CN102250365A - PH-sensitive reduction responsive nanogel and preparation method thereof - Google Patents
PH-sensitive reduction responsive nanogel and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a pH-sensitive reduction responsive nanogel, which comprises a disulfide-bond-crosslinked sodium alginate derivate serving as an active ingredient. A preparation method of the nanogel comprises the following steps of: adding periodate into a sodium alginate aqueous solution according to molar ratio of the glycosyl unit of the sodium alginate aqueous solution to the periodate as 1:(0.01-10), and reacting away from light to obtain dialdehyde sodium alginate; stirring and uniformly mixing a dialdehyde sodium alginate aqueous solution and a 4-aminothiolphenol ethanol solution according to the molar ratio of the aldehyde group of the dialdehyde sodium alginate to the amino group of the 4-aminothiolphenol as 1:(0.01-10) away from light at the temperature of 0-25 DEG C, and then adding sodium borohydride to obtain sulphydryl sodium alginate; and self-assembling the sulphydryl sodium alginate in an aqueous solution and oxidizing the sulphydryl sodium alginate by oxygen in the solution to obtain the nanogel. The nanogel prepared by the invention has stability, pH sensitivity and reduction responsiveness and has a potential application value in the fields of biomedical implants, biological nanotechnology, drug delivery system and the like.
Description
Technical field
The present invention relates to the gelatinous material field, particularly a kind of preparation method of reduction responsive nano hydrogel of pH sensitivity.
Background technology
Nanogel be a kind of size between 10 ~ 1000 nanometers and can be in the aqueous solution dispersive hydrogel particle, formed by the polymer network structure of physics or chemically crosslinked usually.It not only has the water-content height, good biocompatibility and adjustable chemistry and mechanical property, but and high specific surface area coupled biological macromole, cross-linked network can coat the treatment molecule, adjustable grain size is beneficial to regulate in its body and distributes.These characteristics make nanogel insert the potentiality that have a wide range of applications aspect thing, biological nano technology and the drug delivery system in organizational project, biomedicine.
At present, the preparation method of nanogel concludes and can be divided into physical method and chemical process.Physical method is to utilize hydrophilic natural macromolecule or synthetic macromolecule to make molecule self aggregation or particle disperse to obtain nanogel by physics mode (as mode such as stirring, ultrasonic) effect in the presence of linking agent.Chemical process generally is to adopt wetting ability or water-soluble monomer to carry out the heterogeneous polymerization preparation in the presence of functional cross-link agent.
Sodium alginate be a kind of nontoxic, have good biocompatibility, biodegradable natural polysaccharide, be widely used in fields such as medicine, makeup, food.In pharmaceutical preparation, with the sodium alginate the existing report of research that substrate material prepares nanoparticulate carriers, its preparation method can be summarized as three kinds of ionic cross-linking, complex coacervation and self-assembly methods.
Ionic cross-linking be utilize sodium alginate easily and polyvalent cation bonded character prepare nanoparticle, as document (European Journal of Pharmaceutics and Biopharmaceutics, 2009; 73 (1): 25-33) reported with the crosslinked sodium alginate of calcium ion and prepare the nanoparticle that a series of median sizes are 394 ~ 558nm.U.S. Pat 2007/0202183A1 discloses a kind of preparation method of sodium alginate Nano capsule, this method is that the aqueous solution with sodium alginate joins in the oil phase that contains tensio-active agent, obtain the capsule of semicure, obtain the Nano capsule that particle diameter is 100 ~ 1000nm through calcium ion is crosslinked again.Chinese patent CN101549158 discloses a kind of sodium alginate liver-targeted nanometer drug delivery system and preparation method thereof, with the glycyrrhetinic acid is the liver target compound, make glycyrrhetinic acid-sodium alginate by the carboxyl of sodium alginate and the amido reaction of glycyrrhetinic acid-quadrol, again by the sodium alginate liver-targeted drug-carrying nanometer particle of the crosslinked acquisition of calcium ion.
Complex coacervation is character and the compound preparation nanoparticle of polycationic polymer that utilizes the sodium alginate polyanion, as document (Nanomedicine:Nanotechnology, Biology and Medicine, 2007; 3:239-243) reported that the compound median size that made of sodium alginate and chitosan is the nanoparticle of 229nm.
The self-assembly rule is that sodium alginate is carried out hydrophobically modified, make it become amphipathy macromolecule self-assembly formation nanoparticle in solution then, a kind of preparation method and application of acid amide-grafted sodium alginate nanometer material are disclosed as Chinese patent CN101565469, on the sodium alginate carboxylic group, carry out hydrophobic modification and form amphipathic nature material with the method grafting hydrophobic amide of chemosynthesis, self-assembly forms the nanoparticle of particle diameter between 40 ~ 1000nm in deionized water then, and this nanoparticle can be used as the slow-released carrier of various hydrophobic medicine.Document (Journal of Agricultural and Food, 2011; Reported with the oleic acid acyl chlorides sodium alginate has been carried out hydrophobically modified 59:1962-1967) that to form median size be the nanoparticle of 200 ~ 400nm in product self-assembly in the aqueous solution then, as the slow-released carrier of Vitamin D3 500,000 I.U/GM.
The sodium alginate nanoparticle has plurality of advantages as pharmaceutical carrier: (1) can make macromolecular drug smoothly by epithelium, promotes the osmotic absorption of medicine; (2) but prolong drug cycling time in vivo improve the availability of medicine effectively, increase the absorption of medicine; (3) can reduce the untoward reaction of medicine, reduce side effect; (4), can give its targeting to certain organs or lesion tissue by the sodium alginate nanoparticle is carried out suitable modification.
Yet sodium alginate nanoparticle of bibliographical information and preparation method thereof still has the following disadvantages at present:
The stability of particle is not high, easily causes the too early disintegration of nanoparticle in the body, and medicine or promoting agent discharge in advance.
Particle can not respond intracellular environment and discharge medicine as the pharmaceutical carrier of target cell.
The nano particle diameter wider distribution, and assemble easily.
The sodium alginate nanoparticle of ionic cross-linking and complex coacervation preparation can not the hydrophobic medicine of load.
Indivedual preparation methods such as U.S. Pat 2007/0202183A1 have also used tensio-active agent and oil phase organic solvent.
The inside and outside redox potential of human body cell has very big difference, makes the transportation of medicine that potential responsiveness signal be arranged.Redox-potential is being subjected to increasing attention as the stimulating responsive signal aspect the transmission of medicine, what wherein research was the widest is exactly the reversible fracture property preparation reduction responsive nano carrier that utilizes disulfide linkage.This class reduction responsive nano carrier mainly utilizes disulfide linkage to rupture under the effect of reducing substances such as gsh and dithiothreitol (DTT), thereby thereby its changes of properties is brought out in the variation that causes carrier structure, be implemented in the function under the specific environment.Studies show that gsh is the relatively abundant a kind of tripeptides of content in the cell, it will be far above in extracellular concentration in intracellular concentration, the difference on this concentration for the nanogel of design reduction responsiveness provides may.
Summary of the invention
Technical problem to be solved by this invention is: in order to solve problems of the prior art, a kind of preparation method of reduction responsive nano hydrogel of novel pH sensitivity is provided, the nano-hydrogel even structure of this method preparation, stability is high, can realize the original position medicine carrying, the fields such as thing, biological nano technology and drug delivery system of inserting in the biomedicine potentiality that have a wide range of applications.
The present invention solves its technical problem and adopts following technical scheme:
The reduction responsive nano gel of pH sensitivity provided by the invention, it effectively consists of the sodium alginate derivative of disulfide bond crosslinking, this nanogel is made by following method: the aqueous solution of getting sodium alginate, according to the sugar unit of sodium alginate and the mol ratio of periodate is 1:(0.01～10) to wherein adding periodate, the lucifuge reaction obtains the dialdehyde sodium alginate; Get the aqueous solution of dialdehyde sodium alginate and the ethanolic soln of 4-mercaptoaniline then, mol ratio according to the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline is 1:(0.01 ~ 10), mix the back in 0 ~ 25 ℃ of lucifuge and add the hydroborate reaction, obtain the sulfhydrylation sodium alginate; Sulfhydrylation sodium alginate self-assembly and the dioxygen oxidation in solution in the aqueous solution form the nanoparticle of disulfide bond crosslinking, promptly get the reduction responsive nano gel of described pH sensitivity.
Described sodium alginate aqueous solution, by W/V, its concentration is 0.5% ~ 5%.
Described dialdehyde sodium alginate aqueous solution weight concentration is≤5%, and preferred weight concentration is 0.01% ~ 1%.
The weight concentration of the ethanolic soln of described 4-mercaptoaniline is≤50%, and preferred weight concentration is 0.01% ~ 10%.
The preparation method of the reduction responsive nano hydrogel of pH sensitivity provided by the invention, its step comprises:
(1) preparation of dialdehyde sodium alginate:
Getting the aqueous solution of sodium alginate, is 1:(0.01～10 according to the sugar unit of sodium alginate and the mol ratio of periodate) to wherein adding periodate, 20 ~ 40 ℃ of controlled temperature add the ethylene glycol termination reaction behind the lucifuge stirring reaction 8h; Add ethanol then and make it separate out precipitation, and decompress filter obtains white product, this product dissolves again through deionized water, and after separating out again with ethanol, is drying to obtain the dialdehyde sodium alginate of different degree of oxidations;
(2) preparation of sulfhydrylation sodium alginate:
Getting the aqueous solution of dialdehyde sodium alginate, is 1:(0.01 ~ 10 by the mol ratio of the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline), add the ethanolic soln of 4-mercaptoaniline, add NaBH behind the stirring reaction 6h
4, regulating the pH value with 0.1MHCl is 7.0, and temperature control is continuing stirring reaction 1h below 4 ℃, and after the dialysis, lyophilize is promptly under nitrogen protection;
(3) preparation of reduction responsive nano gel:
Get the deionized water solution of 0.5 ~ 5mg/mL sulfhydrylation sodium alginate, leave standstill ultrasonic 3min behind the 24h, promptly get described reduction responsive nano hydrogel.
The reduction responsive nano hydrogel of method for preparing, it is used for biomedicine and inserts thing, biological nano technology or drug delivery system field.
The reduction responsive nano hydrogel of method for preparing, it is used to prepare and reduces the targeted nano gel of responsiveness.Perhaps, by the reduction responsive nano gel surface carboxyl coupling target molecule or the target molecule derivative of aforesaid method step (1), (2) and (3) preparation, obtain the active targeted nano gel of reduction responsiveness.
Described reduction responsive nano gel surface carboxyl coupling target molecule or target molecule derivative are specific part, or high degree of specificity antibody, or at least a specific part and at least a high degree of specificity antibody.
Described specific part is: a kind of in folic acid and derivative thereof, Transferrins,iron complexes, wheat germ agglutinin, semi-lactosi and derivative thereof, seminose and the derivative thereof.
Described high degree of specificity antibody is: Fab antibody fragment, lung endotheliocyte antibody 34A, acute myeloid leukemia cell CD33 antibody, anti-human epidermal growth factor receptor 2's monoclonal antibody Mabs or the monoclonal antibody LL2 of anti-B cell lymphoma.
The present invention adopts, and nontoxic, biodegradable and water-soluble good sodium alginate is a matrix, pass through sulfhydrylation, self-assembly and the dioxygen oxidation in solution form the nanogel of disulfide bond crosslinking in the aqueous solution, and it compared with prior art has following major advantage:
(1) before oxidation cross-linked, by stirring at room, but the self-assembly in the aqueous solution of sulfhydrylation sodium alginate forms nanoparticle, does not need to add other materials such as emulsifying agent.
(2) form disulfide bond crosslinking by atmospheric oxidation sulfydryl original position in the solution, can not only lock the form of nanoparticle, and the nanogel that obtains has good stability.
(3) adopt in-situ cross-linked mode can realize the original position load of medicine, make things convenient for the formulation moulding, have the potential using value as the slow controlled release carrier of medicine; And, be fit to very much the load of thermally labile medicine and the moulding of formulation because whole cross-linking process can carry out in room temperature or below the room temperature.
(4) owing to form disulfide bond crosslinking, the medicine in the nanogel can be avoided discharging in advance; In case the target approach cell can respond the rising of intracellular glutathione concentrations again, disulfide bonds takes place discharge medicine, thereby have intelligent controlled capability.
(5) carboxyl on nanogel surface can obtain the targeted nano gel by coupling target molecule or target molecule derivative.
(6) the carrier matrix material has nontoxic and biodegradable.
Description of drawings
Fig. 1 is the transmission electron microscope picture of the reduction responsive nano gel of the pH sensitivity of the present invention's preparation.
Fig. 2 is the change of size graphic representation of reduction responsive nano gel in different pH buffered soln of the present invention's preparation.
Embodiment
The invention will be further described below in conjunction with embodiment and accompanying drawing, but be not limited to following described content.
The invention provides the reduction responsive nano gel of the pH sensitivity that is different from prior art, it effectively consists of the sodium alginate derivative of disulfide bond crosslinking.This nanogel is made by following method: getting the aqueous solution of sodium alginate, is 1:(0.01～10 according to the sugar unit of sodium alginate and the mol ratio of periodate) to wherein adding periodate, the lucifuge reaction obtains the dialdehyde sodium alginate; Get the aqueous solution of dialdehyde sodium alginate and the ethanolic soln of 4-mercaptoaniline then, mol ratio according to the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline is 1:(0.01 ~ 10), mix the back in 0 ~ 25 ℃ of lucifuge and add the hydroborate reaction, obtain the sulfhydrylation sodium alginate; Sulfhydrylation sodium alginate self-assembly and the dioxygen oxidation in solution in the aqueous solution form the nanoparticle of disulfide bond crosslinking, promptly get the reduction responsive nano gel of described pH sensitivity.
By W/V, the concentration of described sodium alginate aqueous solution is 0.5% ~ 5%.
Described dialdehyde sodium alginate aqueous solution weight concentration is≤5%, and wherein preferred weight concentration is 0.01% ~ 1%.
The weight concentration of the ethanolic soln of described 4-mercaptoaniline is≤50%, and wherein preferred weight concentration is 0.01% ~ 10%.
The reduction responsive nano gel that the present invention also provides following method to prepare the pH sensitivity, for example:
Embodiment 1:
(1) get 1%(W/V) sodium alginate aqueous solution, according to the mol ratio of the sugar unit of sodium alginate and periodate be 1:0.5 to wherein adding periodate, behind 25 ℃ of following lucifuge stirring reaction 8h, add the ethylene glycol termination reaction.Then, add ethanol and make it separate out precipitation, and decompress filter obtains white product.Product dissolves again through deionized water, and after separating out again with ethanol, and it is 44.36% dialdehyde sodium alginate that drying obtains oxidisability.
(2) getting weight percent is 0.3% above-mentioned dialdehyde sodium alginate aqueous solution, is 1:1 by the mol ratio of the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline, adds the ethanolic soln of 4-mercaptoaniline, adds NaBH after mixing stirring reaction 6h
4, regulating the pH value with 0.1MHCl is 7.0, and temperature control is continuing stirring reaction 1h below 4 ℃, and after the dialysis, lyophilize obtains the sulfhydrylation sodium alginate that sulfhydryl content is 298.9 μ mol/g under nitrogen protection.
(3) get the deionized water solution of 1mg/mL sulfhydrylation sodium alginate, leave standstill ultrasonic 3min behind the 24h, obtaining median size is the reduction responsive nano hydrogel (Fig. 1) of 171nm.The reduction responsive nano gel of preparation is divided into two groups, and one group places glutathione concentrations is 0, and in the buffered soln of pH7.4, recording the nanogel particle diameter is 168nm, and polydispersity coefficient is 0.063; It is 10mM that another group places glutathione concentrations, and in the buffered soln of pH7.4, recording nano particle diameter is 197nm, and polydispersity coefficient is 0.183.
Embodiment 2:
(1) get 2%(W/V) sodium alginate aqueous solution, according to the mol ratio of the sugar unit of sodium alginate and periodate be 1:0.5 to wherein adding periodate, behind 25 ℃ of following lucifuge stirring reaction 8h, add the ethylene glycol termination reaction.Then, add ethanol and make it separate out precipitation, and decompress filter obtains white product.Product dissolves again through deionized water, and after separating out again with ethanol, and it is 42.57% dialdehyde sodium alginate that drying obtains oxidisability.
(2) getting weight percent is 0.2% above-mentioned dialdehyde sodium alginate aqueous solution, is 1:0.75 by the mol ratio of the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline, adds the ethanolic soln of 4-mercaptoaniline, adds NaBH after mixing stirring reaction 6h
4, regulating the pH value with 0.1MHCl is 7.0, and temperature control is continuing stirring reaction 1h below 4 ℃, and after the dialysis, lyophilize obtains the sulfhydrylation sodium alginate that sulfhydryl content is 270.1 μ mol/g under nitrogen protection.
(3) get the deionized water solution of 1mg/mL sulfhydrylation sodium alginate, leave standstill ultrasonic 3min behind the 24h, obtaining median size is the reduction responsive nano hydrogel of 180nm.The reduction responsive nano gel of preparation is divided into two groups, and one group places glutathione concentrations is 0, and in the buffered soln of pH7.4, recording the nanogel particle diameter is 177nm, and polydispersity coefficient is 0.060; It is 10mM that another group places glutathione concentrations, and in the buffered soln of pH7.4, recording nano particle diameter is 236nm, and polydispersity coefficient is 0.218.
Embodiment 3:
(1) get 1%(W/V) sodium alginate aqueous solution, according to the mol ratio of the sugar unit of sodium alginate and periodate be 1:0.25 to wherein adding periodate, behind 25 ℃ of following lucifuge stirring reaction 8h, add the ethylene glycol termination reaction.Then, add ethanol and make it separate out precipitation, and decompress filter obtains white product.Product dissolves again through deionized water, and after separating out again with ethanol, and it is 24.66% dialdehyde sodium alginate that drying obtains oxidisability.
(2) getting weight percent is 0.3% above-mentioned dialdehyde sodium alginate aqueous solution, is 1:1.25 by the mol ratio of the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline, adds the ethanolic soln of 4-mercaptoaniline, adds NaBH after mixing stirring reaction 6h
4, regulating the pH value with 0.1MHCl is 7.0, and temperature control is continuing stirring reaction 1h below 4 ℃, and after the dialysis, lyophilize obtains the sulfhydrylation sodium alginate that sulfhydryl content is 191.8 μ mol/g under nitrogen protection.
(3) get the deionized water solution of 1mg/mL sulfhydrylation sodium alginate, leave standstill ultrasonic 3min behind the 24h, obtaining median size is the reduction responsive nano hydrogel of 203nm.The reduction responsive nano gel of preparation is divided into two groups, and one group places glutathione concentrations is 0, and in the buffered soln of pH7.4, recording the nanogel particle diameter is 200nm, and polydispersity coefficient is 0.088; It is 10mM that another group places glutathione concentrations, and in the buffered soln of pH7.4, recording nano particle diameter is 278nm, and polydispersity coefficient is 0.223.
Embodiment 4:
(1) get 3%(W/V) sodium alginate aqueous solution, according to the mol ratio of the sugar unit of sodium alginate and periodate be 1:0.5 to wherein adding periodate, behind 25 ℃ of following lucifuge stirring reaction 8h, add the ethylene glycol termination reaction.Then, add ethanol and make it separate out precipitation, and decompress filter obtains white product.Product dissolves again through deionized water, and after separating out again with ethanol, and it is 40.87% dialdehyde sodium alginate that drying obtains oxidisability.
(2) getting weight percent is 0.25% above-mentioned dialdehyde sodium alginate aqueous solution; mol ratio by the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline is 1:1.5; the ethanolic soln that adds the 4-mercaptoaniline; add NaBH4 after mixing stirring reaction 6h; regulating the pH value with 0.1MHCl is 7.0; temperature control is continuing stirring reaction 1h below 4 ℃, after the dialysis, lyophilize obtains the sulfhydrylation sodium alginate that sulfhydryl content is 310.6 μ mol/g under nitrogen protection.
(3) get the deionized water solution of 1mg/mL sulfhydrylation sodium alginate, leave standstill ultrasonic 3min behind the 24h, obtaining median size is the reduction responsive nano hydrogel of 154nm.The reduction responsive nano gel of preparation is divided into two groups, and one group places glutathione concentrations is 0, and in the buffered soln of pH7.4, recording the nanogel particle diameter is 152nm, and polydispersity coefficient is 0.065; It is 10mM that another group places glutathione concentrations, and in the buffered soln of pH7.4, recording nano particle diameter is 186nm, and polydispersity coefficient is 0.199.
Embodiment 5:
(1) get 1%(W/V) sodium alginate aqueous solution, according to the mol ratio of the sugar unit of sodium alginate and periodate be 1:0.5 to wherein adding periodate, behind 25 ℃ of following lucifuge stirring reaction 8h, add the ethylene glycol termination reaction.Then, add ethanol and make it separate out precipitation, and decompress filter obtains white product.Product dissolves again through deionized water, and after separating out again with ethanol, and it is 49.78% dialdehyde sodium alginate that drying obtains oxidisability.
(2) getting weight percent is 0.2% above-mentioned dialdehyde sodium alginate aqueous solution, is 1:1.5 by the mol ratio of the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline, adds the ethanolic soln of 4-mercaptoaniline, adds NaBH after mixing stirring reaction 6h
4, regulating the pH value with 0.1MHCl is 7.0, and temperature control is continuing stirring reaction 1h below 4 ℃, and after the dialysis, lyophilize obtains the sulfhydrylation sodium alginate that sulfhydryl content is 321.5 μ mol/g under nitrogen protection.
(3) get the deionized water solution of 2mg/mL sulfhydrylation sodium alginate, leave standstill ultrasonic 3min behind the 24h, obtaining median size is the reduction responsive nano hydrogel of 150nm.The reduction responsive nano gel of preparation is divided into two groups, and one group places glutathione concentrations is 0, and in the buffered soln of pH7.4, recording the nanogel particle diameter is 147nm, and polydispersity coefficient is 0.096; It is 10mM that another group places glutathione concentrations, and in the buffered soln of pH7.4, recording nano particle diameter is 202nm, and polydispersity coefficient is 0.232.
Embodiment 6:
(1) get 2%(W/V) sodium alginate aqueous solution, according to the mol ratio of the sugar unit of sodium alginate and periodate be 1:0.75 to wherein adding periodate, behind 25 ℃ of following lucifuge stirring reaction 8h, add the ethylene glycol termination reaction.Then, add ethanol and make it separate out precipitation, and decompress filter obtains white product.Product dissolves again through deionized water, and after separating out again with ethanol, and it is 56.88% dialdehyde sodium alginate that drying obtains oxidisability.
(2) getting weight percent is 0.1% above-mentioned dialdehyde sodium alginate aqueous solution, is 1:2 by the mol ratio of the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline, adds the ethanolic soln of 4-mercaptoaniline, adds NaBH after mixing stirring reaction 6h
4, regulating the pH value with 0.1MHCl is 7.0, and temperature control is continuing stirring reaction 1h below 4 ℃, and after the dialysis, lyophilize obtains the sulfhydrylation sodium alginate that sulfhydryl content is 356.5 μ mol/g under nitrogen protection.
(3) get the deionized water solution of 2mg/mL sulfhydrylation sodium alginate, leave standstill ultrasonic 3min behind the 24h, obtaining median size is the reduction responsive nano hydrogel of 143nm.The reduction responsive nano gel of preparation is divided into two groups, and one group places glutathione concentrations is 0, and in the buffered soln of pH7.4, recording the nanogel particle diameter is 140nm, and polydispersity coefficient is 0.080; It is 10mM that another group places glutathione concentrations, and in the buffered soln of pH7.4, recording nano particle diameter is 211nm, and polydispersity coefficient is 0.215.
It is 0 that the reduction responsive nano gel for preparing in comparison the foregoing description 1,2,3,4,5,6 places glutathione concentrations respectively, the buffered soln of pH7.4 and glutathione concentrations are 10mM, size in the buffered soln of pH7.4 and polydispersity coefficient, the reduction responsive nano gel that can obtain preparing particle diameter in the glutathione solution of 10mM becomes big, it is big that polydispersity coefficient becomes, and illustrates that the reduction responsive nano gel of the present invention's preparation has the reduction responsiveness.
It is 7 groups that the reduction responsive nano gel of preparation in the foregoing description 1,2,3,4 is divided equally, and regulating the pH value respectively is 2.2,3.0,4.0,5.0,6.0,7.0 and 8.0, measures the size of reduction responsive nano gel.The result shows that the reduction responsive nano gel of the present invention's preparation has good pH susceptibility (Fig. 2).In Fig. 2, curve a is the change of size curve of reduction responsive nano gel among the embodiment 1; Curve b is the change of size curve of reduction responsive nano gel among the embodiment 2; Curve c is the change of size curve of reduction responsive nano gel among the embodiment 3; Curve d is the change of size curve of reduction responsive nano gel among the embodiment 4.
The preparation method of the reduction responsive nano gel of pH sensitivity provided by the invention, can also adopt following raw material:
By W/V, the concentration of described sodium alginate aqueous solution is 0.5% ~ 5%.
Described dialdehyde sodium alginate aqueous solution weight concentration is≤5%, and wherein preferred weight concentration is 0.01% ~ 1%.
The weight concentration of the ethanolic soln of described 4-mercaptoaniline is≤50%, and wherein preferred weight concentration is 0.01% ~ 10%.
The reduction responsive nano gel of pH sensitivity provided by the invention, perhaps by the reduction responsive nano gel of the pH sensitivity of method provided by the invention preparation, it is used to prepare and reduces the targeted nano gel of responsiveness.
In the aforesaid method provided by the invention, by the reduction responsive nano gel surface carboxyl coupling target molecule or the target molecule derivative of step (1), (2) and (3) preparation, it is used to prepare and reduces the active targeted nano gel of responsiveness.
Claims (10)
1. the reduction responsive nano gel of a pH sensitivity, the sodium alginate derivative that effectively consists of disulfide bond crosslinking that it is characterized in that this nanogel, this nanogel is made by following method: the aqueous solution of getting sodium alginate, according to the sugar unit of sodium alginate and the mol ratio of periodate is 1:(0.01～10) to wherein adding periodate, the lucifuge reaction obtains the dialdehyde sodium alginate; Get the aqueous solution of dialdehyde sodium alginate and the ethanolic soln of 4-mercaptoaniline then, mol ratio according to the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline is 1:(0.01 ~ 10), mix the back in 0 ~ 25 ℃ of lucifuge and add the hydroborate reaction, obtain the sulfhydrylation sodium alginate; Sulfhydrylation sodium alginate self-assembly and the dioxygen oxidation in solution in the aqueous solution form the nanoparticle of disulfide bond crosslinking, promptly get the reduction responsive nano gel of described pH sensitivity.
2. the reduction responsive nano gel of pH sensitivity according to claim 1 is characterized in that by W/V the concentration of described sodium alginate aqueous solution is 0.5% ~ 5%.
3. the reduction response nano gel of pH sensitivity according to claim 1 is characterized in that described dialdehyde sodium alginate aqueous solution weight concentration is≤5%.
4. the reduction response nano gel of pH sensitivity according to claim 3, the preferred weight concentration that it is characterized in that described dialdehyde sodium alginate aqueous solution is 0.01% ~ 1%.
5. the reduction response nano gel of pH sensitivity according to claim 1, the weight concentration that it is characterized in that the ethanolic soln of described 4-mercaptoaniline is≤50%.
6. the reduction response nano gel of pH sensitivity according to claim 5, the preferred weight concentration that it is characterized in that the ethanolic soln of described 4-mercaptoaniline is 0.01% ~ 10%.
7. the preparation method of the reduction responsive nano hydrogel of a pH sensitivity is characterized in that adopting following method preparation reduction responsive nano gel, and its step comprises:
(1) preparation of dialdehyde sodium alginate:
Getting the aqueous solution of sodium alginate, is 1:(0.01～10 according to the sugar unit of sodium alginate and the mol ratio of periodate) to wherein adding periodate, 20 ~ 40 ℃ of controlled temperature add the ethylene glycol termination reaction behind the lucifuge stirring reaction 8h; Add ethanol then and make it separate out precipitation, and decompress filter obtains white product, this product dissolves again through deionized water, and after separating out again with ethanol, is drying to obtain the dialdehyde sodium alginate of different degree of oxidations;
(2) preparation of sulfhydrylation sodium alginate:
Getting the aqueous solution of dialdehyde sodium alginate, is 1:(0.01 ~ 10 by the mol ratio of the amido of the aldehyde radical of dialdehyde sodium alginate and 4-mercaptoaniline), add the ethanolic soln of 4-mercaptoaniline, add NaBH behind the stirring reaction 6h
4, regulating the pH value with 0.1MHCl is 7.0, and temperature control is continuing stirring reaction 1h below 4 ℃, and after the dialysis, lyophilize is promptly under nitrogen protection;
(3) preparation of reduction responsive nano gel:
Get the deionized water solution of 0.5 ~ 5mg/mL sulfhydrylation sodium alginate, leave standstill ultrasonic 3min behind the 24h, promptly get described reduction responsive nano hydrogel.
8. the purposes of the reduction responsive nano hydrogel of a pH sensitivity is characterized in that: the reduction responsive nano hydrogel of the described method preparation of claim 7 is used for biomedicine inserts thing, biological nano technology or drug delivery system field.
9. the purposes of the reduction responsive nano hydrogel of a pH sensitivity is characterized in that: the reduction responsive nano hydrogel of the described method preparation of claim 7 is used to prepare reduces the targeted nano gel of responsiveness; Perhaps, by the reduction responsive nano gel surface carboxyl coupling target molecule or the target molecule derivative of step (1), (2) and (3) preparation, obtain the active targeted nano gel of reduction responsiveness.
10. purposes according to claim 9, it is characterized in that: described reduction responsive nano gel surface carboxyl coupling target molecule or target molecule derivative are specific part, or high degree of specificity antibody, or at least a specific part and at least a high degree of specificity antibody;
Described specific part is: a kind of in folic acid and derivative thereof, Transferrins,iron complexes, wheat germ agglutinin, semi-lactosi and derivative thereof, seminose and the derivative thereof;
Described high degree of specificity antibody is: Fab antibody fragment, lung endotheliocyte antibody 34A, acute myeloid leukemia cell CD33 antibody, anti-human epidermal growth factor receptor 2's monoclonal antibody Mabs or the monoclonal antibody LL2 of anti-B cell lymphoma.
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| CN105012959A (en) * | 2015-07-20 | 2015-11-04 | 武汉工程大学 | PH-responsive sodium alginate nano gel and production method thereof |
| CN105012959B (en) * | 2015-07-20 | 2018-01-19 | 武汉工程大学 | A kind of pH responses sodium alginate nanogel and preparation method thereof |
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| CN106478995B (en) * | 2016-09-09 | 2019-03-15 | 武汉理工大学 | A kind of sodium alginate based aquagel and preparation method thereof |
| CN106478995A (en) * | 2016-09-09 | 2017-03-08 | 武汉理工大学 | A kind of sodium alginate based aquagel and preparation method thereof |
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| CN106727284B (en) * | 2017-01-09 | 2020-06-02 | 武汉工程大学 | Magnetic reduction enhanced drug sensitive release nanogel and preparation and storage methods thereof |
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| CN110183549A (en) * | 2019-05-05 | 2019-08-30 | 湖北三江航天江河化工科技有限公司 | Light/pH double responsiveness sodium alginate derivative and the preparation method and application thereof |
| CN115698094A (en) * | 2020-03-05 | 2023-02-03 | 加拿大商新科生医股份有限公司 | Amphiphilic alginic acid-oleic acid macromolecule and preparation method thereof |
| CN111514097A (en) * | 2020-05-14 | 2020-08-11 | 燕山大学 | Preparation method of pH-responsive nano hydrogel of walnut shell polyphenol |
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| CN112625661B (en) * | 2021-03-05 | 2021-06-22 | 胜利油田固邦石油装备有限责任公司 | Filtrate reducer and preparation method thereof |
| CN112625661A (en) * | 2021-03-05 | 2021-04-09 | 胜利油田固邦石油装备有限责任公司 | Filtrate reducer and preparation method thereof |
| CN113413490A (en) * | 2021-05-14 | 2021-09-21 | 哈尔滨医科大学 | Ultrasonic-responsive composite hydrogel and preparation method and application thereof |
| CN113413490B (en) * | 2021-05-14 | 2022-05-27 | 哈尔滨医科大学 | Ultrasonic-responsive composite hydrogel and preparation method and application thereof |
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