CN103864953B - Modification gathers polysaccharide and preparation method thereof - Google Patents
Modification gathers polysaccharide and preparation method thereof Download PDFInfo
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- CN103864953B CN103864953B CN201410133893.7A CN201410133893A CN103864953B CN 103864953 B CN103864953 B CN 103864953B CN 201410133893 A CN201410133893 A CN 201410133893A CN 103864953 B CN103864953 B CN 103864953B
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Abstract
The invention provides a kind of modification and gather polysaccharide and preparation method thereof, this modification gathers polysaccharide and comprises: poly-polysaccharide, and it is dextran, pulullan polysaccharide or lentinan; Graft on the first grafted chain shown in formula (I) on the hydroxyl of described poly-polysaccharide and the second grafted chain shown in formula (II) respectively, percentage of grafting is respectively 0 ~ 96% and 4% ~ 100%.This preparation method comprises: glycidyl allyl ether passes through epoxy addition with the hydroxyl of above-mentioned poly-polysaccharide in the basic cpd aqueous solution, obtains the poly-polysaccharide of side chain thiazolinyl functionalization; There is light-initiated sulfydryl-thiazolinyl click chemistry and react in the poly-polysaccharide of sulfhydryl compound and described side chain thiazolinyl functionalization, obtains modification and gather polysaccharide; Described sulfhydryl compound selected from mercapto acetic acid, thiohydracrylic acid, mercaptoethylamine hydrochloride, mercaptoethanol, dimercaptosuccinic acid, halfcystine and reduced glutathion.This modification gathers polysaccharide can be used as pharmaceutical carrier, and its preparation method is safe and reliable, green high-efficient.
Description
Technical field
The present invention relates to poly-polysaccharide technical field, particularly a kind of modification gathers polysaccharide and preparation method thereof.
Background technology
Dextran, as one of the abundantest natural polysaccharide of nature, has been widely used in biotechnology and the field such as biomedical, such as, and medical science and pharmacy, especially plasma substitute, organizational project, gene therapy, biological devices coating and finishing etc.Get on very well particularly, its natural abundant source, excellent water-soluble and biocompatibility, make dextran become a kind of great potential and safe and reliable clinical biomaterial.Because dextran has good security and huge application potential, food and drug administration's approved its for intravenous injection.But, have multiple functional group as amino, carboxyl or sulfonic poly-polysaccharide with other, as chitosan, alginates, chondroitin sulfate, heparin are compared with hyaluronic acid, dextran only has hydroxyl, lack biological activity and cell adhesion ability, this may hinder it further to apply.
By chemical bond and mode, by other chemical functional groups or bioactive molecules and dextran bonding, be expected to give full play to dextran and derivative thereof the application potential at biomedical sector.Usually, the method that dextran side chain is modified mainly comprises esterification, etherificate and reduction amination.Calendar year 2001, Sharpless and colleague propose: utilize click chemistry to react and fast, efficiently and optionally can realize modular chemical bonding.Recently, the Huisgen1 of metallic copper mediation, 3-Dipolar Cycloaddition, the click chemistry reaction of these classics is for hydrophobically modified (PolymerChemistry2013, the 4:2235-8 of poly-polysaccharide; CarbohydratePolymers2013,93:537-46).Use the Huisgen1 of metallic copper mediation, when 3-Dipolar Cycloaddition carries out modification to poly-polysaccharide, in the introducing of polysaccharide side chain is nitrine or alkynyl.
At present, polysaccharide-modified research space is gathered still very greatly to dextran etc., the kind of poly-polysaccharide material can be enriched, be beneficial to application.
Summary of the invention
In order to solve above technical problem, the invention provides a kind of modification and gathering polysaccharide and preparation method thereof, modification provided by the invention gathers polysaccharide and modifies through side chain, can be used as pharmaceutical carrier and medicine inactive ingredients etc.
The invention provides a kind of modification and gather polysaccharide, comprising:
Poly-polysaccharide, described poly-polysaccharide is dextran, pulullan polysaccharide or lentinan;
Graft on the first grafted chain on the hydroxyl of described poly-polysaccharide, the percentage of grafting of described first grafted chain is 0 ~ 96%, described first grafted chain as shown in the formula (I):
With the second grafted chain grafted on the hydroxyl of described poly-polysaccharide, the percentage of grafting of described second grafted chain is 4% ~ 100%, described second grafted chain as shown in the formula (II):
In formula (II) ,-S-R is independently selected from the group after the group after the group after the group after Thiovanic acid dehydrogenation, thiohydracrylic acid dehydrogenation, the group after mercaptoethylamine hydrochloride dehydrogenation, mercaptoethanol dehydrogenation, the group after dimercaptosuccinic acid dehydrogenation, the group after halfcystine dehydrogenation and reduced glutathion dehydrogenation.
Preferably, the molecular weight of described poly-polysaccharide is 5000 ~ 70000.
Compared with prior art, modification provided by the invention gathers polysaccharide and comprises main chain, the first grafted chain and the second grafted chain; Described main chain is formed by these poly-polysaccharide of dextran, pulullan polysaccharide or lentinan; Described first grafted chain and the second grafted chain are grafted on the hydroxyl of described poly-polysaccharide respectively, and percentage of grafting is respectively 0 ~ 96% and 4% ~ 100%; Described first grafted chain as shown in the formula (I), described second grafted chain as shown in the formula (II), in formula (II) ,-S-R is independently selected from the group after the group after the group after the group after Thiovanic acid dehydrogenation, thiohydracrylic acid dehydrogenation, the group after mercaptoethylamine hydrochloride dehydrogenation, mercaptoethanol dehydrogenation, the group after dimercaptosuccinic acid dehydrogenation, the group after halfcystine dehydrogenation and reduced glutathion dehydrogenation.In the present invention, a certain amount of second grafted chain achieves the modification such as carboxylated or aminated of described poly-polysaccharide side chain, modified poly-polysaccharide is made to have biological activity or modify target spot, can pharmaceutical carrier and medicine inactive ingredients etc. be used as and be widely used in life science, be conducive to the range of application expanding this polysaccharide material of birdsing of the same feather flock together.Experiment shows, adopt described modification to gather polysaccharide and support antitumor drug cis-platinum or Zorubicin, carrier micelle has slow-release capability, and presents obvious dosage-medicine efficacy relation.
The present invention also provides a kind of modification to gather the preparation method of polysaccharide, comprises the following steps:
Glycidyl allyl ether in the basic cpd aqueous solution with the hydroxyl generation epoxy ring-opening reaction of poly-polysaccharide, obtain the poly-polysaccharide of side chain thiazolinyl functionalization; Described poly-polysaccharide is dextran, pulullan polysaccharide or lentinan;
Under light trigger existent condition, the poly-polysaccharide of sulfhydryl compound and described side chain thiazolinyl functionalization causes sulfydryl-thiazolinyl click chemistry by UV-light and reacts, and obtains modification and gathers polysaccharide; Described sulfhydryl compound is independently selected from Thiovanic acid, thiohydracrylic acid, mercaptoethylamine hydrochloride, mercaptoethanol, dimercaptosuccinic acid, halfcystine and reduced glutathion.
Preferably, the molecular weight of described poly-polysaccharide is 5000 ~ 70000.
Preferably, described light trigger is water-soluble free radical light trigger.
Preferably, the described basic cpd aqueous solution is aqueous sodium hydroxide solution.
Preferably, the concentration of the described basic cpd aqueous solution is 0.01M ~ 1M.
Preferably, the ratio of the described sulfydryl-sulfydryl of thiazolinyl click chemistry reaction and the amount of substance of thiazolinyl is 3 ~ 50:1.
Preferably, the wavelength of described UV-light is 245nm ~ 365nm.
Preferably, the time of described sulfydryl-thiazolinyl click chemistry reaction is 0.5h ~ 3h.
Compared with prior art, the hydroxyl of glycidyl allyl ether and poly-polysaccharide, first in the basic cpd aqueous solution, is reacted by epoxy addition by the present invention, realizes the side chain thiazolinyl functionalization of these poly-polysaccharide of dextran, pulullan polysaccharide or lentinan; Then, the present invention selects arbitrarily these sulfhydryl compounds of Thiovanic acid, thiohydracrylic acid, mercaptoethylamine hydrochloride, mercaptoethanol, dimercaptosuccinic acid, halfcystine or reduced glutathion, the sulfydryl utilizing UV-light to cause-thiazolinyl click chemistry reaction, realizes the modified side chain of poly-polysaccharide.The modified poly-polysaccharide of the present invention has biological activity or modifies target spot, can be widely used in life science, be conducive to the range of application expanding this polysaccharide material of birdsing of the same feather flock together as pharmaceutical carrier and medicine inactive ingredients etc.
In addition, the preparation method that modification provided by the invention gathers polysaccharide avoids the use of organic solvent and other heavy metal catalysts, and whole reaction process all can realize in aqueous, reaction conditions is gentle, controllability is strong, be a kind of safe, reliable, efficient poly-polysaccharide-modified method, be easy to promote and amplify.
Accompanying drawing explanation
Fig. 1 be the embodiment of the present invention 2 prepare thiazolinyl modify dextran using deuterated dimethyl sulfoxide as solvent time
1hNMR result figure;
Fig. 2 is the infrared spectrogram of the dextran of thiazolinyl modification prepared by the embodiment of the present invention 2;
Fig. 3 be the embodiment of the present invention 2 prepare mercaptoethylamine modify dextran using deuterated dimethyl sulfoxide as solvent time
1hNMR result figure;
Fig. 4 is the infrared spectrogram of the dextran of mercaptoethylamine modification prepared by the embodiment of the present invention 2;
Fig. 5 is the x-ray photoelectron energy spectrogram of the dextran of thiazolinyl modification prepared by the embodiment of the present invention 2 and the dextran of mercaptoethylamine modification;
Fig. 6 be the embodiment of the present invention 28 prepare thiohydracrylic acid modify dextran using deuterated dimethyl sulfoxide as solvent time
1hNMR result figure;
Fig. 7 is the infrared spectrogram of the dextran of thiohydracrylic acid modification prepared by the embodiment of the present invention 28;
Fig. 8 be the embodiment of the present invention 29 prepare dimercaptosuccinic acid modify dextran using deuterated dimethyl sulfoxide as solvent time
1hNMR result figure;
Fig. 9 is the infrared spectrogram of the dextran of dimercaptosuccinic acid modification prepared by the embodiment of the present invention 29;
Figure 10 is the release result of dextran grafts-Zorubicin carrier micelle in phosphoric acid buffer prepared by the embodiment of the present invention 47 and embodiment 55;
Figure 11 is the release result of dextran grafts-cis-platinum carrier micelle in phosphoric acid buffer prepared by the embodiment of the present invention 61 and embodiment 67;
Figure 12 is that the material of the embodiment of the present invention 12,19,34 and 37 preparation is to the Toxicity test result figure of A549 cell;
Figure 13 is that the Zorubicin carrier micelle prepared of the embodiment of the present invention 47 and embodiment 55 and the naked medicine of Zorubicin are to the Toxicity test result figure of A549 cell;
Figure 14 is that the Platinum complexes prepared of the embodiment of the present invention 61 and embodiment 67 and the naked medicine of cis-platinum are to the Effect tests result figure of MCF-7 cell.
Embodiment
In order to understand the present invention further, below in conjunction with embodiment, the preferred embodiment of the invention is described, but should be appreciated that these describe just for further illustrating the features and advantages of the present invention, instead of limiting to the claimed invention.
The invention discloses a kind of modification and gather polysaccharide, comprising: poly-polysaccharide, described poly-polysaccharide is dextran, pulullan polysaccharide or lentinan; Graft on the first grafted chain on the hydroxyl of described poly-polysaccharide, the percentage of grafting of described first grafted chain is 0 ~ 96%, and described first grafted chain as shown in the formula (I); With the second grafted chain grafted on the hydroxyl of described poly-polysaccharide, the percentage of grafting of described second grafted chain is 4% ~ 100%, and described second grafted chain as shown in the formula (II);
In formula (II) ,-S-R is independently selected from the group after the group after the group after the group after Thiovanic acid dehydrogenation, thiohydracrylic acid dehydrogenation, the group after mercaptoethylamine hydrochloride dehydrogenation, mercaptoethanol dehydrogenation, the group after dimercaptosuccinic acid dehydrogenation, the group after halfcystine dehydrogenation and reduced glutathion dehydrogenation.
The modification that the embodiment of the present invention provides gathers polysaccharide and belongs to graftomer, its with poly-polysaccharide for backbone compounds, by the hydroxyl of described poly-polysaccharide, the second grafted chain shown in the first grafted chain shown in grafting formula (I) and formula (II), the non-grafted end group of described second grafted chain is the group after the functional molecular dehydrogenation of some sulfhydrylations, modification can be given gather polysaccharide biological activity or modify target spot, be beneficial to its application in life science.
Modification provided by the invention gathers polysaccharide and comprises poly-polysaccharide, and it forms main chain, and the graft site of described main chain is the hydroxyl of poly-polysaccharide.The structural representation formula of described poly-polysaccharide is as the formula (1):
In the present invention, described poly-polysaccharide is modified as backbone compounds, and it is dextran, pulullan polysaccharide or lentinan, is preferably dextran.As preferably, the molecular weight of described poly-polysaccharide is 5000 ~ 70000, is more preferably 10000 ~ 60000.
Described dextran, pulullan polysaccharide and lentinan are respectively such as formula shown in (III) ~ (V):
Modification provided by the invention gathers polysaccharide and comprises the first grafted chain shown in formula (I), and it is grafted on the hydroxyl of described poly-polysaccharide, and grafts signal formula as the formula (2); Modification provided by the invention gathers polysaccharide and comprises the second grafted chain shown in formula (II), and it is grafted on the hydroxyl of described poly-polysaccharide, and grafts signal formula as the formula (3).
In formula (II) ,-S-R is independently selected from the group after the group after the group after the group after Thiovanic acid dehydrogenation, thiohydracrylic acid dehydrogenation, the group after mercaptoethylamine hydrochloride dehydrogenation, mercaptoethanol dehydrogenation, the group after dimercaptosuccinic acid dehydrogenation, the group after halfcystine dehydrogenation and reduced glutathion dehydrogenation.
In the present invention, the percentage of grafting of described first grafted chain is 0 ~ 96%, is preferably 2% ~ 56%, is more preferably 5% ~ 40%; The percentage of grafting of described second grafted chain is 4% ~ 100%, is preferably 5% ~ 60%, is more preferably 10% ~ 50%.The position relationship of the present invention to described first grafted chain and the second grafted chain is not particularly limited, and that is, graftomer of the present invention can be block polymer, also can be unregulated polymer; The present invention can not have the first grafted chain.
In the present invention, a certain amount of second grafted chain achieves the modification such as carboxylated or aminated of described poly-polysaccharide side chain, modified poly-polysaccharide is made to have biological activity or modify target spot, can pharmaceutical carrier and medicine inactive ingredients etc. be used as and be widely used in life science, be conducive to the range of application expanding this polysaccharide material of birdsing of the same feather flock together.Experiment shows, adopt described modification to gather polysaccharide and support antitumor drug cis-platinum or Zorubicin, carrier micelle has slow-release capability, and presents obvious dosage-medicine efficacy relation.
The invention also discloses the preparation method that a kind of modification gathers polysaccharide, comprise the following steps: glycidyl allyl ether in the basic cpd aqueous solution with the hydroxyl generation epoxy ring-opening reaction of poly-polysaccharide, obtain the poly-polysaccharide of side chain thiazolinyl functionalization; Described poly-polysaccharide is dextran, pulullan polysaccharide or lentinan; Under light trigger existent condition, the poly-polysaccharide of sulfhydryl compound and described side chain thiazolinyl functionalization causes sulfydryl-thiazolinyl click chemistry by UV-light and reacts, and obtains modification and gathers polysaccharide; Described sulfhydryl compound is independently selected from Thiovanic acid, thiohydracrylic acid, mercaptoethylamine hydrochloride, mercaptoethanol, dimercaptosuccinic acid, halfcystine and reduced glutathion.
The present invention, by carrying out aqueous phase modification to these poly-polysaccharide of dextran, pulullan polysaccharide or lentinan, achieves the modified side chain such as carboxyl or amido of poly-polysaccharide.Above-mentioned polysaccharide is widely used in life science as medicine inactive ingredients, pharmaceutical carrier, antitumor drug etc., and there is new biological activity through the poly-polysaccharide derivates of modification or modify target spot, be conducive to the range of application expanding this polysaccharide material of birdsing of the same feather flock together.
First, the embodiment of the present invention adds poly-polysaccharide, the basic cpd aqueous solution and glycidyl allyl ether and carries out epoxy addition reaction in reactor, obtains the poly-polysaccharide end product of side chain thiazolinyl functionalization.
The present invention carries out modification to poly-polysaccharide, and described poly-polysaccharide is dextran, pulullan polysaccharide or lentinan, is preferably dextran; Described dextran, pulullan polysaccharide and lentinan are respectively such as formula shown in (III) ~ (V).The molecular weight of described poly-polysaccharide is preferably 5000 ~ 70000, is more preferably 10000 ~ 60000.
The present invention adopts the hydroxyl generation epoxy ring-opening reaction of glycidyl allyl ether and poly-polysaccharide, prepares the poly-polysaccharide that thiazolinyl is modified.Described glycidyl allyl ether is such as formula shown in (VI):
The poly-polysaccharide that the present invention prepares thiazolinyl modification carries out in the basic cpd aqueous solution, and the described basic cpd aqueous solution is preferably aqueous sodium hydroxide solution; The concentration of the described basic cpd aqueous solution is preferably 0.01M ~ 1M, is more preferably 0.1M ~ 0.5M.In the present invention, the time of described epoxy addition reaction is preferably 12h ~ 72h, is more preferably 12h ~ 24h; The temperature of described epoxy addition reaction is preferably 20 DEG C ~ 50 DEG C, is more preferably 25 DEG C ~ 45 DEG C.
The reaction product of the first step reaction gained of the present invention carries out purifying by dialysis, freeze-drying, and after also can using alcohols rapid subsidence, washing, carry out purifying by dialysis, freeze-drying, described alcohols comprises methyl alcohol, ethanol or Virahol etc.The present invention carries out nucleus magnetic resonance test to products therefrom, and result shows, glycidyl allyl ether and poly-polysaccharide molecule success bonding, and thiazolinyl is incorporated into poly-polysaccharide side chain.
Glycidyl allyl ether is reacted by epoxy addition with the hydroxyl of poly-polysaccharide by the present invention in the basic cpd aqueous solution, realizes the side chain thiazolinyl functionalization of poly-polysaccharide.The efficiency of described epoxy addition reaction is preferably more than 4%, and be more preferably 5% ~ 60%, herein, the efficiency of reaction also can be expressed as the percentage of grafting of side chain thiazolinyl relative to poly-polysaccharide.
Then, the poly-polysaccharide of described side chain thiazolinyl functionalization, light trigger and sulfhydryl compound are added reactor, are preferably in the good quartzy bottle of light transmission by the present invention, carry out sulfydryl-thiazolinyl click chemistry reaction by UV-irradiation, obtain modification and gather polysaccharide graft product.
The present invention adopts sulfhydryl compound, carries out sulfydryl-thiazolinyl click chemistry react with the poly-polysaccharide of described side chain thiazolinyl functionalization.Described sulfhydryl compound is the functional molecular of sulfhydrylation, is expressed as SH-R; Described sulfhydryl compound, independently selected from Thiovanic acid, thiohydracrylic acid, mercaptoethylamine hydrochloride, mercaptoethanol, dimercaptosuccinic acid, halfcystine and reduced glutathion, is preferably Thiovanic acid, mercaptoethylamine hydrochloride or halfcystine.In the present invention, the ratio of the described sulfydryl-sulfydryl of thiazolinyl click chemistry reaction and the amount of substance of thiazolinyl is preferably 3 ~ 50:1, is more preferably 5 ~ 20:1.
When the present invention utilizes sulfydryl-thiazolinyl click chemistry reaction to modify poly-polysaccharide, need to use light trigger, and realized by UV-irradiation.Described light trigger is preferably water-soluble free radical light trigger, is more preferably 2-hydroxyl-4'-(2-hydroxy ethoxy)-2-methyl phenyl ketone, chemical reaction of the present invention can be made to carry out all in aqueous.In the present invention, the ratio of the described sulfydryl-thiazolinyl of thiazolinyl click chemistry reaction and the amount of substance of light trigger is preferably 1 ~ 20:1, is more preferably 5 ~ 15:1.The wavelength of described UV-light is preferably 245nm ~ 365nm, is more preferably 365nm.In the present invention, the time of described sulfydryl-thiazolinyl click chemistry reaction is preferably 0.5h ~ 3h, is more preferably 0.5h ~ 1.5h.
The reaction product of second step reaction gained of the present invention removes small molecular weight impurity by dialysis, obtains white solid product after freeze-drying.The present invention utilizes nucleus magnetic resonance and x-ray photoelectron spectroscopy to test products therefrom, and result shows, the thiazolinyl of sulfhydryl compound and poly-polysaccharide side chain is reacted by sulfydryl-thiazolinyl click chemistry, achieves the modification of poly-polysaccharide side chain.
The present invention, under light trigger existence condition, uses the functional molecular (SH-R) of sulfhydrylation, causes sulfydryl-thiazolinyl click chemistry reaction, realize the modified side chain of poly-polysaccharide by UV-light.The efficiency of described sulfydryl-thiazolinyl click chemistry reaction is preferably more than 80%, and be preferably 90% ~ 99.8%, herein, the efficiency of reaction also can be expressed as the percentage of grafting of sulfydryl relative to the poly-polysaccharide of side chain thiazolinyl functionalization.
The signal formula that the embodiment of the present invention responds can as the formula (4):
The signal formula that the embodiment of the present invention responds can respectively such as formula shown in (5) ~ (7):
Obtain after modification gathers polysaccharide, the present invention is supported antitumor drug cis-platinum or Zorubicin, and carries out the experiments such as Effect tests.Result shows, carrier micelle has slow-release capability, and presents obvious dosage-medicine efficacy relation.
In sum, the invention provides a kind of method realizing poly-polysaccharide modified side chain, described poly-polysaccharide comprises dextran, pulullan polysaccharide or lentinan.The method of described modification is in two steps: first, glycidyl allyl ether in the basic cpd aqueous solution with above-mentioned poly-polysaccharide by epoxy addition, realize the side chain thiazolinyl functionalization of poly-polysaccharide; Then, utilize light-initiated sulfydryl-thiazolinyl click chemistry reaction, realize the modified side chain of poly-polysaccharide.
Modification prepared by the present invention gathers polysaccharide to be had biological activity or modifies target spot, can be used as pharmaceutical carrier and medicine inactive ingredients etc. and be widely used in life science, be conducive to the range of application expanding this polysaccharide material of birdsing of the same feather flock together.In addition, the preparation method that modification provided by the invention gathers polysaccharide belongs to a kind of Green Chemistry modified method, and whole reaction process can be carried out completely in aqueous, without the need to using expensive and there is the metal catalyst of physical toxicity.Meanwhile, mild condition needed for whole reaction process, controllability is strong, is easy to promote and amplify.
In order to understand the present invention further, below in conjunction with embodiment, polysaccharide and preparation method thereof being gathered to modification provided by the invention and being specifically described.
Embodiment 1
The dextran that 1.0216g molecular weight is 5000 is added in the reaction flask of 50mL, be after the abundant stirring and dissolving of sodium hydroxide solution of 0.1M by 20mL concentration, add 0.2157g glycidyl allyl ether, 12h is reacted under the condition of 25 DEG C, then with the product that the precipitation reaction of ice ethanol obtains, again successively through filtering, ice washing with alcohol three times, vacuum-drying, obtain white solid product, finally fully dissolve described white solid product with deionized water, through dialysis tubing dialysis 48h, change water 10 times, after lyophilize, obtain end product, for precursor polymer, i.e. dextran-glycidyl allyl ether grafts (Dex-AGE).Carry out nucleus magnetic resonance test to described end product, calculating its percentage of grafting is 5.4%, and reaction yield is 78%.
Dex-AGE prepared by 0.2189g is added in the quartzy bottle of drying; after dissolving by 6mL deionized water and stirring, logical argon gas 0.5h, under room temperature, argon shield condition; add 1.6mg2-hydroxyl-4'-(2-hydroxy ethoxy)-2-methyl phenyl ketone and 0.0373g thiohydracrylic acid; by the UV-irradiation reaction 2h that wavelength is 365nm, by the product dialysis 72h be obtained by reacting, change water 12 times; after lyophilize; obtaining white lyophilized powder product, is graft product, i.e. modified glucan.Carry out nucleus magnetic resonance test to described graft product, calculating its percentage of grafting is 93.7%, and reaction yield is 92%.
Embodiment 2
The dextran that 5.0010g molecular weight is 40000 is added in the reaction flask of 250mL, be after the abundant stirring and dissolving of sodium hydroxide solution of 0.1M by 100mL concentration, add 3.5205g glycidyl allyl ether, 24h is reacted under the condition of 35 DEG C, then with the product that ethanol precipitation reaction obtains, again successively through filtering, ice washing with alcohol three times, vacuum-drying, obtain white solid product, finally fully dissolve described white solid product with deionized water, through dialysis tubing dialysis 72h, change water 12 times, after lyophilize, obtain end product, for precursor polymer, i.e. Dex-AGE.
Carry out nucleus magnetic resonance test to described end product, calculating its percentage of grafting is 22.9%, and reaction yield is 62%; Spectrogram as shown in Figure 1, Fig. 1 be the embodiment of the present invention 2 prepare thiazolinyl modify dextran using deuterated dimethyl sulfoxide as solvent time
1hNMR result figure.Utilize infrared spectra to carry out structural analysis to described end product, result is the infrared spectrogram of the dextran of thiazolinyl modification prepared by the embodiment of the present invention 2 see Fig. 2, Fig. 2.Result shows, glycidyl allyl ether and dextran molecule success bonding, and thiazolinyl is incorporated into dextran side chain.
Dex-AGE prepared by 0.2132g is added in the quartzy bottle of drying; after dissolving by 10mL deionized water and stirring, logical argon gas 0.5h, under room temperature, argon shield condition; add 5.8mg2-hydroxyl-4'-(2-hydroxy ethoxy)-2-methyl phenyl ketone and 0.2946g mercaptoethylamine hydrochloride; by the UV-irradiation reaction 1h that wavelength is 365nm, by the product dialysis 72h be obtained by reacting, change water 12 times; after lyophilize; obtaining white lyophilized powder product, is graft product, i.e. modified glucan.
Carry out nucleus magnetic resonance test to described graft product, calculating its percentage of grafting is 99.1%, and reaction yield is 92%; Spectrogram as shown in Figure 3, Fig. 3 be the embodiment of the present invention 2 prepare mercaptoethylamine modify dextran using deuterated dimethyl sulfoxide as solvent time
1hNMR result figure.Utilize infrared spectra to carry out structural analysis to described graft product, result is the infrared spectrogram of the dextran of mercaptoethylamine modification prepared by the embodiment of the present invention 2 see Fig. 4, Fig. 4.Result shows, the thiazolinyl of mercaptoethylamine and dextran side chain is reacted by sulfydryl-thiazolinyl click chemistry, achieves the aminated modification of dextran side chain.
X-ray photoelectron spectroscopy is utilized to carry out ultimate analysis to the precursor polymer of preparation and aminated dextran, result is the x-ray photoelectron energy spectrogram of the dextran of thiazolinyl modification prepared by the embodiment of the present invention 2 and the dextran of mercaptoethylamine modification see Fig. 5, Fig. 5.In Fig. 5, the corresponding precursor polymer of A curve, the corresponding aminated dextran of B curve.B curve is attributed to S2p at the peak at 168.3eV and 163.2eV place, confirms the existence of element sulphur in product modification dextran, confirms that the success of sulfydryl-thiazolinyl click chemistry reaction is carried out further.
Embodiment 3 ~ 27
According to the method for embodiment 1, embodiment 3 ~ 27, through the first step reaction and second step reaction, prepares modified glucan respectively.The content of embodiment 3 ~ 27 the first step reaction is see table 1, and table 1 is the content of the embodiment of the present invention 3 ~ 27 the first step reaction; The content of embodiment 3 ~ 27 second step reaction is see table 2, and table 2 is the content of the embodiment of the present invention 3 ~ 27 second step reaction.
The content of table 1 embodiment of the present invention 3 ~ 27 the first step reaction
The content of table 2 embodiment of the present invention 3 ~ 27 second step reaction
Note: embodiment 8,15 and 16,21 ~ 23,26 and 27 does not have second step to react.
Embodiment 28
The Dex-AGE prepared with embodiment 2 is for precursor polymer.
Dex-AGE prepared by 0.2301g embodiment 2 is added in the quartzy bottle of drying; after dissolving by 10mL deionized water and stirring, logical argon gas 0.5h, under room temperature, argon shield condition; add 6.3mg2-hydroxyl-4'-(2-hydroxy ethoxy)-2-methyl phenyl ketone and 0.2970g thiohydracrylic acid; by the UV-irradiation reaction 1h that wavelength is 365nm, by the product dialysis 72h be obtained by reacting, change water 12 times; after lyophilize; obtaining white lyophilized powder product, is graft product, i.e. modified glucan.
Carry out nucleus magnetic resonance test to described graft product, calculating its percentage of grafting is 95.3%, and reaction yield is 93%; Spectrogram as shown in Figure 6, Fig. 6 be the embodiment of the present invention 28 prepare thiohydracrylic acid modify dextran using deuterated dimethyl sulfoxide as solvent time
1hNMR result figure.Result shows, the thiazolinyl of thiohydracrylic acid and dextran side chain is reacted by sulfydryl-thiazolinyl click chemistry, achieves the carboxylated modification of dextran side chain.
Utilize infrared spectra to carry out structural analysis to described graft product, result is the infrared spectrogram of the dextran of thiohydracrylic acid modification prepared by the embodiment of the present invention 28 see Fig. 7, Fig. 7.As can be seen from Figure 7,1571cm
-1the stretching vibration peak of the visible significantly carbonyl in place, confirms the successful introducing of carboxyl in polymkeric substance further.
Embodiment 29
The Dex-AGE prepared with embodiment 2 is for precursor polymer.
Dex-AGE prepared by 0.2589g embodiment 2 is added in the quartzy bottle of drying; after dissolving by 15mL deionized water and stirring, logical argon gas 0.5h, under room temperature, argon shield condition; add 7.1mg2-hydroxyl-4'-(2-hydroxy ethoxy)-2-methyl phenyl ketone and 0.4728g dimercaptosuccinic acid; by the UV-irradiation reaction 1h that wavelength is 365nm, by the product dialysis 72h be obtained by reacting, change water 12 times; after lyophilize; obtaining white lyophilized powder product, is graft product, i.e. modified glucan.
Carry out nucleus magnetic resonance test to described graft product, calculating its percentage of grafting is 93.4%, and reaction yield is 90%; Spectrogram as shown in Figure 8, Fig. 8 be the embodiment of the present invention 29 prepare dimercaptosuccinic acid modify dextran using deuterated dimethyl sulfoxide as solvent time
1hNMR result figure.Result shows, the thiazolinyl of dimercaptosuccinic acid and dextran side chain is reacted by sulfydryl-thiazolinyl click chemistry, achieves the carboxylated modification of dextran side chain.
Utilize infrared spectra to carry out structural analysis to described graft product, result is the infrared spectrogram of the dextran of dimercaptosuccinic acid modification prepared by the embodiment of the present invention 29 see Fig. 9, Fig. 9.As can be seen from Figure 9,1585cm
-1the stretching vibration peak of the visible significantly carbonyl in place, confirms the successful introducing of carboxyl in polymkeric substance.
Embodiment 30 ~ 44
The Dex-AGE prepared with embodiment is before for raw material, and according to the method for embodiment 28 second step reaction, embodiment 30 ~ 44 prepares modified glucan respectively.The content that embodiment 30 ~ 44 is reacted is see table 3, and table 3 is the content that the embodiment of the present invention 30 ~ 44 is reacted.
The content that table 3 embodiment of the present invention 30 ~ 44 is reacted
Embodiment 45 ~ 56
The carboxylic dextran of the side chain utilizing above-described embodiment to prepare, antitumor drug Zorubicin is supported by electrostatic compound action, method is: be dissolved in deionized water by the dextran of functionalization, adjust ph 7.0 ~ 8.0, add Lipodox, room temperature lucifuge stirs 24h, pure water dialysis 48h, change water 8 times to remove free Zorubicin, obtain the nano-micelle supporting Zorubicin.By the aseptically lyophilize of described nano-micelle, obtain adriamycin nano-particles lyophilized powder.
Utilize ultraviolet-visible spectrum in the absorption of 480nm, measure the concentration of Zorubicin in the adriamycin nano-particles obtained, by the encapsulation efficiency of following formulae discovery Zorubicin in nanoparticle (DLE) and retention volume (DLC);
Embodiment 45 ~ 56 supports the content of medicine see table 4, and table 4 is the content that the embodiment of the present invention 45 ~ 56 supports medicine.
Table 4 embodiment of the present invention 45 ~ 56 supports the content of medicine
Embodiment 57 ~ 72
The carboxylic dextran of the side chain utilizing above-described embodiment to prepare, antitumor drug cis-platinum is supported by the coordination of carboxyl and platinum, concrete grammar is: be dissolved in deionized water by the dextran of functionalization, adjust ph 7.4 ~ 8.2, add cis-platinum, 37 DEG C of lucifuges stir 72h, pure water dialysis 36h, change water 8 times to remove free cis-platinum, obtain the micella of Platinum complexes.By the aseptically lyophilize of the micella of described Platinum complexes, obtain Platinum complexes lyophilized powder, its Pt content utilizes inductivity coupled plasma mass spectrometry to measure.
Embodiment 57 ~ 72 supports the content of medicine see table 5, and table 5 is the content that the embodiment of the present invention 57 ~ 72 supports medicine.
Table 5 embodiment of the present invention 57 ~ 72 supports the content of medicine
Embodiment 73
Get the embodiment 47 of 5mg and the Zorubicin carrier micelle of embodiment 55 preparation, the pH value being dissolved in 5mL concentration 0.01M is in the phosphate buffer soln of 7.4, then the dialysis tubing that molecular weight cut-off is 3500 is transferred to, dialyse with 40mL damping fluid under 37 DEG C of conditions, sample 3mL respectively at 1h, 3h, 5h, 7h, 10h, 16h, 24h, 36h, 48h, 60h, and add the damping fluid of respective amount.Use ultraviolet-visible spectrometer test doxorubicin concentration, obtain the variation relation that cumulative release per-cent increased along with the time, as shown in Figure 10, Figure 10 is the release result of dextran grafts-Zorubicin carrier micelle in phosphoric acid buffer prepared by the embodiment of the present invention to release result.In Fig. 10, carrier micelle prepared by the corresponding embodiment 47 of A curve, carrier micelle prepared by the corresponding embodiment 55 of B curve.Result shows, Zorubicin carrier micelle prepared by embodiment 47 and embodiment 55 all has slow-release capability.
Embodiment 74
Get the embodiment 61 of 5mg and the cis-platinum carrier micelle of embodiment 67 preparation, to be dissolved in 5mL concentration be the pH value of 0.01M is in the phosphate buffer soln of 7.4, then the dialysis tubing that molecular weight cut-off is 3500 is transferred to, dialyse with 40mL damping fluid under 37 DEG C of conditions, sample 3mL respectively at 1h, 6h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, and add the damping fluid of respective amount.Inductivity coupled plasma mass spectrometry is utilized to carry out quantitative analysis, obtain the variation relation that cumulative percentage release increased along with the time, as shown in figure 11, Figure 11 is the release result of dextran grafts-cis-platinum carrier micelle in phosphoric acid buffer prepared by the embodiment of the present invention 61 and embodiment 67 to release result.In fig. 11, carrier micelle prepared by the corresponding embodiment 61 of A curve, carrier micelle prepared by the corresponding embodiment 67 of B curve.Result shows, cis-platinum carrier micelle prepared by embodiment 61 and embodiment 67 has slow-release capability, effectively can reduce the toxicity of small molecules cis-platinum, improves body tolerance.
Embodiment 75
Collect logarithmic phase A549 cell, adjustment cell concn, inoculates in 96 orifice plates, containing 100 μ L(about 10 in every hole
4individual) cell, abandon nutrient solution after cultivating 24h at 37 DEG C;
It is the sample of 1.0g/L, 0.5g/L, 0.25g/L, 0.125g/L, 0.0625g/L, 0.03125g/L6 concentration that material prepared by precursor polymer embodiment 12 prepared with substratum and modified glucan, embodiment 19, embodiment 34, embodiment 37 dilutes respectively;
Each sample is added 96 orifice plates, and every hole adds 200 μ L, often kind of concentration 6 multiple holes;
At 37 DEG C, saturated humidity, 5%CO
224h is cultivated in cell culture incubator;
After 24h, it is the tetrazolium bromide of 5mg/mL that every hole adds 20 μ L concentration, continues to cultivate 4h;
Stop cultivating, suck nutrient solution in hole, every hole adds 150 μ L dimethyl sulfoxide (DMSO), and low-speed oscillation 10min detects the absorption value of each hole at 492nm place by microplate reader, converts and obtains the cell survival rate of each concentration.
The relatively cell compatibility of above-mentioned materials, result is that the material of the embodiment of the present invention 12,19,34 and 37 preparation is to the Toxicity test result figure of A549 cell see Figure 12, Figure 12.In fig. 12, material prepared by the modified glucan that A, B, C, D, E are followed successively by precursor polymer prepared by embodiment 12, prepared by embodiment 12, embodiment 19, embodiment 34, embodiment 37 investigates result to the cytotoxicity of A549 cell.As shown in Figure 12, above-mentioned materials has good biocompatibility to cell.
Embodiment 76
Collect logarithmic phase A549 cell, adjustment cell concn, inoculates in 96 orifice plates, containing 100 μ L(about 10 in every hole
4individual) cell, abandon nutrient solution after cultivating 24h at 37 DEG C;
Be the sample of 0.02g/L, 0.01g/L, 0.005g/L, 0.0025g/L, 0.00125g/L, 0.000625g/L6 concentration by naked for Zorubicin medicine dilution with substratum, adriamycin composite embodiment 47 and embodiment 55 prepared with substratum is the sample of 0.02g/L, 0.01g/L, 0.005g/L, 0.0025g/L, 0.00125g/L, 0.000625g/L6 concentration respectively according to doxorubicin concentration dilution;
Each sample is added 96 orifice plates, and every hole adds 200 μ L, often kind of concentration 6 multiple holes;
At 37 DEG C, saturated humidity, 5%CO
224h is cultivated in cell culture incubator;
After 24h, it is the tetrazolium bromide of 5mg/mL that every hole adds 20 μ L concentration, continues to cultivate 4h;
Stop cultivating, suck nutrient solution in hole, every hole adds 150 μ L dimethyl sulfoxide (DMSO), and low-speed oscillation 10min detects the absorption value of each hole at 492nm place by microplate reader, converts and obtains the survival rate of cell.
The relatively effect of the naked medicine of Zorubicin and adriamycin composite micella cell inhibitory effect, result is that the Zorubicin carrier micelle prepared of the embodiment of the present invention 47 and embodiment 55 and the naked medicine of Zorubicin are to the Toxicity test result figure of A549 cell see Figure 13, Figure 13.Wherein, curve A is that the naked medicine of Zorubicin is to the toxic effect of A549 cell, curve B be embodiment 47 prepare adriamycin composite micella to the toxic effect of A549 cell, curve C be embodiment 55 prepare adriamycin composite micella to the toxic effect of A549 cell.As shown in Figure 13, compared with the naked medicine of Zorubicin, carrier micelle maintains the anti-tumor activity of former medicine, and presents obvious dosage-medicine efficacy relation.
Embodiment 77
Collect logarithmic phase MCF-7 cell, adjustment cell concn, inoculates in 96 orifice plates, containing 100 μ L(about 10 in every hole
4individual) cell, abandon nutrient solution after cultivating 24h at 37 DEG C;
Be the sample of 150 μMs/L, 75 μMs/L, 37.5 μMs/L, 18.75 μMs/L, 9.375 μMs/L, a 4.6875 μMs/L6 concentration by naked for cis-platinum medicine dilution with substratum, Platinum complexes embodiment 61 and embodiment 67 prepared with substratum is the sample of 300 μMs/L, 150 μMs/L, 75 μMs/L, 37.5 μMs/L, 18.75 μMs/L, a 9.375 μMs/L6 concentration respectively according to Pt concentration dilution in cis-platinum;
Each sample is added 96 orifice plates, and every hole adds 200 μ L, often kind of concentration 6 multiple holes;
At 37 DEG C, saturated humidity, 5%CO
272h is cultivated in cell culture incubator;
After 72h, it is the tetrazolium bromide of 5mg/mL that every hole adds 20 μ L concentration, continues to cultivate 4h;
Stop cultivating, suck nutrient solution in hole, every hole adds 150 μ L dimethyl sulfoxide (DMSO), and low-speed oscillation 10min detects the absorption value of each hole at 492nm place by microplate reader, and conversion obtains using the survival rate of cell after the suitable naked medicine platinum of each concentration and Platinum complexes.
The relatively effect of the naked medicine of cis-platinum and Platinum complexes effect, result is that the Platinum complexes prepared of the embodiment of the present invention 61 and embodiment 67 and the naked medicine of cis-platinum are to the Effect tests result figure of MCF-7 cell see Figure 14, Figure 14.Wherein, curve A be the naked medicine of cis-platinum to the toxic effect of MCF-7 cell, curve B be embodiment 61 prepare Platinum complexes to the toxic effect of MCF-7 cell, curve C be embodiment 67 prepare Platinum complexes to the toxic effect of MCF-7 cell.As shown in Figure 14, compared with the naked medicine of cis-platinum, Platinum complexes has slow-release function, significantly reduces former medicine toxicity, and presents obvious dosage-medicine efficacy relation.
As seen from the above embodiment, the present invention has prepared a kind of modification and has gathered polysaccharide, its side chain has carboxyl or aminated modification, thus there is biological activity or modify target spot, can pharmaceutical carrier and medicine inactive ingredients etc. be used as and be widely used in life science, be conducive to the range of application expanding this polysaccharide material of birdsing of the same feather flock together.
In addition, the preparation method that modification provided by the invention gathers polysaccharide avoids the use of organic solvent and other heavy metal catalysts, and whole reaction process all can realize in aqueous, reaction conditions is gentle, controllability is strong, be a kind of safe, reliable, efficient poly-polysaccharide-modified method, be easy to promote and amplify.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.
Claims (10)
1. modification gathers a polysaccharide, comprising:
Poly-polysaccharide, described poly-polysaccharide is dextran, pulullan polysaccharide or lentinan;
Graft on the first grafted chain on the hydroxyl of described poly-polysaccharide, the percentage of grafting of described first grafted chain is 0 ~ 96%, described first grafted chain as shown in the formula (I):
With the second grafted chain grafted on the hydroxyl of described poly-polysaccharide, the percentage of grafting of described second grafted chain is 4% ~ 100%, described second grafted chain as shown in the formula (II):
In formula (II) ,-S-R is independently selected from the group after the group after the group after the group after Thiovanic acid dehydrogenation, thiohydracrylic acid dehydrogenation, the group after mercaptoethylamine hydrochloride dehydrogenation, mercaptoethanol dehydrogenation, the group after dimercaptosuccinic acid dehydrogenation, the group after halfcystine dehydrogenation and reduced glutathion dehydrogenation.
2. modification according to claim 1 gathers polysaccharide, it is characterized in that, the molecular weight of described poly-polysaccharide is 5000 ~ 70000.
3. modification gathers a preparation method for polysaccharide, comprises the following steps:
Glycidyl allyl ether in the basic cpd aqueous solution with the hydroxyl generation epoxy ring-opening reaction of poly-polysaccharide, obtain the poly-polysaccharide of side chain thiazolinyl functionalization; Described poly-polysaccharide is dextran, pulullan polysaccharide or lentinan;
Under light trigger existent condition, the poly-polysaccharide of sulfhydryl compound and described side chain thiazolinyl functionalization causes sulfydryl-thiazolinyl click chemistry by UV-light and reacts, and obtains modification and gathers polysaccharide; Described sulfhydryl compound is independently selected from Thiovanic acid, thiohydracrylic acid, mercaptoethylamine hydrochloride, mercaptoethanol, dimercaptosuccinic acid, halfcystine and reduced glutathion.
4. preparation method according to claim 3, is characterized in that, the molecular weight of described poly-polysaccharide is 5000 ~ 70000.
5. preparation method according to claim 4, is characterized in that, described light trigger is water-soluble free radical light trigger.
6. preparation method according to claim 5, is characterized in that, the described basic cpd aqueous solution is aqueous sodium hydroxide solution.
7. preparation method according to claim 6, is characterized in that, the concentration of the described basic cpd aqueous solution is 0.01M ~ 1M.
8. the preparation method according to any one of claim 3 to 6, is characterized in that, the ratio of the described sulfydryl-sulfydryl of thiazolinyl click chemistry reaction and the amount of substance of thiazolinyl is 3 ~ 50:1.
9. the preparation method according to any one of claim 3 to 6, is characterized in that, the wavelength of described UV-light is 245nm ~ 365nm.
10. the preparation method according to any one of claim 3 to 6, is characterized in that, the time of described sulfydryl-thiazolinyl click chemistry reaction is 0.5h ~ 3h.
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