CN103120797A - Nano-drug carrier for reductive response, nano-drug particle, nano-drug particle preparation and preparation methods thereof - Google Patents
Nano-drug carrier for reductive response, nano-drug particle, nano-drug particle preparation and preparation methods thereof Download PDFInfo
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Abstract
The invention relates to a nano-drug carrier for reductive response, a nano-drug particle, nano-drug particle preparation and preparation methods thereof. The nano-drug carrier for reductive response is two block polymers formed by polyethylene glycol and modified glucosan in connection; and the modified glucosan is formed by glucosan connected with amino through a disulfide bond. The nano-drug carrier for reductive response has positive electricity; the drug with negative electricity is complexed on the carrier through electrostatic interaction; and the amino with positive electricity is separated from the glucosan under a reducing environment. Thus, the drug with negative electricity is rapidly released on a target point to play the effect.
Description
Technical field
The present invention relates to medical technical field, particularly relate to a kind of nano-medicament carrier, Nano medication granule and Nano medication granular preparation and preparation method thereof that reduces response.
Background technology
Nano-medicament carrier typically refers to the system with nano-grade size that can one or more medicines of load.Due to its there is quantum size effect, have concurrently specific surface area large, be easy to the advantage such as finishing, therefore aspect medicine transmission, controlled release, there is various advantages.Usually nano-medicament carrier has the various ways such as liposome, polymer micelle, dendritic, CNT, quantum dot.Wherein polymer micelle because its preparation is simple, Stability Analysis of Structures, material therefor be easy to degraded etc. and be subject to people and pay close attention to widely.
When nano-medicament carrier carries performance except medicine being had to good bag, also need to realize the good control of medicine is discharged at target spot.Traditional release generally realizes by passive diffusion, still, in order to improve the therapeutic effect of medicine, sometimes needs to discharge rapidly after medicine arrival target spot, thereby improves the local concentration of medicine at the target spot position.Thereby the 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 of the reduction response that can make medicine discharge rapidly at target spot.
A kind of Nano medication granule of reduction response of the nano-medicament carrier that uses this reduction to respond further, is provided.
A kind of Nano medication granular preparation and preparation method thereof that reduces response also is provided.
A kind of nano-medicament carrier that reduces response, be 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.
In embodiment, the mass ratio of described Polyethylene Glycol and described modified glucan is 1:1 ~ 4 therein.
In embodiment, the molecular weight of described Polyethylene Glycol is 2000 ~ 5000 therein, and the molecular weight of described modified glucan is 6000.
A kind of Nano medication granule responded that reduces, the nano-medicament carrier that comprises electronegative medicine and reduction as described as claim 1 ~ 3 any one response, wherein, described modified glucan and described electronegative medicine form kernel, and described Polyethylene Glycol is positioned at the surface of described kernel.
In embodiment, described electronegative medicine is selected from least one in indocyanine green and modification cisplatin therein.
In embodiment, the particle diameter of the Nano medication granule of described reduction response is 100 nanometers ~ 200 nanometers therein.
In embodiment, the mass ratio of the nano-medicament carrier of described electronegative medicine and described reduction response is 0.05 ~ 0.2:1 therein.
In embodiment, also comprise the glutaraldehyde that forms cross-linked network with described modified glucan therein.
A kind of Nano medication granular preparation responded that reduces comprises ultra-pure water and is scattered in the Nano medication granule that the reduction as claimed in claim 4 in described ultra-pure water responds that the concentration of the Nano medication granule of described reduction response is 0.5 ~ 4mg/mL.
A kind of preparation method of Nano medication granular preparation of reducing response, comprise the steps:
To hold methoxy poly (ethylene glycol), triethylamine and p-nitrophenyl chloro-formate to be dissolved in oxolane, react 12 hours ~ 24 hours, precipitation, collection, vacuum drying, obtain activated polyethylene glycol;
Glucosan and sodium cyanoborohydride are dissolved in dimethyl sulfoxide, react after 1 day and add ethylenediamine, react 1 day, precipitation, collection, vacuum drying, obtain holding glycosaminoglycan;
Described activated polyethylene glycol and described end glycosaminoglycan are dissolved in dimethyl sulfoxide, react 1 day, dialysis, obtain Polyethylene Glycol-glucosan block polymer after lyophilizing;
Described Polyethylene Glycol-glucosan block polymer, succinic anhydride and triethylamine are dissolved in dimethyl sulfoxide, react 12 hours ~ 24 hours, dialysis, obtain 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 is dissolved in dimethyl sulfoxide and activates 1 hour, by the Polyethylene Glycol-glucosan after activation-carboxyl block polymer, 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 the nano-medicament carrier of reduction response 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,
The nano-medicament carrier of described reduction response is soluble in water, add electronegative medicine, after stirring 20 minutes, with filter, filter the Nano medication granular preparation of the reduction response that to obtain concentration be 0.5 ~ 4mg/mL.
Therein in embodiment, described stirring is after 20 minutes, also comprise crosslinked step 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 under reducing environment, the amino of positively charged separates with glucosan, thereby makes electronegative medicine discharge fast at target spot, the performance drug effect.
The accompanying drawing explanation
The structural representation of the Nano medication granule of the reduction response that Fig. 1 is an embodiment;
The structural representation of the Nano medication granule of the reduction response that Fig. 2 is another embodiment;
The view that the Nano medication granule that Fig. 3 is the reduction response shown in Fig. 2 discharges in cell;
The preparation method flow chart of the Nano medication granular preparation of the reduction response that Fig. 4 is an embodiment;
The schematic diagram of the step S160 of the preparation method of the Nano medication granular preparation that Fig. 5 is the reduction response shown in Fig. 4;
The particle size distribution figure of the Nano medication granule of the reduction response in the Nano medication granular preparation that Fig. 6 is the reduction response for preparing of embodiment 1;
The fluorescence curve of the Nano medication granular preparation that Fig. 7 is the reduction response for preparing of embodiment 1 under reducing environment and non-reduced environment and the fluorescence curve of indocyanine green;
The Nano medication granular preparation fluorescent quenching in the culture medium of MCF-7 cell and irreducibility and recovery lab diagram respectively that Fig. 8 is the reduction response for preparing of embodiment 1.
The specific embodiment
For above-mentioned purpose of the present invention, feature and advantage can be become apparent more, below in conjunction with accompanying drawing, the specific embodiment of the present invention is described in detail.A lot of details have been set forth in the following description so that fully understand the present invention.But the present invention can implement much to be different from alternate manner described here, those skilled in the art can be in the situation that do similar improvement without prejudice to intension of the present invention, so the present invention is not subject to the restriction of following public concrete enforcement.
The nano-medicament carrier of the reduction of one embodiment response, the bi-block copolymer be connected to form for Polyethylene Glycol (PEG) and modified glucan.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 refers under the environment existed at reducing agent, the nano-medicament carrier generation scission of link of reduction response and dissociating; Do not having under the environment of reducing agent, the nano-medicament carrier of reduction response keeps stable, does not change.
Polyethylene Glycol is that a kind of process U.S. food and drug administration (FDA) ratify, can be used for clinical high polymer.It is good, nontoxic that PEG has a biological safety, and the advantage that can improve stability after its modification for nano-medicament carrier, reduce non-specific adsorption, extend the blood circulation time of nano-medicament carrier.
Preferably, the molecular weight of Polyethylene Glycol is 2000 ~ 5000, the separation and purification of material for the ease of synthetic the time.
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, uses 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, make the nano-medicament carrier of this reduction response to pass through the electrostatic interaction complexation with electronegative medicine, formation is uniformly dispersed, constitutionally stable Nano medication granule.Under reducing environment, the amino of the positively charged of modified glucan separates rapidly with glucosan, makes the medicine of complexation be released to rapidly targeting moiety, improves the local concentration of medicine at targeting moiety, is conducive to bring into play drug effect.
The Nano medication granule of the reduction response of one embodiment, comprise the nano-medicament carrier that electronegative medicine and above-mentioned reduction respond.Refer to Fig. 1, label 10 means modified glucan, and label 20 means crosslinked electronegative medicine, and label 30 means 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 absorption; Modified glucan section and the electronegative medicine of positively charged form stable stratum nucleare.
Preferably, electronegative medicine is 0.05 ~ 0.2:1 with the mass ratio of the nano-medicament carrier of reduction response.
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 while complexation indocyanine green and modification cisplatin, brings into play dual curative effect.
Preferably, the particle diameter of the Nano medication granule of reduction response is 100 nanometers ~ 200 nanometers.
Preferably, the Nano medication granule of above-mentioned reduction response also comprises the glutaraldehyde that forms cross-linked network with modified glucan.Glutaraldehyde reacts and forms cross-linked network with the amino of modified glucan, and electronegative medicine is complexed on modified glucan by electrostatic interaction and embeds 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 existed at reducing agent glutathion (GSH), on the modified glucan of the Nano medication granule of this reduction response, the amino of positively charged separates with glucosan, and the Nano medication granule of reduction response is dissociated, thereby by drug release.
Under the environment that there is no 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 be realized at the blood circulation Chinese medicine substantially without discharging, escape and arrive Cytoplasm by quick endocytosis, lysosome after arriving tumor locus, then by reduction, responding to stimulate dissociates and rapid delivery of pharmaceuticals the Nano medication granule of reduction response, can make medicine discharge rapidly at the target spot position, the performance drug effect.
A kind of Nano medication granular preparation responded that reduces comprises ultra-pure water and is scattered in the Nano medication granule that the above-mentioned reduction in ultra-pure water responds that 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, illustrate that the Nano medication granular preparation character that this reduction responds is comparatively stable.
Use the Nano medication granular preparation of this reduction response to be treated, can realize at the blood circulation Chinese medicine responding stimulation rapid delivery of pharmaceuticals by reduction substantially without discharging after the arrival tumor locus, medicine is discharged rapidly, good effect at the target spot position.
Refer to Fig. 4, the preparation method of the Nano medication granular preparation of the reduction response of an embodiment, comprise the steps:
Step S110: will hold methoxy poly (ethylene glycol), triethylamine and p-nitrophenyl chloro-formate to be dissolved in oxolane, react 12 hours ~ 24 hours, precipitation, collection, vacuum drying, obtain 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, so that Polyethylene Glycol can carry out subsequent reactions.
Step S120: glucosan and sodium cyanoborohydride are dissolved in dimethyl sulfoxide, react after 1 day and add ethylenediamine, react 1 day, precipitation, collection, vacuum drying, obtain holding glycosaminoglycan.
The solid-to-liquid ratio of glucosan, sodium cyanoborohydride, dimethyl sulfoxide and ethylenediamine is 0.5g:0.5g:15mL:1mL.
Step S130: activated polyethylene glycol and end glycosaminoglycan are dissolved in dimethyl sulfoxide, react 1 day, dialysis, obtain Polyethylene Glycol-glucosan block polymer after lyophilizing.
The solid-to-liquid ratio of activated polyethylene glycol, end glycosaminoglycan and dimethyl sulfoxide is 0.5g:0.5g:10mL.
React after 1 day, activated polyethylene glycol reacts with the end glycosaminoglycan, and Polyethylene Glycol is connected by amido link with glucosan, forms Polyethylene Glycol-glucosan block polymer, is expressed as PEG-dextran.
Dialysis except desolventizing and unnecessary reactant after, lyophilizing obtains pure, dry Polyethylene Glycol-glucosan block polymer (PEG-dextran).
Step S 140: Polyethylene Glycol-glucosan block polymer, succinic anhydride and triethylamine are dissolved in dimethyl sulfoxide, react 12 hours ~ 24 hours, dialysis, obtain 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, introduce carboxyl on the glucosan of Polyethylene Glycol-glucosan block polymer, with obtaining pure, dry Polyethylene Glycol-glucosan-carboxyl block polymer 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 is dissolved in DMSO and activates 1 hour, the mixture of the Polyethylene Glycol-glucosan after activation-carboxyl block polymer, 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, obtain the nano-medicament carrier that reduction responds 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 is dissolved in solvent and activates 1 hour, with the carboxyl in activated polyethylene glycol-glucosan-carboxyl block polymer (PEG-dextran (COOH)), carboxyl in PEG-dextran (COOH) is reacted with amino and dimethyl trident maple in 2-aminoethyl disulfide dihydrochloride, 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: the nano-medicament carrier of response of reducing is soluble in water, adds electronegative medicine, after stirring 20 minutes, with filter, filters, the Nano medication granular preparation of the reduction response that to obtain concentration be 1mg/mL.
Electronegative medicine is selected from least one in indocyanine green and modification cisplatin.
The solid-to-liquid ratio of nano-medicament carrier, water and the electronegative medicine of reduction response is 1mg:1ml:0.1mg.
Please consult Fig. 5 simultaneously, electronegative medicine is complexed to by electrostatic interaction on the modified glucan of nano-medicament carrier of reduction response, 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, the nano-medicament carrier that reduction is responded, water reach, the mixture of electronegative medicine stirred after 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, obtain the Nano medication granule of crosslinked reduction response, as shown in Figure 5.
Glutaraldehyde reacts the crosslinked network of formation with the amino on modified glucan, electronegative drug molecule is adsorbed on modified glucan, and embed in this crosslinked network, make comparatively stable being adsorbed on kernel of electronegative medicine, prepare the Nano medication granule of the crosslinked reduction response that stability is higher.
The preparation method preparation process of the Nano medication granular preparation of above-mentioned reduction response is simple, nano-medicament carrier and the electronegative medicine responded that can directly will reduce in water assembled the Nano medication granule that obtains the reduction response, assembling process is without organic solvent, and simple to operate.The stability of Nano medication granular preparation for preparing reduction response is higher.
It is below specific embodiment.
1, the nano-medicament carrier of preparation reduction response:
(1) 0.5g is held methoxy poly (ethylene glycol) (molecular weight is 2000), 500 microlitre triethylamines and 0.2g p-nitrophenyl chloro-formate are dissolved in the 10ml oxolane, react 12 hours, precipitation, collection, vacuum drying, obtain activated polyethylene glycol.
(2) 0.5g glucosan and 0.5g sodium cyanoborohydride are dissolved in the 15mL dimethyl sulfoxide, react 1 day, add the 1ml ethylenediamine, react 1 day, precipitation, collection, vacuum drying, obtain holding glycosaminoglycan.
(3) 0.5g is held glycosaminoglycan and 0.5g activated polyethylene glycol are dissolved in the 10mL dimethyl sulfoxide, 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 the 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-being dissolved in dimethyl sulfoxide, (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) activates 1 hour, by the Polyethylene Glycol-glucosan after activation-carboxyl block polymer, 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 the 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 the nano-medicament carrier (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 the 0.25mg glutaraldehyde, with 0.45 μ m filter, filters after stirring 3h, the Nano medication granular preparation that the reduction that to obtain concentration be 1mg/mL responds.
As shown in Figure 6, the hydration particle diameter of the Nano medication granule of this reduction response is 120 nanometer left and right 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+the 40mV left and right to show that the Nano medication granular preparation of this reduction response is comparatively stable.
Refer to Fig. 7, simple indocyanine green is with near-infrared fluorescent, as shown in curve I.Using dithiothreitol, DTT (DTT) as reducing agent.Not having under the environment of reducing agent, in the Nano medication granule of reduction response, is fluorescent quenching when indocyanine green is enclosed in granule interior, as shown in curve II.Under the DDT of 10mM environment, the Nano medication granule of reduction response dissociates, and makes can to recover by fluorescence after indocyanine green release, as shown in curve III.
Refer to Fig. 8, in the culture medium of irreducibility, the process that the Nano medication granular preparation of above-mentioned reduction response does not have fluorescence to recover; And, in the MCF-7 cellular environment, can see cancellation recovery process clearly, characterize the quick release of indocyanine green.
1, the nano-medicament carrier of preparation reduction response:
(1) 1.0g is held methoxy poly (ethylene glycol) (molecular weight is 5000), 1000 microlitre triethylamines and 0.4g p-nitrophenyl chloro-formate are dissolved in the 20ml oxolane, react 24 hours, precipitation, collection, vacuum drying, obtain activated polyethylene glycol.
(2) 1.0g glucosan and 1.0g sodium cyanoborohydride are dissolved in the 30mL dimethyl sulfoxide, react 1 day, add the 2ml ethylenediamine, react 1 day, precipitation, collection, vacuum drying, obtain holding glycosaminoglycan.
(3) 1.0g is held glycosaminoglycan and 1.0g activated polyethylene glycol are dissolved in the 20mL dimethyl sulfoxide, 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 the 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-being dissolved in dimethyl sulfoxide, (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) activates 1 hour, by the Polyethylene Glycol-glucosan after activation-carboxyl block polymer, 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 the 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 the nano-medicament carrier (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 the 0.025mg glutaraldehyde, with 0.45 μ m filter, filters after stirring 3h, the Nano medication granular preparation that the reduction that to obtain concentration be 0.5mg/mL responds.
1, the nano-medicament carrier of preparation reduction response:
(1) 1.0g is held methoxy poly (ethylene glycol) (molecular weight is 5000), 1000 microlitre triethylamines and 0.4g p-nitrophenyl chloro-formate are dissolved in the 20ml oxolane, react 24 hours, precipitation, collection, vacuum drying, obtain activated polyethylene glycol.
(2) 3.0g glucosan and 3.0g sodium cyanoborohydride are dissolved in the 90mL dimethyl sulfoxide, react 1 day, add the 6ml ethylenediamine, react 1 day, precipitation, collection, vacuum drying, obtain holding glycosaminoglycan.
(3) 3.0g is held glycosaminoglycan and 1.0g activated polyethylene glycol are dissolved in the 20mL dimethyl sulfoxide, 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 the 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-being dissolved in dimethyl sulfoxide, (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) activates 1 hour, by the Polyethylene Glycol-glucosan after activation-carboxyl block polymer, 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 the 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 the nano-medicament carrier (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 the 0.025mg glutaraldehyde, with 0.45 μ m filter, filters after stirring 3h, the Nano medication granular preparation that the reduction that to obtain concentration be 0.5mg/mL responds.
The above embodiment has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore 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 (11)
1. one kind is reduced the nano-medicament carrier of response, it is characterized in that, and 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, 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, is characterized in that, the molecular weight of described Polyethylene Glycol is 2000 ~ 5000, and the molecular weight of described modified glucan is 6000.
One kind reduce the response the Nano medication granule, it is characterized in that, the nano-medicament carrier that comprises electronegative medicine and reduction as described as claim 1 ~ 3 any one response, 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, is characterized in that, described electronegative medicine is selected from least one in indocyanine green and modification cisplatin.
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 nanometers ~ 200 nanometers.
7. the Nano medication granule of reduction response according to claim 4, is characterized in that, the mass ratio of the nano-medicament carrier of described electronegative medicine and described reduction response is 0.05 ~ 0.2:1.
8. the Nano medication granule of reduction response according to claim 4, is characterized in that, also comprises the glutaraldehyde that forms cross-linked network with described modified glucan.
One kind reduce the response the Nano medication granular preparation, it is characterized in that, comprise ultra-pure water and be scattered in the Nano medication granule that the reduction as claimed in claim 4 in described ultra-pure water responds, the concentration of the Nano medication granule of described reduction response is 0.5 ~ 4mg/mL.
10. one kind is reduced the preparation method of Nano medication granular preparation of response, it is characterized in that, comprises the steps:
To hold methoxy poly (ethylene glycol), triethylamine and p-nitrophenyl chloro-formate to be dissolved in oxolane, react 12 hours ~ 24 hours, precipitation, collection, vacuum drying, obtain activated polyethylene glycol;
Glucosan and sodium cyanoborohydride are dissolved in dimethyl sulfoxide, react after 1 day and add ethylenediamine, react 1 day, precipitation, collection, vacuum drying, obtain holding glycosaminoglycan;
Described activated polyethylene glycol and described end glycosaminoglycan are dissolved in dimethyl sulfoxide, react 1 day, dialysis, obtain Polyethylene Glycol-glucosan block polymer after lyophilizing;
Described Polyethylene Glycol-glucosan block polymer, succinic anhydride and triethylamine are dissolved in dimethyl sulfoxide, react 12 hours ~ 24 hours, dialysis, obtain 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 is dissolved in dimethyl sulfoxide and activates 1 hour, by the Polyethylene Glycol-glucosan after activation-carboxyl block polymer, 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 the nano-medicament carrier of reduction response 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,
The nano-medicament carrier of described reduction response is soluble in water, add electronegative medicine, after stirring 20 minutes, with filter, filter the Nano medication granular preparation of the reduction response that to obtain concentration be 0.5 ~ 4mg/mL.
11. the preparation method of the Nano medication granular preparation of reduction response according to claim 10, it is characterized in that, described stirring is after 20 minutes, also comprise crosslinked step 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105434357A (en) * | 2015-12-21 | 2016-03-30 | 江南大学 | Preparation for amphoteric nanoparticle |
| CN108341967A (en) * | 2018-03-26 | 2018-07-31 | 温岭汉德高分子科技有限公司 | A kind of reduction response based on polysaccharide is from depolymerization graft polymers and preparation method thereof, purposes |
| CN109745338A (en) * | 2019-01-17 | 2019-05-14 | 南开大学 | Containing Vorinostat has the preparation method and application of Pt (IV) polymeric prodrugs micella of reduction response |
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| CN102250365A (en) * | 2011-05-09 | 2011-11-23 | 武汉理工大学 | PH-sensitive reduction responsive nanogel and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105434357A (en) * | 2015-12-21 | 2016-03-30 | 江南大学 | Preparation for amphoteric nanoparticle |
| CN108341967A (en) * | 2018-03-26 | 2018-07-31 | 温岭汉德高分子科技有限公司 | A kind of reduction response based on polysaccharide is from depolymerization graft polymers and preparation method thereof, purposes |
| CN108341967B (en) * | 2018-03-26 | 2021-09-24 | 温岭汉德高分子科技有限公司 | Polysaccharide-based reduction response self-depolymerization graft polymer and preparation method and application thereof |
| CN109745338A (en) * | 2019-01-17 | 2019-05-14 | 南开大学 | Containing Vorinostat has the preparation method and application of Pt (IV) polymeric prodrugs micella of reduction response |
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