1 day, dialysis, obtains Polyethylene Glycol-glucosan block polymer after lyophilizing;
Be dissolved in dimethyl sulfoxide by described Polyethylene Glycol-glucosan block polymer, succinic anhydride and triethylamine, react 12 hours ~ 24 hours, dialysis, obtains Polyethylene Glycol-glucosan-carboxyl block polymer after lyophilizing;
By described Polyethylene Glycol-glucosan-carboxyl block polymer, N-hydroxy-succinamide and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride are dissolved in dimethyl sulfoxide and activate 1 hour, by the Polyethylene Glycol-glucosan-carboxyl block polymer after activation, the mixture of N-hydroxy-succinamide and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and solvent drops in 2-aminoethyl disulfide dihydrochloride solution, react 24 hours, dialysis, obtain reducing the nano-medicament carrier responded after lyophilizing, the nano-medicament carrier of described reduction response is the bi-block copolymer that Polyethylene Glycol and modified glucan are connected to form, described modified glucan is connected to form by disulfide bond and amino by glucosan,
By soluble in water for the nano-medicament carrier of described reduction response, add electronegative medicine, stir after 20 minutes, filter with filter, obtain the Nano medication granular preparation that concentration is the reduction response of 0.5 ~ 4mg/mL.
Wherein in an embodiment, described stirring is after 20 minutes, crosslinked step is also comprised before filtering with filter, described crosslinked step is specially: described stirring is after 20 minutes, add glutaraldehyde in the mixture of nano-medicament carrier, water and electronegative medicine that the reduction after stirring responds, stir 3 hours.
The nano-medicament carrier of above-mentioned reduction response is the bi-block copolymer that Polyethylene Glycol and modified glucan are connected to form, and modified glucan is connected to form by disulfide bond and amino by glucosan.The nano-medicament carrier positively charged of this reduction response, electronegative medicine is complexed on this carrier by electrostatic interaction, and in a reducing environment, the amino of positively charged is separated with glucosan, thus electronegative medicine is discharged fast at target spot, plays drug effect.
Accompanying drawing explanation
Fig. 1 is the structural representation of the Nano medication granule of the reduction response of an embodiment;
Fig. 2 is the structural representation of the Nano medication granule of the reduction response of another embodiment;
The view that the Nano medication granule that Fig. 3 is the reduction response shown in Fig. 2 discharges in cell;
Fig. 4 is the preparation method flow chart of the Nano medication granular preparation of the reduction response of an embodiment;
Fig. 5 is the schematic diagram of the step S160 of the preparation method of the Nano medication granular preparation of the reduction response shown in Fig. 4;
Fig. 6 is the grain size distribution of the Nano medication granule that the reduction in the Nano medication granular preparation of the reduction response that embodiment 1 prepares responds;
Fig. 7 is the fluorescence curve of Nano medication granular preparation under reducing environment and non-reduced environment and the fluorescence curve of indocyanine green of the reduction response that embodiment 1 prepares;
Fig. 8 is the fluorescent quenching respectively in the culture medium of MCF-7 cell and irreducibility of the Nano medication granular preparation of the reduction response that embodiment 1 prepares and recovery lab diagram.
Detailed description of the invention
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, are described in detail the specific embodiment of the present invention below in conjunction with accompanying drawing.Set forth a lot of detail in the following description so that fully understand the present invention.But the present invention can be much different from alternate manner described here to implement, those skilled in the art can when without prejudice to doing similar improvement when intension of the present invention, therefore the present invention is by the restriction of following public concrete enforcement.
The nano-medicament carrier of the reduction response of one embodiment is the bi-block copolymer that Polyethylene Glycol (PEG) and modified glucan are connected to form.Polyethylene Glycol is connected by amido link with modified glucan, and modified glucan is connected to form by disulfide bond and amino by glucosan (dextran).The nano-medicament carrier of this reduction response is expressed as PEG-dextran (-SS-NH
2).
The mass ratio of Polyethylene Glycol and modified glucan is 1:1 ~ 4.
Reduction response refer to reducing agent exist environment under, reduction response nano-medicament carrier generation scission of link and dissociate; Under the environment not having reducing agent, the nano-medicament carrier of reduction response keeps stable, does not change.
Polyethylene Glycol is that one is ratified through U.S. food and drug administration (FDA), be can be used for clinical high polymer.It is good, nontoxic that PEG has biological safety, and its modified advantage improving stability, reduce non-specific adsorption, extend the blood circulation time of nano-medicament carrier of nano-medicament carrier.
Preferably, the molecular weight of Polyethylene Glycol is 2000 ~ 5000, for the ease of the separation and purification of material when synthesis.
Glucosan have good biocompatibility, safe and reliable, wide material sources, cheap, biodegradable, be easy to the many merits such as modification.
Preferably, the molecular weight of modified glucan is 6000.
The nano-medicament carrier of above-mentioned reduction response combines Polyethylene Glycol and glucosan advantage, has low toxicity, good, the biodegradable characteristic of biological safety, use safety.
The amino positively charged of modified glucan, Polyethylene Glycol and modified glucan are connected to form the bi-block copolymer of positively charged by amido link, the nano-medicament carrier that this reduction is responded can with electronegative medicine by electrostatic interaction complexation, and formation is uniformly dispersed, constitutionally stable Nano medication granule.In a reducing environment, the amino of the positively charged of modified glucan is separated rapidly with glucosan, makes the medicine of complexation be released to targeting moiety rapidly, improves the local concentration of medicine at targeting moiety, is conducive to playing drug effect.
The Nano medication granule of the reduction response of one embodiment, comprises the nano-medicament carrier of electronegative medicine and above-mentioned reduction response.Refer to Fig. 1, label 10 represents modified glucan, and label 20 represents crosslinked electronegative medicine, and label 30 represents Polyethylene Glycol.Modified glucan and electronegative medicine form kernel, and Polyethylene Glycol is located at the surface of kernel.
PEG, as shell, has and stablizes this nano-particle, reduces the effect of non-specific adsorption; Modified glucan section and the electronegative medicine of positively charged form stable stratum nucleare.
Preferably, electronegative medicine is 0.05 ~ 0.2:1 with reducing the mass ratio of nano-medicament carrier responded.
Electronegative medicine is selected from least one in indocyanine green and modification cisplatin.The nano-medicament carrier of above-mentioned reduction response can pass through electrostatic interaction complexation indocyanine green or modification cisplatin, or complexation indocyanine green and modification cisplatin simultaneously, performance dual activity.
Preferably, the particle diameter of the Nano medication granule of reduction response is 100 nanometer ~ 200 nanometers.
Preferably, the Nano medication granule of above-mentioned reduction response also comprises the glutaraldehyde forming cross-linked network with modified glucan.The amino of glutaraldehyde and modified glucan reacts and forms cross-linked network, and electronegative medicine to be complexed on modified glucan by electrostatic interaction and to embed in this cross-linked network, as shown in Figure 2.The stability of the Nano medication granule of this reduction response is higher.
Refer to Fig. 3, under the environment that reducing agent glutathion (GSH) exists, on the modified glucan of the Nano medication granule of this reduction response, the amino of positively charged is separated with glucosan, and the Nano medication granule that reduction is responded dissociates, thus by drug release.
Under the environment not having reducing agent glutathion (GSH), the structure of the Nano medication granule of this reduction response keeps complete, and pharmaceutically active is farthest kept.
In blood circulation, reducing agent content is considerably less, the Nano medication granule of above-mentioned reduction response can realize at blood circulation Chinese medicine substantially without release, escaped by quick endocytosis, lysosome after arriving tumor locus and arrive Cytoplasm, then the Nano medication granule that reduction is responded is stimulated to dissociate and rapid delivery of pharmaceuticals by reduction response, medicine can be made to discharge rapidly at target spot position, play drug effect.
Reduce the Nano medication granular preparation of response, comprise ultra-pure water and be scattered in the Nano medication granule of the above-mentioned reduction response in ultra-pure water, the concentration of the Nano medication granule of reduction response is 0.5 ~ 4mg/mL.
After measured, the Zeta potential size of the Nano medication granular preparation of this reduction response is+30mV ~+50mV, illustrates that the Nano medication granular preparation character that this reduction responds is comparatively stable.
The Nano medication granular preparation using this reduction to respond is treated, and can realize, at blood circulation Chinese medicine substantially without release, being responded and stimulating rapid delivery of pharmaceuticals, medicine is discharged rapidly at target spot position, good effect after arriving tumor locus by reduction.
Refer to Fig. 4, the preparation method of the Nano medication granular preparation of the reduction response of an embodiment, comprises the steps:
Step S110: be dissolved in oxolane by end methoxy poly (ethylene glycol), triethylamine and p-nitrophenyl chloro-formate, reacts 12 hours ~ 24 hours, and precipitation, collection, vacuum drying, obtains activated polyethylene glycol.
The solid-to-liquid ratio of end methoxy poly (ethylene glycol), triethylamine, p-nitrophenyl chloro-formate and oxolane is 0.5g:500 μ L:0.5g:10mL.
React after 12 hours ~ 24 hours, will be precipitated and carry out drying and obtain activated polyethylene glycol, and carry out subsequent reactions to enable Polyethylene Glycol.
Step S120: be dissolved in dimethyl sulfoxide by glucosan and sodium cyanoborohydride, reacts and adds ethylenediamine after 1 day, reacts 1 day, and precipitation, collection, vacuum drying, obtains Amino End Group glucosan.
The solid-to-liquid ratio of glucosan, sodium cyanoborohydride, dimethyl sulfoxide and ethylenediamine is 0.5g:0.5g:15mL:1mL.
Step S130: be dissolved in dimethyl sulfoxide by activated polyethylene glycol and Amino End Group glucosan, reacts 1 day, and dialysis, obtains Polyethylene Glycol-glucosan block polymer after lyophilizing.
The solid-to-liquid ratio of activated polyethylene glycol, Amino End Group glucosan and dimethyl sulfoxide is 0.5g:0.5g:10mL.
React after 1 day, activated polyethylene glycol and Amino End Group glucosan react, and Polyethylene Glycol is connected by amido link with glucosan, form Polyethylene Glycol-glucosan block polymer, are expressed as PEG-dextran.
Dialysis is except after desolventizing and unnecessary reactant, and lyophilizing obtains pure, dry Polyethylene Glycol-glucosan block polymer (PEG-dextran).
Step S 140: be dissolved in dimethyl sulfoxide by Polyethylene Glycol-glucosan block polymer, succinic anhydride and triethylamine, reacts 12 hours ~ 24 hours, and dialysis, obtains Polyethylene Glycol-glucosan-carboxyl block polymer after lyophilizing.
The solid-to-liquid ratio of Polyethylene Glycol-glucosan block polymer, succinic anhydride, triethylamine and dimethyl sulfoxide is 0.2g:0.2g:100 μ L:5mL.
React 12 hours ~ 24 hours, the glucosan of Polyethylene Glycol-glucosan block polymer introduces carboxyl, obtain pure, dry Polyethylene Glycol-glucosan-carboxyl block polymer with after ultra-pure water dialysis, lyophilizing, be expressed as PEG-dextran (-COOH).
Step S150: Polyethylene Glycol-glucosan-carboxyl block polymer, N-hydroxy-succinamide and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride are dissolved in DMSO and activate 1 hour, the mixture of the Polyethylene Glycol-glucosan-carboxyl block polymer after activation, N-hydroxy-succinamide and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and solvent is dropped in 2-aminoethyl disulfide dihydrochloride solution, react 24 hours, dialysis, obtains reducing the nano-medicament carrier responded after lyophilizing.
Polyethylene Glycol-glucosan-carboxyl block polymer (PEG-dextran (-COOH)), N-hydroxy-succinamide (NHS), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) are 0.5g:0.85g:0.14g:100mL with the solid-to-liquid ratio of dimethyl sulfoxide.
By Polyethylene Glycol-glucosan-carboxyl block polymer, N-hydroxy-succinamide and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride are dissolved in solvent and activate 1 hour, with the carboxyl in activated polyethylene glycol-glucosan-carboxyl block polymer (PEG-dextran (-COOH)), amino in the middle carboxyl of PEG-dextran (-COOH) and 2-aminoethyl disulfide dihydrochloride and dimethyl trident maple are reacted, generate the nano-medicament carrier of reduction response, the nano-medicament carrier of this reduction response is the bi-block copolymer that Polyethylene Glycol and modified glucan are connected to form, modified glucan is connected to form by disulfide bond and amino by glucosan, be expressed as PEG-dextran (-SS-NH
2).
Step S160: by soluble in water for the nano-medicament carrier of reduction response, add electronegative medicine, stir after 20 minutes, filter with filter, obtains the Nano medication granular preparation that concentration is the reduction response of 1mg/mL.
Electronegative medicine is selected from least one in indocyanine green and modification cisplatin.
The solid-to-liquid ratio of the nano-medicament carrier that reduction responds, water and electronegative medicine is 1mg:1ml:0.1mg.
Please refer to Fig. 5, electronegative medicine is complexed on the modified glucan of the nano-medicament carrier of reduction response by electrostatic interaction, modified glucan and electronegative medicine form kernel, and Polyethylene Glycol is positioned at the surface of kernel, form the Nano medication granule of reduction response.
Preferably, by the nano-medicament carrier of reduction response, water and, after the mixture of electronegative medicine stirs 20 minutes, before filtering with filter, also comprise crosslinked step.Crosslinked step is specially: add glutaraldehyde in the mixture of nano-medicament carrier, water and electronegative medicine that the reduction after stirring responds, stir 3 hours, obtains the Nano medication granule of the reduction response be cross-linked, as shown in Figure 5.
Amino on glutaraldehyde and modified glucan reacts and forms crosslinked network, electronegative drug molecule is adsorbed on modified glucan, and embed in this crosslinked network, make electronegative medicine comparatively stable be adsorbed on kernel, prepare the Nano medication granule of the higher crosslinked reduction response of stability.
The preparation method preparation process of the Nano medication granular preparation of above-mentioned reduction response is simple, can directly the nano-medicament carrier of reduction response and electronegative medicine be carried out assembling in water and obtain reducing the Nano medication granule responded, assembling process is without the need to organic solvent, and simple to operate.The stability preparing the Nano medication granular preparation of reduction response is higher.
It is below specific embodiment.
Embodiment 1
1, the nano-medicament carrier of preparation reduction response:
(1) held by 0.5g methoxy poly (ethylene glycol) (molecular weight is 2000), 500 microlitre triethylamines and 0.2g p-nitrophenyl chloro-formate to be dissolved in 10ml oxolane, react 12 hours, precipitation, collection, vacuum drying, obtains activated polyethylene glycol.
(2) be dissolved in 15mL dimethyl sulfoxide by 0.5g glucosan and 0.5g sodium cyanoborohydride, react 1 day, add 1ml ethylenediamine, react 1 day, precipitation, collection, vacuum drying, obtains Amino End Group glucosan.
(3) be dissolved in 10mL dimethyl sulfoxide by 0.5g Amino End Group glucosan and 0.5g activated polyethylene glycol, react 1 day, dialysis, lyophilizing obtains Polyethylene Glycol-glucosan block polymer, is expressed as PEG-dextran.
(4) 0.2g PEG-dextran, 0.2g succinic anhydride and 100 microlitre triethylamines are dissolved in 5mL dimethyl sulfoxide, react 12 hours, dialysis, lyophilizing obtains Polyethylene Glycol-glucosan-carboxyl block polymer, is expressed as PEG-dextran (-COOH).
(5) by 0.5g PEG-dextran (-COOH), 0.85gN-N-Hydroxysuccinimide (NHS), 0.14g1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) is dissolved in dimethyl sulfoxide and activates 1 hour, by the Polyethylene Glycol-glucosan-carboxyl block polymer after activation, N-hydroxy-succinamide, the mixture of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and solvent drops in 100mL 2-aminoethyl disulfide dihydrochloride solution, reaction 24h, dialysis, lyophilizing must reduce response nano-medicament carrier, the nano-medicament carrier of this reduction response is the bi-block copolymer that Polyethylene Glycol and modified glucan connect to form, modified glucan is connected to form by disulfide bond and amino by glucosan.The nano-medicament carrier of this reduction response is expressed as PEG-dextran (-SS-NH
2).
2, the preparation of the Nano medication granular preparation of reduction response:
Take nano-medicament carrier (the PEG-dextran (-SS-NH of above-mentioned reduction response
2)) 10mg is dissolved in 10mL water, adds the indocyanine green of 1mg, stirs 20min, adds 0.25mg glutaraldehyde, filters after stirring 3h with 0.45 μm of filter, obtaining concentration is the Nano medication granular preparation that the reduction of 1mg/mL responds.
As shown in Figure 6, the hydration particle diameter of the Nano medication granule of this reduction response is 120 ran to the particle size distribution of the Nano medication granule of the reduction response in the Nano medication granular preparation of the reduction response prepared.
After measured, the Zeta potential of the Nano medication granular preparation of this reduction response is about+40mV, shows that the Nano medication granular preparation that this reduction responds is comparatively stable.
Refer to Fig. 7, simple indocyanine green with near-infrared fluorescent, as shown in curve I.Using dithiothreitol, DTT (DTT) as reducing agent.Under the environment not having reducing agent, in the Nano medication granule of reduction response, be fluorescent quenching when indocyanine green is enclosed in granule interior, as shown in curve II.Under the DDT environment of 10mM, the Nano medication granule of reduction response dissociates, and can recover, as shown in curve III by fluorescence after indocyanine green is discharged.
Refer to Fig. 8, in the culture medium of irreducibility, the process that the Nano medication granular preparation that above-mentioned reduction responds does not have fluorescence to recover; And in MCF-7 cellular environment, cancellation recovery process clearly can be seen, characterize the quick release of indocyanine green.
Embodiment 2
1, the nano-medicament carrier of preparation reduction response:
(1) held by 1.0g methoxy poly (ethylene glycol) (molecular weight is 5000), 1000 microlitre triethylamines and 0.4g p-nitrophenyl chloro-formate to be dissolved in 20ml oxolane, react 24 hours, precipitation, collection, vacuum drying, obtains activated polyethylene glycol.
(2) be dissolved in 30mL dimethyl sulfoxide by 1.0g glucosan and 1.0g sodium cyanoborohydride, react 1 day, add 2ml ethylenediamine, react 1 day, precipitation, collection, vacuum drying, obtains Amino End Group glucosan.
(3) be dissolved in 20mL dimethyl sulfoxide by 1.0g Amino End Group glucosan and 1.0g activated polyethylene glycol, react 1 day, dialysis, lyophilizing obtains Polyethylene Glycol-glucosan block polymer, is expressed as PEG-dextran.
(4) 0.4g PEG-dextran, 0.4g succinic anhydride and 200 microlitre triethylamines are dissolved in 2.5mL dimethyl sulfoxide, reaction xx hour, dialysis, lyophilizing obtains Polyethylene Glycol-glucosan-carboxyl block polymer, is expressed as PEG-dextran (-COOH).
(5) by 1.0g PEG-dextran (-COOH), 1.7gN-N-Hydroxysuccinimide (NHS), 0.28g1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) is dissolved in dimethyl sulfoxide and activates 1 hour, by the Polyethylene Glycol-glucosan-carboxyl block polymer after activation, N-hydroxy-succinamide, the mixture of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and solvent drops in 200mL 2-aminoethyl disulfide dihydrochloride solution, reaction 24h, dialysis, lyophilizing must reduce response nano-medicament carrier, the nano-medicament carrier of this reduction response is the bi-block copolymer that Polyethylene Glycol and modified glucan connect to form, modified glucan is connected to form by disulfide bond and amino by glucosan.The nano-medicament carrier of this reduction response is expressed as PEG-dextran (-SS-NH
2).
2, the preparation of the Nano medication granular preparation of reduction response:
Take nano-medicament carrier (the PEG-dextran (-SS-NH of above-mentioned reduction response
2)) 1mg is dissolved in 2mL water, adds the modification cisplatin of 0.05mg, stirs 20min, adds 0.025mg glutaraldehyde, filters after stirring 3h with 0.45 μm of filter, obtaining concentration is the Nano medication granular preparation that the reduction of 0.5mg/mL responds.
Embodiment 3
1, the nano-medicament carrier of preparation reduction response:
(1) held by 1.0g methoxy poly (ethylene glycol) (molecular weight is 5000), 1000 microlitre triethylamines and 0.4g p-nitrophenyl chloro-formate to be dissolved in 20ml oxolane, react 24 hours, precipitation, collection, vacuum drying, obtains activated polyethylene glycol.
(2) be dissolved in 90mL dimethyl sulfoxide by 3.0g glucosan and 3.0g sodium cyanoborohydride, react 1 day, add 6ml ethylenediamine, react 1 day, precipitation, collection, vacuum drying, obtains Amino End Group glucosan.
(3) be dissolved in 20mL dimethyl sulfoxide by 3.0g Amino End Group glucosan and 1.0g activated polyethylene glycol, react 1 day, dialysis, lyophilizing obtains Polyethylene Glycol-glucosan block polymer, is expressed as PEG-dextran.
(4) 0.4g PEG-dextran, 0.4g succinic anhydride and 200 microlitre triethylamines are dissolved in 2.5mL dimethyl sulfoxide, react 12 hours, dialysis, lyophilizing obtains Polyethylene Glycol-glucosan-carboxyl block polymer, is expressed as PEG-dextran (-COOH).
(5) by 1.0g PEG-dextran (-COOH), 1.7gN-N-Hydroxysuccinimide (NHS), 0.28g1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) is dissolved in dimethyl sulfoxide and activates 1 hour, by the Polyethylene Glycol-glucosan-carboxyl block polymer after activation, N-hydroxy-succinamide, the mixture of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and solvent drops in 200mL 2-aminoethyl disulfide dihydrochloride solution, reaction 24h, dialysis, lyophilizing must reduce response nano-medicament carrier, the nano-medicament carrier of this reduction response is the bi-block copolymer that Polyethylene Glycol and modified glucan connect to form, modified glucan is connected to form by disulfide bond and amino by glucosan.The nano-medicament carrier of this reduction response is expressed as PEG-dextran (-SS-NH
2).
2, the preparation of the Nano medication granular preparation of reduction response:
Take nano-medicament carrier (the PEG-dextran (-SS-NH of above-mentioned reduction response
2)) 1mg is dissolved in 2mL water, adds the modification cisplatin of 0.2mg, stirs 20min, adds 0.025mg glutaraldehyde, filters after stirring 3h with 0.45 μm of filter, obtaining concentration is the Nano medication granular preparation that the reduction of 0.5mg/mL responds.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (10)
1. reduce response a nano-medicament carrier, it is characterized in that, be the bi-block copolymer that Polyethylene Glycol and modified glucan are connected to form, described modified glucan is connected to form by disulfide bond and amino by glucosan.
2. the nano-medicament carrier of reduction response according to claim 1, it is characterized in that, the mass ratio of described Polyethylene Glycol and described modified glucan is 1:1 ~ 4.
3. the nano-medicament carrier of reduction response according to claim 1, it is characterized in that, the molecular weight of described Polyethylene Glycol is 2000 ~ 5000, and the molecular weight of described modified glucan is 6000.
4. one kind reduce response Nano medication granule, it is characterized in that, comprise the nano-medicament carrier of electronegative medicine and the response of the reduction as described in any one of claims 1 to 3, wherein, described modified glucan and described electronegative medicine form kernel, and described Polyethylene Glycol is positioned at the surface of described kernel.
5. the Nano medication granule of reduction response according to claim 4, it is characterized in that, described electronegative medicine is indocyanine green.
6. the Nano medication granule of reduction response according to claim 4, is characterized in that, the particle diameter of the Nano medication granule of described reduction response is 100 nanometer ~ 200 nanometers.
7. the Nano medication granule of reduction response according to claim 4, it is characterized in that, described electronegative medicine and the described mass ratio reducing the nano-medicament carrier responded are 0.05 ~ 0.2:1.
8. the Nano medication granule of reduction response according to claim 4, is characterized in that, also comprise the glutaraldehyde forming cross-linked network with described modified glucan.
9. reduce the preparation method of Nano medication granular preparation of response, it is characterized in that, comprise the steps:
Be dissolved in oxolane by end methoxy poly (ethylene glycol), triethylamine and p-nitrophenyl chloro-formate, react 12 hours ~ 24 hours, precipitation, collection, vacuum drying, obtains activated polyethylene glycol;
Be dissolved in dimethyl sulfoxide by glucosan and sodium cyanoborohydride, react and add ethylenediamine after 1 day, react 1 day, precipitation, collection, vacuum drying, obtains Amino End Group glucosan;
Be dissolved in dimethyl sulfoxide by described activated polyethylene glycol and described Amino End Group glucosan, react 1 day, dialysis, obtains Polyethylene Glycol-glucosan block polymer after lyophilizing;
Be dissolved in dimethyl sulfoxide by described Polyethylene Glycol-glucosan block polymer, succinic anhydride and triethylamine, react 12 hours ~ 24 hours, dialysis, obtains Polyethylene Glycol-glucosan-carboxyl block polymer after lyophilizing;
By described Polyethylene Glycol-glucosan-carboxyl block polymer, N-hydroxy-succinamide and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride are dissolved in dimethyl sulfoxide and activate 1 hour, by the Polyethylene Glycol-glucosan-carboxyl block polymer after activation, the mixture of N-hydroxy-succinamide and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and solvent drops in 2-aminoethyl disulfide dihydrochloride solution, react 24 hours, dialysis, obtain reducing the nano-medicament carrier responded after lyophilizing, the nano-medicament carrier of described reduction response is the bi-block copolymer that Polyethylene Glycol and modified glucan are connected to form, described modified glucan is connected to form by disulfide bond and amino by glucosan,
By soluble in water for the nano-medicament carrier of described reduction response, add electronegative medicine, stir after 20 minutes, filter with filter, obtain the Nano medication granular preparation that concentration is the reduction response of 0.5 ~ 4mg/mL.
10. the preparation method of the Nano medication granular preparation of reduction response according to claim 9, it is characterized in that, described stirring is after 20 minutes, crosslinked step is also comprised before filtering with filter, described crosslinked step is specially: described stirring is after 20 minutes, add glutaraldehyde in the mixture of nano-medicament carrier, water and electronegative medicine that the reduction after stirring responds, stir 3 hours.
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