CN102127231B - Glucan/polycaprolactone amphiphilic block polymer and preparation method and application thereof - Google Patents
Glucan/polycaprolactone amphiphilic block polymer and preparation method and application thereof Download PDFInfo
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- CN102127231B CN102127231B CN201110038332.5A CN201110038332A CN102127231B CN 102127231 B CN102127231 B CN 102127231B CN 201110038332 A CN201110038332 A CN 201110038332A CN 102127231 B CN102127231 B CN 102127231B
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- 229920001610 polycaprolactone Polymers 0.000 title claims abstract description 133
- 239000004632 polycaprolactone Substances 0.000 title claims abstract description 133
- 229920000642 polymer Polymers 0.000 title claims abstract description 87
- 238000002360 preparation method Methods 0.000 title claims abstract description 61
- 229920001503 Glucan Polymers 0.000 title 1
- 239000002245 particle Substances 0.000 claims abstract description 73
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- 239000003814 drug Substances 0.000 claims abstract description 33
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- 229930012538 Paclitaxel Natural products 0.000 claims abstract description 25
- 229960001592 paclitaxel Drugs 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 24
- 229940079593 drug Drugs 0.000 claims abstract description 22
- 238000011068 loading method Methods 0.000 claims abstract description 13
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 54
- 238000013019 agitation Methods 0.000 claims description 40
- 150000001412 amines Chemical group 0.000 claims description 39
- 239000007864 aqueous solution Substances 0.000 claims description 36
- 230000008021 deposition Effects 0.000 claims description 33
- 150000001299 aldehydes Chemical group 0.000 claims description 29
- 239000011259 mixed solution Substances 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 22
- 239000000047 product Substances 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 19
- 238000000502 dialysis Methods 0.000 claims description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 14
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 claims description 10
- 238000009835 boiling Methods 0.000 claims description 7
- JBFHTYHTHYHCDJ-UHFFFAOYSA-N gamma-caprolactone Chemical compound CCC1CCC(=O)O1 JBFHTYHTHYHCDJ-UHFFFAOYSA-N 0.000 claims description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 229960004217 benzyl alcohol Drugs 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 5
- 238000000975 co-precipitation Methods 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 238000004062 sedimentation Methods 0.000 claims description 2
- 125000002456 taxol group Chemical group 0.000 claims 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 abstract description 31
- 239000000693 micelle Substances 0.000 abstract description 9
- 238000012377 drug delivery Methods 0.000 abstract description 6
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000000149 argon plasma sintering Methods 0.000 description 7
- 229920001400 block copolymer Polymers 0.000 description 7
- 238000011088 calibration curve Methods 0.000 description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 7
- -1 polyoxytrimethylene Polymers 0.000 description 7
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
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- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
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- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
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Abstract
一种葡聚糖/聚己内酯两亲嵌段聚合物，它是由胺端基葡聚糖和醛端基聚己内酯通过偶联反应生成，其中葡聚糖链段的数均分子量范围为3000～10000、聚己内酯链段的数均分子量范围为3000～10000，两个链段以-NH-CH2-键相连。本发明的葡聚糖/聚己内酯嵌段聚合物可以作为难溶于水的药物的载体材料用于制备载药纳米粒，载药纳米粒为球形，平均粒径为100～300nm，多分散系数为0.2左右，载药量可达20%。本发明提供的制备葡聚糖/聚己内酯嵌段聚合物的方法具有反应条件温和、操作简便、易于实施、产率较高的特点。本发明提供的载药纳米粒可作为紫杉醇的一种新型聚合物胶束给药系统，它具有亲水性好、生物降解性和生物相容性好、易于化学修饰的葡聚糖壳层。本发明公开了它们的制法。A dextran/polycaprolactone amphiphilic block polymer, which is produced by coupling reaction of amine-terminated dextran and aldehyde-terminated polycaprolactone, wherein the number-average molecular weight of the dextran segment The range is 3000-10000, the number-average molecular weight range of the polycaprolactone chain segment is 3000-10000, and the two chain segments are connected by -NH- CH2 -bond. The dextran/polycaprolactone block polymer of the present invention can be used as a carrier material for insoluble drugs in water to prepare drug-loaded nanoparticles, the drug-loaded nanoparticles are spherical, and the average particle diameter is 100-300nm The dispersion coefficient is about 0.2, and the drug loading can reach 20%. The method for preparing the dextran/polycaprolactone block polymer provided by the invention has the characteristics of mild reaction conditions, simple operation, easy implementation and high yield. The drug-loaded nanoparticle provided by the invention can be used as a novel polymer micelle drug delivery system for paclitaxel, which has a dextran shell layer with good hydrophilicity, good biodegradability and biocompatibility, and easy chemical modification. The invention discloses their preparation methods.
Description
Technical field
The present invention relates to a kind of drug-carrying nanometer particle based on VISOSE/polycaprolactone amphiphilic block polymer and preparation method thereof.
Background technology
A lot of antitumor drugs are (like taxol; Paclitaxel) have shortcomings such as solubleness in water is extremely low, toxic side effect is big usually; Its application in clinical treatment is restricted; Therefore the novel drug delivery system of developing this type of medicine becomes the focus of research (referring to CN 101006998A, CN 101439020A).Wherein, Polymer micelle administration system by the amphiphilic block polymer preparation receives broad research; The result shows that this drug delivery system has the following advantages: (1) polymer micelle has tangible nucleocapsid structure; Oil loving nuclear energy enough effectively dissolves poorly water soluble drugs, and hydrophilic shell plays stable and provide protection to micella; (2) small particle size of polymer micelle (being generally less than 200nm) and wetting ability shell can prevent that micella from being absorbed by the identification of human body reticuloendothelial system, are implemented in the long circulation in the blood of human body; (3) the tumor tissues blood vessel endothelium has hypertonicity and high anelasticity, and the small particle size of polymer micelle helps its accumulation at tumor tissues, realizes its passive target to tumor tissues, improves bioavailability of medicament and reduces toxic side effect.Therefore, the polymer micelle administration system has become one of the drug delivery system of the hydrophobic nature antitumor drug of tool application prospect.
In the preparation of amphiphilic block polymer; The kind of hydrophobic chain segment is more; Like aliphatic polyester, polyamino acid, polyoxytrimethylene etc.; And the hydrophilic segment majority is selected polyoxyethylene glycol (PEG) for use, and this is because good, the good biocompatibility of PEG possess hydrophilic property, toxicity are low, the series of advantages such as identification that can avoid the human body reticuloendothelial system.Yet; Also there are some shortcomings in the PEG segment: the one, and itself does not possess biodegradable; Have only the low PEG of molecular weight just can excrete by cytophagy or through the kidney filter membrane, if as the drug carrier material long term in human body, very likely produce toxic side effect; The 2nd, lack reactive group (only the end of the chain has a hydroxyl) on its molecular chain, be unfavorable for the micella shell is carried out follow-up modification, give initiatively target property of carrier micelle as connecting the target group.Given this, have the investigator to be devoted to seek the more good hydrophilic segment of performance, as Vinylpyrrolidone polymer (referring to:
Journal of Controlled Release, 2010,142:438 – 446), gather (2-methylacryoyloxyethyl Phosphorylcholine) (referring to:
J Polym Sci, Part A:Polym Chem, 2007,45 (4): 688 – 698) etc.
VISOSE mainly is a kind of linear polysaccharide that is connected to form by α (1,6) glycosidic link, and it has following characteristic: wetting ability is strong; Favorable biological degradability, itself and degraded product in vivo are to human non-toxic; Excellent biological compatibility can be used as plasma substitute and uses clinically; Molecular chain is submissive, and contains great amount of hydroxy group on the molecular chain.Prepare VISOSE/aliphatic polyester amphiphilic block polymer if substitute PEG with VISOSE, it is not enough to overcome above-mentioned PEG segmental, becomes the one type solid support material more excellent more than PEG/ aliphatic polyester amphiphilic block polymer performance.Yet the research report of relevant VISOSE/aliphatic polyester block polymer is less.Liu etc. (
Carbohydrate Polymers, 2007,69:196 – 201) prepared VISOSE/polycaprolactone bi-block copolymer and its micellization behavior has been studied, the preparation method is: at first VISOSE and reacting ethylenediamine are made the amine end groups VISOSE; Then terminal hydroxy group polycaprolactone and acrylate chloride reaction are made acryl end group polycaprolactone; Through linked reaction amine end groups VISOSE and acryl end group polycaprolactone are coupled together and make VISOSE/polycaprolactone bi-block copolymer, this step reaction might cause the oxidation of VISOSE for pyroreaction (at 120 ℃ of reaction 8h down).Sun etc. (
Biomacromolecules, 2010,11:848 – 854) and the polymer micelle administration system that prepared VISOSE/polycaprolactone bi-block copolymer and be used to construct Zorubicin, one of preparation method is: at first make the amine end groups polycaprolactone, then at NaCNBH
3Directly amine end groups polycaprolactone and VISOSE coupling are got up to make VISOSE/polycaprolactone bi-block copolymer under the catalysis, productive rate is lower, is 45%.Preparing method's two is: at first VISOSE and mercaptamine reaction are made sulfydryl end group VISOSE (Dex-SH), again with Dex-SH and 2,2'-two sulphur, two pyridines (Py-SS-Py) reaction makes Dex-SS-Py; Make sulfydryl end group polycaprolactone (PCL-SH) then; Through linked reaction Dex-SS-Py and PCL-SH are coupled together again and make VISOSE/polycaprolactone bi-block copolymer; This method reactions step is more, has used multiple solvent system (DMSO/H in the preparation process
2O, H
2O, DMF/LiCl) dissolve VISOSE and verivate thereof, and the productive rate of VISOSE/polycaprolactone bi-block copolymer is lower, is 49%.VISOSE/polycaprolactone bi-block copolymer the maximum differential structurally of reports such as Liu etc. and Sun is: because the preparation method is different, cause the linking group difference between VISOSE segment and the polycaprolactone segment.
Summary of the invention
The objective of the invention is to overcome the weak point of prior art; A kind of drug-carrying nanometer particle based on VISOSE/polycaprolactone amphiphilic block polymer is provided; This drug-carrying nanometer particle is made the wetting ability shell with VISOSE; Possess hydrophilic property is good, biological degradability and good biocompatibility, be easy to advantages such as chemically modified, has potential using value in medicine controlled releasing, especially targeted drug controlled release field.
Another object of the present invention is to provide the preparation method of above-mentioned drug-carrying nanometer particle based on VISOSE/polycaprolactone amphiphilic block polymer.
The object of the invention is realized through following technical proposals:
A kind of VISOSE/polycaprolactone block polymer, it is by amine end groups (NH
2) (CHO) polycaprolactone generates through linked reaction, and wherein the number-average molecular weight scope of VISOSE segment is 3000～10000, polycaprolactone segmental number-average molecular weight scope is 3000～10000, two segments with-NH-CH for VISOSE and aldehyde end group
2-key links to each other.
Above-mentioned VISOSE/polycaprolactone block polymer, described amine end groups VISOSE are that VISOSE and reacting ethylenediamine make; Described aldehyde end group polycaprolactone is with the end capped polycaprolactone of terephthalaldehydic acid.
A kind of method for preparing above-mentioned glucose/polycaprolactone block polymer, it comprises the steps:
The preparation of step 1. amine end groups VISOSE:
Under 55～65 ℃, be that 3000～10000 VISOSE and quadrol are dissolved in the methyl-sulphoxide with the number-average molecular weight scope, be dissolved with 0.02～0.03g VISOSE in every milliliter of methyl-sulphoxide, said quadrol amount of substance is 10～15 times of VISOSE amount of substance; Add catalyst n aCNBH
3Back stirring reaction 6～8 days adds 0.4～0.5mg NaCNBH in every milliliter of methyl-sulphoxide
3, and add the NaCNBH of equal in quality every day
3After reaction finishes; With gained mixed solution cool to room temperature, under agitation add 5～6 times then and in the methyl alcohol of methyl-sulphoxide volume, form deposition, filter and precipitate with methanol wash; Drying under reduced pressure obtains product amine end groups VISOSE then, the part not amine end groupsization VISOSE also coprecipitation get off.
The preparation of step 2. aldehyde end group polycaprolactone:
Step 2.1. at first gets phenylcarbinol, Sn (Oct)
2, 6-caprolactone reaction 22～24 hours in argon gas atmosphere, under 120～130 ℃ of air-proof conditions, the ratio of the amount of substance of said Ben Jia Chun ︰ 6-caprolactone is 1 ︰ 25～90, said Sn (Oct)
2Amount of substance be 6-caprolactone amount of substance 0.01%～0.02%; After reaction finishes; Obtain polymers soln with the THF dissolving; Go out product terminal hydroxy group polycaprolactone with ether sedimentation; Subsequent use behind filtration, drying under reduced pressure, the volume ratio of said THF and ether consumption is 1 ︰ 10～12, and prepared terminal hydroxy group polycaprolactone number-average molecular weight scope is 3000～10000;
Step 2.2. is then with the prepared terminal hydroxy group polycaprolactone of step 2.1 and terephthalaldehydic acid, N; N-NSC 57182 (DCC), 4-Dimethylamino pyridine (DMAP) are dissolved in the THF together; At room temperature sealed reaction is 2～4 days; Wherein be dissolved with 0.01～0.02mmol terminal hydroxy group polycaprolactone in every milliliter of THF; The amount of substance of said terephthalaldehydic acid is 2～4 times of terminal hydroxy group polycaprolactone, and the amount of substance of DCC equates that with terephthalaldehydic acid the amount of said DMAP is to dissolve 1～1.5mg in every milliliter of THF; After reaction finishes, filter, filtrating is under agitation joined 10～12 times in the ether of its volume, form deposition, filter and with the methanol wash deposition, drying under reduced pressure obtains product aldehyde end group polycaprolactone then;
The preparation of step 3. VISOSE/polycaprolactone block polymer:
Under 55～65 ℃, the amine end groups VISOSE that step 1 is made, aldehyde end group polycaprolactone and the catalyst n aCNBH that step 2 makes
3Be dissolved in the methyl-sulphoxide together; The insulated and stirred reaction is 4～6 days then; Wherein be dissolved with 0.01～0.02g amine end groups VISOSE in every milliliter of methyl-sulphoxide, the amount of substance of said aldehyde end group polycaprolactone is 1.5～2.5 times of amount of substance of amine end groups VISOSE, said NaCNBH
3Amount be that every milliliter of methyl-sulphoxide adds 0.4～0.5mg, add the NaCNBH of equal in quality every day between the reaction period
3After reaction finishes; With gained mixed solution cool to room temperature, under agitation 3～4 times of THFs to its volume slowly are added dropwise in the mixed solution then, sufficient standing is after spinning gets supernatant liquid; After boiling off 95% above THF; Under agitation 3～4 times of water to its volume slowly are added dropwise in the mixed solution, sufficient standing under agitation adds 3～4 times of methyl alcohol to its volume and forms deposition after spinning gets the upper strata stillness of night; Filtration obtains deposition, and drying under reduced pressure obtains VISOSE/polycaprolactone block polymer then.
The entire reaction equation of above-mentioned preparation VISOSE/polycaprolactone block polymer is following:
VISOSE of the present invention/polycaprolactone block polymer can be used as the solid support material that is insoluble in the water medicine and is used to prepare VISOSE/polycaprolactone block polymer drug-carrying nanometer particle.
The preparation of VISOSE/polycaprolactone block polymer drug-carrying nanometer particle:
Under 55～60 ℃; VISOSE/polycaprolactone block polymer, the medicine that is insoluble in water are dissolved in the methyl-sulphoxide; Be dissolved with 25～35mg VISOSE/polycaprolactone block polymer in said every milliliter of methyl-sulphoxide, the described medicine that is insoluble in water accounts for 10～40wt% of VISOSE/polycaprolactone block polymer; Under agitation dripping the volume that adds water to methyl-sulphoxide then accounts for about 15%; Gained solution packed in the dialysis tubing and be placed on saturated be insoluble in the water pharmaceutical aqueous solution dialysis and remove methyl-sulphoxide; Again through removing by filter not by the drug molecule of embedding; Just obtain the stable drug-carrying nanometer particle aqueous solution, with getting the solid drug-carrying nanometer particle after this drug-carrying nanometer particle aqueous solution lyophilize.
Above-mentioned VISOSE/polycaprolactone block polymer drug-carrying nanometer particle, described drug-carrying nanometer particle are spherical, and average particle size range is 100～300nm, and polydispersity coefficient is about 0.2; Drug loading can reach 20%.
Above-mentioned VISOSE/polycaprolactone block polymer drug-carrying nanometer particle, the described medicine that is insoluble in water can be a taxol.
The present invention has following advantage and beneficial effect with respect to prior art:
(1) method for preparing VISOSE/polycaprolactone block polymer provided by the invention has reaction conditions gentleness, easy and simple to handle, easy to implement, characteristics that productive rate is higher.
(2) drug-carrying nanometer particle of VISOSE provided by the invention/polycaprolactone amphiphilic block polymer can be used as a kind of new polymers micelle administration system of antitumor drug taxol; This drug delivery system not only has higher drug loading; Also good, biological degradability and good biocompatibility of possess hydrophilic property, be easy to the VISOSE shell of chemically modified, this drug delivery system has using value in medicine controlled releasing, especially targeted drug controlled release field.
Description of drawings
Fig. 1 is VISOSE of the present invention/polycaprolactone amphiphilic block polymer
1The HNMR collection of illustrative plates.
Fig. 2 has provided the uv-visible absorption spectra of taxol, the uv-visible absorption spectra of drug-carrying nanometer particle and the A-C typical curve of taxol.
Fig. 3 is the size distribution figure that measures the drug-carrying nanometer particle aqueous solution of the present invention that obtains with dynamic light scattering.
Fig. 4 is the transmission electron microscope photo of the drug-carrying nanometer particle aqueous solution of the present invention.
Embodiment
Below in conjunction with embodiment and accompanying drawing the present invention is described in further detail, but the working of an invention mode is not limited thereto.
Embodiment 1
One, the preparation of VISOSE/polycaprolactone block polymer
(1) preparation of amine end groups VISOSE: under 60 ℃, with 1.5g VISOSE (M
n=6000, Sigma company) and the 0.15g quadrol be dissolved in the 50ml methyl-sulphoxide, add 20mg NaCNBH
3Back stirring reaction 7 days, and add 20mg NaCNBH every day
3After reaction finishes; With gained mixed solution cool to room temperature; Under agitation be added drop-wise to then and form deposition in the 300ml methyl alcohol; Filter and remove residual quadrol with methyl alcohol repetitive scrubbing deposition, drying under reduced pressure obtains product amine end groups VISOSE then, partly not the VISOSE of amine end groupsization also coprecipitation get off.Productive rate:>90%.
(2) preparation of aldehyde end group polycaprolactone: took by weighing phenylcarbinol, Sn (Oct) than 1: 0.0026: 26 by amount of substance
2, ε-CL in a polymerizing pipe, vacuumize repeatedly/applying argon gas 3 times after, under vacuum state, carry out the hot melt tube sealing, then polymerizing pipe is placed 130 ℃ oil bath reaction 22 hours.After reaction finishes, obtain polymers soln, and be settled out product terminal hydroxy group polycaprolactone with ether (volume is 12 times of volume of THF) with the THF dissolving, subsequent use behind filtration, drying under reduced pressure.Productive rate: 91%.
1HNMR（in?CDCl
3，300MHz）δppm：1.40，1.64，2.33，4.05（CH
2）；7.34（aromatic?H）；5.11（Ar CH
2 O）；3.65（CH
2OH）。Warp
1It is 3300 that HNMR analyzes the number-average molecular weight that obtains PCL-OH.
0.5mmol terminal hydroxy group polycaprolactone, 1.5mmol terephthalaldehydic acid, 1.5mmol DCC and 30mg DMAP are dissolved in the 30ml THF, at room temperature sealed stirring reaction then 2 days.After reaction finishes; With NSC 30023 (DCU) the deposition elimination that generates; Gained filtrating under agitation is added drop-wise to and forms deposition in the 360ml ether; Filtration obtains deposition, and removes residual terephthalaldehydic acid small molecules with methyl alcohol repetitive scrubbing deposition, and drying under reduced pressure obtains product aldehyde end group polycaprolactone then.Productive rate: 90%.
1HNMR（in?CDCl
3，300MHz）δppm：1.40，1.64，2.33，4.05（CH
2）；7.34，7.96，8.20（aromatic?H）；5.11（Ar-CH
2-O）；4.36（ CH
2OCOAr CHO）；10.1（ CHO）。
(3) preparation of VISOSE/polycaprolactone block polymer: under 60 ℃, the amine end groups VISOSE that 1g step (1) is made, aldehyde end group polycaprolactone and the 20mg NaCNBH that 1g step (2) makes
3Be dissolved in the 50ml methyl-sulphoxide, and stirring reaction 5 days, add 20mg NaCNBH every day between the reaction period
3After reaction finishes; The gained mixed solution is cooled off; Under agitation slowly be added drop-wise to the 200ml THF in the mixed solution then; Behind the sufficient standing, the VISOSE of generation/polycaprolactone block polymer and not the aldehyde end group polycaprolactone of complete reaction be retained in light yellow, the translucent tetrahydrofuran solution, the amine end groups VISOSE of complete reaction does not then precipitate; Spinning gets supernatant liquid; After boiling off 95% above THF, under agitation 200ml water slowly is added drop-wise in the mixed solution, behind the sufficient standing; VISOSE/polycaprolactone the block polymer that generates is retained in the milky solution, and the aldehyde end group polycaprolactone of complete reaction does not then precipitate; Spinning gets supernatant liquid, under agitation 1000ml methyl alcohol is added to form deposition in the milky solution, promptly gets product VISOSE/polycaprolactone block polymer, productive rate: 68% through filtration, drying under reduced pressure then.Fig. 1 is VISOSE/polycaprolactone block polymer
1HNMR (in d
6-DMSO, 300MHz) collection of illustrative plates.
Two, the preparation of drug-carrying nanometer particle
Under 55 ℃; VISOSE/polycaprolactone block polymer, the 28mg taxol of the above-mentioned preparation of 70mg are dissolved in the 2ml methyl-sulphoxide; Under agitation dropwise add 10ml water in the 15min then, naturally cool to room temperature after dropwising, pack into gained solution in the dialysis tubing again and be placed on that dialysis 24h removes methyl-sulphoxide in the saturated taxol aqueous solution of 1000ml; Water filtering head through 0.45um removes by filter not by the taxol of embedding again, just obtains the stable drug-carrying nanometer particle aqueous solution.With getting the solid drug-carrying nanometer particle after the lyophilize of the drug-carrying nanometer particle aqueous solution.
To the drug-carrying nanometer particle aqueous solution, it is 176.8nm that light scattering method records its median size, and polydispersity coefficient is 0.211.
To the solid drug-carrying nanometer particle, the measuring method of drug loading is following: at first prepare the taxol dimethyl sulfoxide solution of a series of concentration C, measure its absorbance A at the 264nm place (making reference with methyl-sulphoxide), draw out the A-C typical curve; Accurately take by weighing the solid drug-carrying nanometer particle then and it is dissolved in the methyl-sulphoxide; Measure its absorbancy (dimethyl sulfoxide solution with the VISOSE/polycaprolactone block polymer of equal in quality concentration is made reference), obtain drug loading with the A-C calibration curve method at the 264nm place.Fig. 2 has provided the uv-visible absorption spectra of taxol, the uv-visible absorption spectra of drug-carrying nanometer particle and the A-C typical curve of taxol, and the drug loading that records thus is 10.9%.
Embodiment 2
One, the preparation of VISOSE/polycaprolactone block polymer
(1) preparation of amine end groups VISOSE: the preparation of amine end groups VISOSE is with embodiment 1 in the present embodiment.
(2) preparation of aldehyde end group polycaprolactone: took by weighing phenylcarbinol, Sn (Oct) than 1: 0.0052: 52 by amount of substance
2, ε-CL in a polymerizing pipe, vacuumize repeatedly/applying argon gas 3 times after, under vacuum state, carry out the hot melt tube sealing, then polymerizing pipe is placed 130 ℃ oil bath reaction 24 hours.After reaction finishes, obtain polymers soln, and be settled out product terminal hydroxy group polycaprolactone with ether (volume is 10 times of volume of THF) with the THF dissolving, subsequent use behind filtration, drying under reduced pressure.Productive rate: 91%.
1HNMR（in?CDCl
3，300MHz）δppm：1.40，1.64，2.33，4.05（CH
2）；7.34（aromatic?H）；5.11（Ar CH
2 O）；3.65（CH
2OH）。Warp
1It is 6316 that HNMR analyzes the number-average molecular weight that obtains PCL-OH.
0.5mmol terminal hydroxy group polycaprolactone, 1.5mmol terephthalaldehydic acid, 1.5mmol DCC and 40mg DMAP are dissolved in the 40ml THF, at room temperature sealed stirring reaction then 3 days.After reaction finishes; With NSC 30023 (DCU) the deposition elimination that generates; Gained filtrating under agitation is added drop-wise to and forms deposition in the 400ml ether; Filtration obtains deposition, and removes residual terephthalaldehydic acid small molecules with methyl alcohol repetitive scrubbing deposition, and drying under reduced pressure obtains product aldehyde end group polycaprolactone then.Productive rate: 92%.
1HNMR（in?CDCl
3，300MHz）δppm：1.40，1.64，2.33，4.05（CH
2）；7.34，7.96，8.20（aromatic?H）；5.11（Ar-CH
2-O）；4.36（ CH
2OCOAr CHO）；10.1（ CHO）。
(3) preparation of VISOSE/polycaprolactone block polymer: under 60 ℃, the amine end groups VISOSE that 1g step (1) is made, aldehyde end group polycaprolactone and the 30mg NaCNBH that 2g step (2) makes
3Be dissolved in the 75ml methyl-sulphoxide, and stirring reaction 6 days, add 30mg NaCNBH every day between the reaction period
3After reaction finishes,, under agitation slowly be added drop-wise to the 300ml THF in the mixed solution then with the cooling of gained mixed solution; Spinning gets supernatant liquid behind the sufficient standing; After boiling off 95% above THF, under agitation 300ml water slowly is added drop-wise in the mixed solution, spinning gets supernatant liquid behind the sufficient standing; Under agitation add 1200ml methyl alcohol and form deposition, promptly get product VISOSE/polycaprolactone block polymer through filtration, drying under reduced pressure then.Productive rate: 60%.
Two, the preparation of drug-carrying nanometer particle
Under 55 ℃; VISOSE/polycaprolactone block polymer, the 20mg taxol of the above-mentioned preparation of 50mg are dissolved in the 2ml methyl-sulphoxide; Under agitation dropwise add 10ml water in the 15min then, naturally cool to room temperature after dropwising, pack into gained solution in the dialysis tubing again and be placed on that dialysis 24h removes methyl-sulphoxide in the saturated taxol aqueous solution of 1000ml; Water filtering head through 0.45um removes by filter not by the taxol of embedding again, just obtains the stable drug-carrying nanometer particle aqueous solution.With getting the solid drug-carrying nanometer particle after the lyophilize of the drug-carrying nanometer particle aqueous solution.
To the drug-carrying nanometer particle aqueous solution, it is 254.5nm that light scattering method records its median size, and polydispersity coefficient is 0.147, and the result is as shown in Figure 3; Transmission electron microscope records it and is shaped as sphere, and the result is as shown in Figure 4.
To the solid drug-carrying nanometer particle, the drug loading that the A-C calibration curve method records is 17.4%.
Embodiment 3
One, the preparation of VISOSE/polycaprolactone block polymer
The preparation of VISOSE in the present embodiment/polycaprolactone block polymer is with embodiment 2.
Two, the preparation of drug-carrying nanometer particle
Under 55 ℃; VISOSE/polycaprolactone block polymer, the 12.5mg taxol of the above-mentioned preparation of 50mg are dissolved in the 2ml methyl-sulphoxide; Under agitation dropwise add 10ml water in the 15min then, naturally cool to room temperature after dropwising, pack into gained solution in the dialysis tubing again and be placed on that dialysis 24h removes methyl-sulphoxide in the saturated taxol aqueous solution of 1000ml; Water filtering head through 0.45um removes by filter not by the taxol of embedding again, just obtains the stable drug-carrying nanometer particle aqueous solution.With getting the solid drug-carrying nanometer particle after the lyophilize of the drug-carrying nanometer particle aqueous solution.
To the drug-carrying nanometer particle aqueous solution, it is 246.1 nm that light scattering method records its median size, and polydispersity coefficient is 0.254.
To the solid drug-carrying nanometer particle, the drug loading that the A-C calibration curve method records is 12.4%.
Embodiment 4
One, the preparation of VISOSE/polycaprolactone block polymer
The preparation of VISOSE in the present embodiment/polycaprolactone block polymer is with embodiment 2.
Two, the preparation of drug-carrying nanometer particle
Under 55 ℃; VISOSE/polycaprolactone block polymer, the 7.5mg taxol of the above-mentioned preparation of 50mg are dissolved in the 2ml methyl-sulphoxide; Under agitation dropwise add 10ml water in the 15min then, naturally cool to room temperature after dropwising, pack into gained solution in the dialysis tubing again and be placed on that dialysis 24h removes methyl-sulphoxide in the saturated taxol aqueous solution of 1000ml; Water filtering head through 0.45um removes by filter not by the taxol of embedding again, just obtains the stable drug-carrying nanometer particle aqueous solution.With getting the solid drug-carrying nanometer particle after the lyophilize of the drug-carrying nanometer particle aqueous solution.
To the drug-carrying nanometer particle aqueous solution, it is 243.1nm that light scattering method records its median size, and polydispersity coefficient is 0.262.
To the solid drug-carrying nanometer particle, the drug loading that the A-C calibration curve method records is 8.7%.
Embodiment 5
One, the preparation of VISOSE/polycaprolactone block polymer
(1) preparation of amine end groups VISOSE: the preparation of amine end groups VISOSE is with embodiment 1 in the present embodiment.
(2) preparation of aldehyde end group polycaprolactone: took by weighing phenylcarbinol, Sn (Oct) than 1: 0.009: 90 by amount of substance
2, ε-CL in a polymerizing pipe, vacuumize repeatedly/applying argon gas 3 times after, under vacuum state, carry out the hot melt tube sealing, then polymerizing pipe is placed 130 ℃ oil bath reaction 24 hours.After reaction finishes, obtain polymers soln, and be settled out product terminal hydroxy group polycaprolactone with ether (volume is 10 times of volume of THF) with the THF dissolving, subsequent use behind filtration, drying under reduced pressure.Productive rate: 92%.
1HNMR（in?CDCl
3，300MHz）δppm：1.40，1.64，2.33，4.05（CH
2）；7.34（aromatic?H）；5.11（Ar CH
2 O）；3.65（CH
2OH）。Warp
1It is 9850 that HNMR analyzes the number-average molecular weight that obtains PCL-OH.
0.5mmol terminal hydroxy group polycaprolactone, 2mmol terephthalaldehydic acid, 2mmol DCC and 50mg DMAP are dissolved in the 50ml THF, at room temperature sealed stirring reaction then 4 days.After reaction finishes; With NSC 30023 (DCU) the deposition elimination that generates; Gained filtrating under agitation is added drop-wise to and forms deposition in the 500ml ether; Filtration obtains deposition, and removes residual terephthalaldehydic acid small molecules with methyl alcohol repetitive scrubbing deposition, and drying under reduced pressure obtains product aldehyde end group polycaprolactone then.Productive rate: 93%.
1HNMR（in?CDCl
3，300MHz）δppm：1.40，1.64，2.33，4.05（CH
2）；7.34，7.96，8.20（aromatic?H）；5.11（Ar-CH
2-O）；4.36（ CH
2OCOAr CHO）；10.1（ CHO）。
(3) preparation of VISOSE/polycaprolactone block polymer: under 60 ℃, the amine end groups VISOSE that 1g step (1) is made, aldehyde end group polycaprolactone and the 50mg NaCNBH that 3.3g step (2) makes
3Be dissolved in the 100ml methyl-sulphoxide, and stirring reaction 6 days, add 50mg NaCNBH every day between the reaction period
3After reaction finishes,, under agitation slowly be added drop-wise to the 400ml THF in the mixed solution then with the cooling of gained mixed solution; Spinning gets supernatant liquid behind the sufficient standing; After boiling off 95% above THF, under agitation 400ml water slowly is added drop-wise in the mixed solution, spinning gets supernatant liquid behind the sufficient standing; Under agitation add 1500ml methyl alcohol and form deposition, promptly get product VISOSE/polycaprolactone block polymer through filtration, drying under reduced pressure then.Productive rate: 50%.
Two, the preparation of drug-carrying nanometer particle
Under 60 ℃; VISOSE/polycaprolactone block polymer, the 20mg taxol of the above-mentioned preparation of 50mg are dissolved in the 2ml methyl-sulphoxide; Under agitation dropwise add 10ml water in the 15min then, naturally cool to room temperature after dropwising, pack into gained solution in the dialysis tubing again and be placed on that dialysis 24h removes methyl-sulphoxide in the saturated taxol aqueous solution of 1000ml; Water filtering head through 0.45um removes by filter not by the taxol of embedding again, just obtains the stable drug-carrying nanometer particle aqueous solution.With getting the solid drug-carrying nanometer particle after the lyophilize of the drug-carrying nanometer particle aqueous solution.
To the drug-carrying nanometer particle aqueous solution, it is 289.4 nm that light scattering method records its median size, and polydispersity coefficient is 0.252.
To the solid drug-carrying nanometer particle, the drug loading that the A-C calibration curve method records is 19.9%.
Embodiment 6
One, the preparation of VISOSE/polycaprolactone block polymer
(1) preparation of amine end groups VISOSE: under 55 ℃, with 1.5g VISOSE (M
n=3000) and the 0.3g quadrol be dissolved in the 50ml methyl-sulphoxide, add 20mg NaCNBH
3Back stirring reaction 6 days, and add 20mg NaCNBH every day
3After reaction finishes; With gained mixed solution cool to room temperature; Under agitation be added drop-wise to then and form deposition in the 300ml methyl alcohol; Filter and remove residual quadrol with methyl alcohol repetitive scrubbing deposition, drying under reduced pressure obtains product amine end groups VISOSE then, partly not the VISOSE of amine end groupsization also coprecipitation get off.Productive rate:>90%.
(2) preparation of aldehyde end group polycaprolactone: the preparation of aldehyde end group polycaprolactone is with embodiment 1 in the present embodiment.
(3) preparation of VISOSE/polycaprolactone block polymer: under 55 ℃, the amine end groups VISOSE that 1g step (1) is made, aldehyde end group polycaprolactone and the 20mg NaCNBH that 0.75g step (2) makes
3Be dissolved in the 50ml methyl-sulphoxide, and stirring reaction 4 days, add 20mg NaCNBH every day between the reaction period
3After reaction finishes,, under agitation slowly be added drop-wise to the 150ml THF in the mixed solution then with the cooling of gained mixed solution; Spinning gets supernatant liquid behind the sufficient standing; After boiling off 95% above THF, under agitation 150ml water slowly is added drop-wise in the mixed solution, spinning gets supernatant liquid behind the sufficient standing; Under agitation add 1000ml methyl alcohol and form deposition, promptly get product VISOSE/polycaprolactone block polymer through filtration, drying under reduced pressure then.Productive rate: 76%.
Two, the preparation of drug-carrying nanometer particle
Under 55 ℃; VISOSE/polycaprolactone block polymer, the 7mg taxol of the above-mentioned preparation of 70mg are dissolved in the 2ml methyl-sulphoxide; Under agitation dropwise add 10ml water in the 15min then, naturally cool to room temperature after dropwising, pack into gained solution in the dialysis tubing again and be placed on that dialysis 24h removes methyl-sulphoxide in the saturated taxol aqueous solution of 1000ml; Filtering head through 0.45um removes by filter not by the taxol of embedding again, just obtains the stable drug-carrying nanometer particle aqueous solution.With getting the solid drug-carrying nanometer particle after the lyophilize of the drug-carrying nanometer particle aqueous solution.
To the drug-carrying nanometer particle aqueous solution, it is 143.4nm that light scattering method records its median size, and polydispersity coefficient is 0.193.
To the solid drug-carrying nanometer particle, the drug loading that the A-C calibration curve method records is 3.6%.
Embodiment 7
One, the preparation of VISOSE/polycaprolactone block polymer
(1) preparation of amine end groups VISOSE: under 65 ℃, with 1.5g VISOSE (M
n=10000) and the 0.135g quadrol be dissolved in the 75ml methyl-sulphoxide, add 35mg NaCNBH
3Back stirring reaction 8 days, and add 35mg NaCNBH every day
3After reaction finishes; With gained mixed solution cool to room temperature; Under agitation be added drop-wise to then and form deposition in the 400ml methyl alcohol; Filter and remove residual quadrol with methyl alcohol repetitive scrubbing deposition, drying under reduced pressure obtains product amine end groups VISOSE then, partly not the VISOSE of amine end groupsization also coprecipitation get off.Productive rate:>90%.
(2) preparation of aldehyde end group polycaprolactone: the preparation of aldehyde end group polycaprolactone is with embodiment 5 in the present embodiment.
(3) preparation of VISOSE/polycaprolactone block polymer: under 65 ℃, the amine end groups VISOSE that 1g step (1) is made, aldehyde end group polycaprolactone and the 50mg NaCNBH that 2.5g step (2) makes
3Be dissolved in the 100ml methyl-sulphoxide, and stirring reaction 6 days, add 50mg NaCNBH every day between the reaction period
3After reaction finishes,, under agitation slowly be added drop-wise to the 400ml THF in the mixed solution then with the cooling of gained mixed solution; Spinning gets supernatant liquid behind the sufficient standing; After boiling off 95% above THF, under agitation 400ml water slowly is added drop-wise in the mixed solution, spinning gets supernatant liquid behind the sufficient standing; Under agitation add 1500ml methyl alcohol and form deposition, promptly get product VISOSE/polycaprolactone block polymer through filtration, drying under reduced pressure then.Productive rate: 39%.
Two, the preparation of drug-carrying nanometer particle
Under 60 ℃; VISOSE/polycaprolactone block polymer, the 12.5mg taxol of the above-mentioned preparation of 50mg are dissolved in the 2ml methyl-sulphoxide; Under agitation dropwise add 10ml water in the 15min then, naturally cool to room temperature after dropwising, pack into gained solution in the dialysis tubing again and be placed on that dialysis 24h removes methyl-sulphoxide in the saturated taxol aqueous solution of 1000ml; Filtering head through 0.45um removes by filter not by the taxol of embedding again, just obtains the stable drug-carrying nanometer particle aqueous solution.With getting the solid drug-carrying nanometer particle after the lyophilize of the drug-carrying nanometer particle aqueous solution.
To the drug-carrying nanometer particle aqueous solution, it is 297.6nm that light scattering method records its median size, and polydispersity coefficient is 0.264.
To the solid drug-carrying nanometer particle, the drug loading that the A-C calibration curve method records is 14%.
The foregoing description is a preferred implementation of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (7)
1. VISOSE/polycaprolactone block polymer; It is characterized in that: it is to be generated through linked reaction by amine end groups VISOSE and aldehyde end group polycaprolactone; Wherein the number-average molecular weight scope of VISOSE segment is 3000～10000, polycaprolactone segmental number-average molecular weight scope is 3000～10000, two segments with-NH-CH
2-key links to each other.
2. glucose according to claim 1/polycaprolactone block polymer is characterized in that: described amine end groups VISOSE is that VISOSE and reacting ethylenediamine make; Described aldehyde end group polycaprolactone is with the end capped polycaprolactone of terephthalaldehydic acid.
3. a method for preparing the described glucose of claim 1/polycaprolactone block polymer is characterized in that it comprises the steps:
The preparation of step 1. amine end groups VISOSE:
Under 55～65 ℃, be that 3000～10000 VISOSE and quadrol are dissolved in the methyl-sulphoxide with number-average molecular weight, be dissolved with 0.02～0.03g VISOSE in every milliliter of methyl-sulphoxide, said quadrol amount of substance is 10～15 times of VISOSE amount of substance; Add catalyst n aCNBH
3Back stirring reaction 6～8 days adds 0.4～0.5mg NaCNBH in every milliliter of methyl-sulphoxide
3, and add the NaCNBH of equal in quality every day
3After reaction finishes; With gained mixed solution cool to room temperature, under agitation add 5～6 times then and in the methyl alcohol of methyl-sulphoxide volume, form deposition, filter and precipitate with methanol wash; Drying under reduced pressure obtains product amine end groups VISOSE then, the part not amine end groupsization VISOSE also coprecipitation get off;
The preparation of step 2. aldehyde end group polycaprolactone:
Step 2.1. at first gets phenylcarbinol, Sn (Oct)
2, 6-caprolactone reaction 22～24 hours in argon gas atmosphere, under 120～130 ℃ of air-proof conditions, the ratio of the amount of substance of said Ben Jia Chun ︰ 6-caprolactone is 1 ︰ 25～90, said Sn (Oct)
2Amount of substance be 6-caprolactone amount of substance 0.01%～0.02%; After reaction finishes; Obtain polymers soln with the THF dissolving; Go out product terminal hydroxy group polycaprolactone with ether sedimentation; Subsequent use behind filtration, drying under reduced pressure, the volume ratio of said THF and ether consumption is 1 ︰ 10～12, and prepared terminal hydroxy group polycaprolactone number-average molecular weight scope is 3000～10000;
Step 2.2. is then with the prepared terminal hydroxy group polycaprolactone of step 2.1 and terephthalaldehydic acid, N; N-NSC 57182,4-Dimethylamino pyridine are dissolved in the THF together; At room temperature sealed reaction is 2～4 days; Wherein be dissolved with 0.01～0.02mmol terminal hydroxy group polycaprolactone in every milliliter of THF, the amount of substance of said terephthalaldehydic acid is 2～4 times of terminal hydroxy group polycaprolactone, N; The amount of substance of N-NSC 57182 equates that with terephthalaldehydic acid the amount of said 4-Dimethylamino pyridine is to dissolve 1～1.5mg in every milliliter of THF; After reaction finishes, filter, filtrating is under agitation joined 10～12 times in the ether of its volume, form deposition, filter and with the methanol wash deposition, drying under reduced pressure obtains product aldehyde end group polycaprolactone then;
The preparation of step 3. VISOSE/polycaprolactone block polymer:
Under 55～65 ℃, the amine end groups VISOSE that step 1 is made, aldehyde end group polycaprolactone and the catalyst n aCNBH that step 2 makes
3Be dissolved in the methyl-sulphoxide together; The insulated and stirred reaction is 4～6 days then; Wherein be dissolved with 0.01～0.02g amine end groups VISOSE in every milliliter of methyl-sulphoxide, the amount of substance of said aldehyde end group polycaprolactone is 1.5～2.5 times of amount of substance of amine end groups VISOSE, said NaCNBH
3Amount be that every milliliter of methyl-sulphoxide adds 0.4～0.5mg, add the NaCNBH of equal in quality every day between the reaction period
3After reaction finishes; With gained mixed solution cool to room temperature, under agitation 3～4 times of THFs to its volume slowly are added dropwise in the mixed solution then, sufficient standing is after spinning gets supernatant liquid; After boiling off 95% above THF; Under agitation 3～4 times of water to its volume slowly are added dropwise in the mixed solution, sufficient standing under agitation adds 3～4 times of methyl alcohol to its volume and forms deposition after spinning gets supernatant liquid; Filtration obtains deposition, and drying under reduced pressure obtains VISOSE/polycaprolactone block polymer then.
4. the application of the described glucose of claim 1/polycaprolactone block polymer in preparation VISOSE/polycaprolactone block polymer drug-carrying nanometer particle.
5. method for making for preparing the VISOSE described in the claim 4/polycaprolactone block polymer drug-carrying nanometer particle is characterized in that:
Under 55～60 ℃; VISOSE/polycaprolactone block polymer, the medicine that is insoluble in water are dissolved in the methyl-sulphoxide; Be dissolved with 25～35mg VISOSE/polycaprolactone block polymer in said every milliliter of methyl-sulphoxide, the described medicine that is insoluble in water accounts for 10～40wt% of VISOSE/polycaprolactone block polymer; Under agitation drip the volume that adds water to methyl-sulphoxide then and account for 15%; Gained solution packed in the dialysis tubing and be placed on saturated be insoluble in the water pharmaceutical aqueous solution dialysis and remove methyl-sulphoxide; Again through removing by filter not by the drug molecule of embedding; Just obtain the stable drug-carrying nanometer particle aqueous solution, with getting the solid drug-carrying nanometer particle after this drug-carrying nanometer particle aqueous solution lyophilize.
6. the VISOSE that method according to claim 5 makes/polycaprolactone block polymer drug-carrying nanometer particle is characterized in that: described drug-carrying nanometer particle is for spherical, and average particle size range is 100～300nm, and polydispersity coefficient is 0.2; Drug loading can reach 20%.
7. glucose according to claim 6/polycaprolactone block polymer drug-carrying nanometer particle is characterized in that: the described medicine that is insoluble in water is a taxol.
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| CN1262697A (en) * | 1997-07-09 | 2000-08-09 | 阿温提斯研究技术两合公司 | Thermoplastic mixture containing 1,4-alpha-D-polyglucane, method for making same and use thereof |
| CN101250235A (en) * | 2008-02-03 | 2008-08-27 | 中山大学 | A fully biodegradable amphiphilic polysaccharide graft and its preparation method and application |
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