CN112142932A - 一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法 - Google Patents
一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法 Download PDFInfo
- Publication number
- CN112142932A CN112142932A CN202010984457.6A CN202010984457A CN112142932A CN 112142932 A CN112142932 A CN 112142932A CN 202010984457 A CN202010984457 A CN 202010984457A CN 112142932 A CN112142932 A CN 112142932A
- Authority
- CN
- China
- Prior art keywords
- chitosan
- hydrogel
- allyl
- cross
- drugs
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229920001661 Chitosan Polymers 0.000 title claims abstract description 113
- 239000000017 hydrogel Substances 0.000 title claims abstract description 56
- 239000003814 drug Substances 0.000 title claims abstract description 43
- 229940079593 drug Drugs 0.000 title claims abstract description 42
- 230000006399 behavior Effects 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 230000004044 response Effects 0.000 title claims abstract description 14
- 230000001105 regulatory effect Effects 0.000 title claims abstract description 12
- 230000001276 controlling effect Effects 0.000 title claims abstract description 10
- 239000000243 solution Substances 0.000 claims abstract description 24
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 16
- 239000011259 mixed solution Substances 0.000 claims abstract description 14
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 claims abstract description 9
- 239000012736 aqueous medium Substances 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 12
- 239000008367 deionised water Substances 0.000 claims description 12
- 229910021641 deionized water Inorganic materials 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000004593 Epoxy Substances 0.000 claims description 9
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000502 dialysis Methods 0.000 claims description 8
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- 238000000227 grinding Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 239000006143 cell culture medium Substances 0.000 claims description 2
- 229940093181 glucose injection Drugs 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
- 239000012890 simulated body fluid Substances 0.000 claims description 2
- 239000008354 sodium chloride injection Substances 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 239000008366 buffered solution Substances 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 230000008961 swelling Effects 0.000 abstract description 10
- 238000004132 cross linking Methods 0.000 abstract description 6
- 230000004043 responsiveness Effects 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000004048 modification Effects 0.000 abstract description 4
- 238000012986 modification Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229920002521 macromolecule Polymers 0.000 abstract description 3
- 229920001222 biopolymer Polymers 0.000 abstract description 2
- 230000009977 dual effect Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 12
- 125000003277 amino group Chemical group 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000004205 dimethyl polysiloxane Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 4
- -1 polydimethylsiloxane Polymers 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 125000003700 epoxy group Chemical group 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000001678 irradiating effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- KLGDRWGOXDJNPH-UHFFFAOYSA-N P(=O)(O)(O)O.C1(=CC=CC=C1)C=1C(=C(C(=O)[Li])C(=CC1C)C)C Chemical compound P(=O)(O)(O)O.C1(=CC=CC=C1)C=1C(=C(C(=O)[Li])C(=CC1C)C)C KLGDRWGOXDJNPH-UHFFFAOYSA-N 0.000 description 1
- 150000004753 Schiff bases Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- NKLPQNGYXWVELD-UHFFFAOYSA-M coomassie brilliant blue Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=C1 NKLPQNGYXWVELD-UHFFFAOYSA-M 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000001259 photo etching Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F299/00—Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/46—Polymerisation initiated by wave energy or particle radiation
- C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2355/00—Characterised by the use of homopolymers or copolymers, obtained by polymerisation reactions only involving carbon-to-carbon unsaturated bonds, not provided for in groups C08J2323/00 - C08J2353/00
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Dispersion Chemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法。本发明属于生物高分子材料合成与改性领域。本发明的目的是为了解决现有UV交联壳聚糖衍生物缺乏pH响应性、UV辐照强度高和辐照时间长和无法调控大分子/小分子药物使其具有相反释放行为的技术问题。本发明的制备方法:一、将O‑烯丙基壳聚糖溶于水性介质,得到O‑烯丙基壳聚糖的水性溶液;二、向步骤一的溶液中加入四臂巯基PEG和光引发剂LAP,得到混合溶液,将混合溶液置于UV辐照下15s内固化成水凝胶,即得到pH响应UV交联壳聚糖水凝胶。本发明的方法在15s内快速UV交联成水凝胶,所得水凝胶的pH响应性溶胀行为实现了加速小分子药物释放速度和降低大分子药物的释放速度双重功能。
Description
技术领域
本发明属于生物高分子材料合成与改性领域,具体涉及一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法。
背景技术
近年来,随着生物药业的广泛发展,药物缓释的载体被研究的越来越受到关注,因为药物载体能够缓慢释放药物,从而提高药物利用率并减少药物的副作用。其中水凝胶载体是一种优秀的选择对象,目前基于水凝胶的药物释放得到了广泛的发展,因为水凝胶是一种独特的柔软的、亲水的、聚合物的三维网络,可以在保持原有结构的同时保持和保留大量的水,使得水凝胶更具有应用型。在制备水凝胶的过程中,通过调节凝胶的结构,可以实现对药物释放速度的控制。例如可以在水凝胶中加入磁性粒子,实现磁控制的药物释放。引入温敏性单元,可以实现温度控制的药物缓释。而pH作为人体可调节的因素,也作为一种改变因素去调控药物的释放速度。
作为自然界中唯一的碱性多糖,壳聚糖基水凝胶在药物释放上显示了非同寻常的优势,壳聚糖分子内的氨基提供了生物活性,粘附性和抗菌性,并且壳聚糖能够被体内的酶降解,生成可以被人体吸收的寡糖。在目前的基于壳聚糖水凝胶的药物缓释体系中,希夫碱结构的水凝胶研究最多,其结构简单,反应可控,合成方便,且能够被酸性的环境调节药物释放速度。然而,其不能实现对碱性条件下的药物释放的调控。其主要原因为改性后的壳聚糖由于失去大量的氨基,导致了壳聚糖失去了自身的pH响应性。因此,在对壳聚糖改性时,必须保留氨基,使反应基团仅与羟基反应成为了研究的关键所在。
环氧基团是一种高活性的反应基团,能够和氨基与羟基在一定条件发生反应,在壳聚糖分子中,氨基的反应活性大于羟基,因此,要实现保留氨基基团,必须对氨基进行保护,待反应基团与羟基反应后再脱掉保护基团,从而实现氨基的保留。尽管在目前的研究中,环氧基团已经被作为反应基团来引入其他功能性基团到壳聚糖分子中,然而这些壳聚糖衍生物的合成方法及壳聚糖水凝胶性能仍存在以下问题:(1)现有UV交联壳聚糖衍生物因氨基修饰导致其缺乏pH响应性;(2)UV交联壳聚糖水凝胶需要UV辐照强度高(大于10mW/cm2)且辐照时间长(多于1分钟),不利于后续的生物学研究。
发明内容
本发明的目的是为了解决现有UV交联壳聚糖衍生物缺乏pH响应性、UV辐照强度高和辐照时间长和无法调控大分子/小分子药物使其具有相反释放行为的技术问题,而提供一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法。
本发明的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法按以下步骤进行:
一、将O-烯丙基壳聚糖溶于水性介质,得到O-烯丙基壳聚糖的水性溶液;
二、向步骤一得到的O-烯丙基壳聚糖的水性溶液中加入四臂巯基PEG和光引发剂LAP[苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐)],得到混合溶液,将混合溶液置于UV辐照下15s内固化成水凝胶,即得到pH响应UV交联壳聚糖水凝胶。
进一步限定,步骤一中所述水性介质为去离子水、生理盐水、模拟体液、氯化钠注射液、葡萄糖注射液、磷酸缓冲溶液或细胞培养基。
进一步限定,步骤一中所述O-烯丙基壳聚糖的水性溶液中O-烯丙基壳聚糖的浓度为15mg/mL~25mg/mL。
进一步限定,步骤一中所述O-烯丙基壳聚糖的水性溶液中O-烯丙基壳聚糖的浓度为20mg/mL。
进一步限定,步骤一中所述O-烯丙基壳聚糖的制备过程为:步骤1、将壳聚糖溶解于乙酸溶液中,室温配制成壳聚糖的乙酸溶液,然后加入苯甲醛,于60℃下反应12h,反应结束后加入2mol/L的氢氧化钠溶液,醇沉后烘干研磨,得到苯甲醛保护的壳聚糖;步骤2、将苯甲醛保护的壳聚糖溶解于NaOH溶液中,然后缓慢加入环氧烯丙醚,于20~120℃搅拌条件下水浴反应12h,反应后倒入2mol/L的盐酸中,继续反应4h,然后置于透析袋中,于去离子水的环境中透析3~5天,每隔6h~12h更换去离子水,透析完成后,冷冻干燥,得到白色海绵状O-烯丙基壳聚糖,其结构式为
进一步限定,所述环氧烯丙醚与苯甲醛保护的壳聚糖的质量比为(1~20):1。
进一步限定,加入环氧烯丙醚后于80℃搅拌条件下水浴反应12h。
进一步限定,步骤二中所述四臂巯基PEG与步骤一中所述O-烯丙基壳聚糖中单个丙烯基的摩尔比为(0.05~0.2):1。
进一步限定,步骤二中所述四臂巯基PEG与步骤一中所述O-烯丙基壳聚糖中单个丙烯基的摩尔比为0.1:1。
进一步限定,步骤二中所述混合溶液中光引发剂LAP的浓度为0.05wt%。
进一步限定,步骤二中所述UV辐照波长为360nm~480nm,UV辐照度为10mW/cm2。
本发明与现有技术相比具有的优点:
1)本发明利用壳聚糖的氨基保护与脱保护反应,并结合氨基与环氧基团开环反应,合成了壳聚糖C6位特异性修饰O-烯丙基壳聚糖,实现具有pH响应且O-烯丙基壳聚糖可控合成。本发明通过化学选择性修饰合成O-烯丙基壳聚糖以保留壳聚糖的氨基,赋予水凝胶pH响应性。
2)本发明通过环氧基团与羟基的反应引入可UV交联的烯丙基基团,通过加入四臂巯基PEG赋予了快速UV交联效果,巯基能够在UV辐照下快速生成巯基自由基,进而引发烯丙基中双键在15s内快速与壳聚糖酰化衍生物(O-烯丙基壳聚糖)发生交联,其中O-烯丙基壳聚糖中的烯丙基接枝率可达52%。此外,烯丙基的引入破坏了壳聚糖分子内的氢键,使其能够溶于pH为中性的水性介质。
3)本发明可通过UV光刻或UV交联技术制备任意形状与尺寸的水凝胶(微米~厘米尺寸范围),在组织工程支架、药物释放和创面修复等领域有很大的应用前景。
4)本发明所得pH响应UV交联壳聚糖水凝胶的pH响应性溶胀行为实现了加速小分子药物释放速度和降低大分子药物的释放速度双重功能。酸性条件下溶胀增大了凝胶的空间网络,使得大分子药物更容易通过;碱性条件下的收缩能够挤压空间网络,挤压的驱动力会加速小分子的释放,而小的网络结构则阻碍了大分子的进去通道,从而减少了释放量。
附图说明
图1为具体实施方式一步骤一中壳聚糖与O-烯丙基壳聚糖的1H NMR谱图;
图2为具体实施方式一中四臂巯基PEG与O-烯丙基壳聚糖溶液UV交联后和未UV交联的照片;其中A-交联后,B-未交联;
图3为具体实施方式一的壳聚糖水凝胶在不同pH条件下的溶胀变化曲线图;
图4为具体实施方式二的壳聚糖水凝胶在不同pH条件下的溶胀变化曲线图;
图5为具体实施方式三的壳聚糖水凝胶在不同pH条件下的溶胀变化曲线图;
图6为具体实施方式四的水凝胶释放DOX的曲线图;
图7为具体实施方式五的水凝胶释放BSA的曲线图。
具体实施方式
具体实施方式一:本实施方式的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法按以下步骤进行:
一、将0.1g的O-烯丙基壳聚糖溶于5mL去离子水,得到浓度为20mg/mL的O-烯丙基壳聚糖的水溶液;
二、向步骤一得到的O-烯丙基壳聚糖的水性溶液中加入四臂巯基PEG和0.05wt%的光引发剂LAP,得到混合溶液,将混合溶液置于圆柱形的聚二甲基硅氧烷模具中,在UV辐照波长为360~480nm,UV辐照度为10mW/cm2的紫外光下辐照15s,得到直径为0.5cm的圆柱形水凝胶,即pH响应UV交联壳聚糖水凝胶;所述四臂巯基PEG与步骤一中所述O-烯丙基壳聚糖中单个丙烯基的摩尔比为0.1:1;
其中步骤一中所述O-烯丙基壳聚糖的制备过程为:步骤1、将5.0g的壳聚糖溶解于浓度为0.5%(v/v)的乙酸溶液中,室温配制成浓度为1%(w/v)的壳聚糖的乙酸溶液,然后加入20mL苯甲醛,于60℃下反应12h,反应结束后加入50mL浓度为2mol/L的氢氧化钠溶液,倒入1L乙醇中进行醇沉,烘干研磨,得到苯甲醛保护的壳聚糖;步骤2、将1.0g苯甲醛保护的壳聚糖溶解于浓度为0.5%(v/v)的NaOH溶液中,然后缓慢加入5.0g环氧烯丙醚,于80℃搅拌条件下水浴反应12h,反应后倒入2mol/L的盐酸中,继续反应4h,然后置于透析袋中,于去离子水的环境中透析3天,每隔10h更换去离子水,透析完成后,冷冻干燥,得到白色海绵状O-烯丙基壳聚糖,其结构式为
具体实施方式二:本实施方式与具体实施方式一不同的是:步骤二中所述四臂巯基PEG与步骤一中所述O-烯丙基壳聚糖中单个丙烯基的摩尔比为0.2:1。其他步骤及参数与具体实施方式一相同。
具体实施方式三:本实施方式与具体实施方式一不同的是:步骤二中所述四臂巯基PEG与步骤一中所述O-烯丙基壳聚糖中单个丙烯基的摩尔比为0.05:1。其他步骤及参数与具体实施方式一相同。
检测试验(一):采用核磁共振氢谱(1H-NMR)对具体实施方式一步骤一中壳聚糖和O-烯丙基壳聚糖进行表征,得到如图1所示的壳聚糖和O-烯丙基壳聚糖的1H-NMR谱图(上面的曲线为CS,下面的曲线位OAL-CS)。从图1可以看出,在化学位移为5.54ppm与5.80ppm处有两条谱线,这是乙烯基质子(=CH2)对应的化学位移。这说明化学改性后壳聚糖分子链上引入了带有双键的烯丙基基团。通过未改性壳聚糖的1H NMR图谱,计算乙酰基中甲基的含量,通过O-烯丙基壳聚糖的1H NMR图谱,得到烯丙基在化学位移5.80ppm的积分面积,与乙酰基中甲基的积分面积相比,从而得到烯丙基的接枝率为52%。
检测试验(二):将具体实施方式一至三得到的pH响应UV交联壳聚糖水凝胶置于不同pH的PBS溶液中,37℃下放置一定的时间后用滤纸吸走凝胶表面的水,称其溶胀后的重量,计算其溶胀比(溶胀后重量与原始重量的比值)。其对应的溶胀曲线图如图3~5所示,从图3~5可以看出,在所有的时间段之内,水凝胶均显示为收缩或者溶胀的状态。
具体实施方式四:本实施方式的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法按以下步骤进行:
一、将0.1g的O-烯丙基壳聚糖溶于5mL去离子水,得到浓度为20mg/mL的O-烯丙基壳聚糖的水溶液;
二、向步骤一得到的O-烯丙基壳聚糖的水性溶液中加入四臂巯基PEG和0.05wt%的光引发剂LAP,得到混合溶液,向混合溶液中加入小分子药物DOX,然后置于圆柱形的聚二甲基硅氧烷模具中,在UV辐照波长为360~480nm,UV辐照度为10mW/cm2的紫外光下辐照15s,得到包含药物(DOX:10wt%)的直径为0.5cm的圆柱形水凝胶;所述四臂巯基PEG与步骤一中所述O-烯丙基壳聚糖中单个丙烯基的摩尔比为0.1:1;
其中步骤一中所述O-烯丙基壳聚糖的制备过程为:步骤1、将5.0g的壳聚糖溶解于浓度为0.5%(v/v)的乙酸溶液中,室温配制成浓度为1%(w/v)的壳聚糖的乙酸溶液,然后加入20mL苯甲醛,于60℃下反应12h,反应结束后加入50mL浓度为2mol/L的氢氧化钠溶液,倒入1L乙醇中进行醇沉,烘干研磨,得到苯甲醛保护的壳聚糖;步骤2、将1.0g苯甲醛保护的壳聚糖溶解于浓度为0.5%(v/v)的NaOH溶液中,然后缓慢加入5.0g环氧烯丙醚,于80℃搅拌条件下水浴反应12h,反应后倒入2mol/L的盐酸中,继续反应4h,然后置于透析袋中,于去离子水的环境中透析3天,每隔10h更换去离子水,透析完成后,冷冻干燥,得到白色海绵状O-烯丙基壳聚糖,其结构式为
将具体实施方式四得到的包含药物的水凝胶置于5mL(pH为5.0,6.8和8.0)的PBS溶液中,37℃下释放一定的时间后,取出0.5mL测其在490nm的吸光度,再补充0.5mL新鲜的PBS溶液继续释放,测定释放过程中各时间段取出溶液中DOX的量,绘制得到如图6所示的DOX释放曲线图,从图6可以看出,水凝胶的pH响应性溶胀行为加速了小分子药物释放速度。
具体实施方式五:本实施方式与具体实施方式四不同的是:步骤二中向混合溶液中加入大分子药物BSA,加入量为水凝胶质量的10%。其他步骤及参数与具体实施方式四相同。
将具体实施方式五得到的包含药物的水凝胶置于5mL(pH为5.0,6.8和8.0)的PBS溶液中,37℃下释放一定的时间后,取出0.5mL加入考马斯亮蓝测其在590nm的吸光度,再补充0.5mL新鲜的PBS溶液继续释放,测定释放过程中各时间段取出溶液中BSA的量,绘制得到如图7所示的BSA释放曲线图,从图7可以看出,水凝胶的pH响应性溶胀行为降低了大分子药物的释放速度。
Claims (10)
1.一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,该制备方法按以下步骤进行:
一、将O-烯丙基壳聚糖溶于水性介质,得到O-烯丙基壳聚糖的水性溶液;
二、向步骤一得到的O-烯丙基壳聚糖的水性溶液中加入四臂巯基PEG和光引发剂LAP,得到混合溶液,将混合溶液置于UV辐照下15s内固化成水凝胶,即得到pH响应UV交联壳聚糖水凝胶。
2.根据权利要求1所述的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,步骤一中所述水性介质为去离子水、生理盐水、模拟体液、氯化钠注射液、葡萄糖注射液、磷酸缓冲溶液或细胞培养基。
3.根据权利要求1所述的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,步骤一中所述O-烯丙基壳聚糖的水性溶液中O-烯丙基壳聚糖的浓度为15mg/mL~25mg/mL。
4.根据权利要求1所述的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,步骤一中所述O-烯丙基壳聚糖的水性溶液中O-烯丙基壳聚糖的浓度为20mg/mL。
5.根据权利要求1所述的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,步骤一中所述O-烯丙基壳聚糖的制备过程为:步骤1、将壳聚糖溶解于乙酸溶液中,室温配制成壳聚糖的乙酸溶液,然后加入苯甲醛,于60℃下反应12h,反应结束后加入2mol/L的氢氧化钠溶液,醇沉后烘干研磨,得到苯甲醛保护的壳聚糖;步骤2、将苯甲醛保护的壳聚糖溶解于NaOH溶液中,然后缓慢加入环氧烯丙醚,于20~120℃搅拌条件下水浴反应12h,反应后倒入2mol/L的盐酸中,继续反应4h,然后置于透析袋中,于去离子水的环境中透析3~5天,每隔6h~12h更换去离子水,透析完成后,冷冻干燥,得到白色海绵状O-烯丙基壳聚糖,其结构式为
6.根据权利要求5所述的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,所述环氧烯丙醚与苯甲醛保护的壳聚糖的质量比为(1~20):1。
7.根据权利要求5所述的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,加入环氧烯丙醚后于80℃搅拌条件下水浴反应12h。
8.根据权利要求1所述的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,步骤二中所述四臂巯基PEG与步骤一中所述O-烯丙基壳聚糖中单个丙烯基的摩尔比为(0.05~0.2):1。
9.根据权利要求1所述的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,步骤二中所述混合溶液中光引发剂LAP的浓度为0.05wt%。
10.根据权利要求1所述的一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法,其特征在于,步骤二中所述UV辐照波长为360nm~480nm,UV辐照度为10mW/cm2。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010984457.6A CN112142932B (zh) | 2020-09-18 | 2020-09-18 | 一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010984457.6A CN112142932B (zh) | 2020-09-18 | 2020-09-18 | 一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112142932A true CN112142932A (zh) | 2020-12-29 |
CN112142932B CN112142932B (zh) | 2022-05-24 |
Family
ID=73893151
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010984457.6A Expired - Fee Related CN112142932B (zh) | 2020-09-18 | 2020-09-18 | 一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112142932B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106750398A (zh) * | 2016-11-25 | 2017-05-31 | 暨南大学 | 载药壳聚糖/海藻酸钠双重交联水凝胶及其制法和应用 |
CN108314790A (zh) * | 2018-03-16 | 2018-07-24 | 东华大学 | 一种用于组织粘合剂的光交联巯基壳聚糖-聚乙二醇甲基丙烯酸酯水凝胶及其制备方法 |
CN111533927A (zh) * | 2020-06-04 | 2020-08-14 | 哈尔滨工业大学 | 一种pH和温度双响应UV交联壳聚糖可注射水凝胶的制备方法 |
-
2020
- 2020-09-18 CN CN202010984457.6A patent/CN112142932B/zh not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106750398A (zh) * | 2016-11-25 | 2017-05-31 | 暨南大学 | 载药壳聚糖/海藻酸钠双重交联水凝胶及其制法和应用 |
CN108314790A (zh) * | 2018-03-16 | 2018-07-24 | 东华大学 | 一种用于组织粘合剂的光交联巯基壳聚糖-聚乙二醇甲基丙烯酸酯水凝胶及其制备方法 |
CN111533927A (zh) * | 2020-06-04 | 2020-08-14 | 哈尔滨工业大学 | 一种pH和温度双响应UV交联壳聚糖可注射水凝胶的制备方法 |
Non-Patent Citations (3)
Title |
---|
DING HAICHANG等: ""Decoupled pH- and Thermo-Responsive Injectable Chitosan/PNIPAM Hydrogel via Thiol-Ene Click Chemistry for Potential Applications in Tissue Engineering"", 《ADVANCED HEALTHCARE MATERIALS》 * |
TAN HAINA等: ""Study of glycol chitosan-carboxymethyl beta-cyclodextrins as anticancer drugs carrier"", 《CARBOHYDRATE POLYMERS》 * |
ZHU LIDA等: ""pH sensitive methacrylated chitosan hydrogels with tunable physical and chemical properties"", 《BIOCHEMICAL ENGINEERING JOURNAL》 * |
Also Published As
Publication number | Publication date |
---|---|
CN112142932B (zh) | 2022-05-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10294335B2 (en) | Preparation method, product and application of non-free radical photo-crosslinked hydrogel material | |
CN107550921B (zh) | 一种纳米颗粒-高分子可注射复合水凝胶双载药体系及其制备方法 | |
Draget et al. | Alginate based new materials | |
CN110885455B (zh) | 一种活性氧响应水凝胶的制备及应用 | |
JP2634813B2 (ja) | 高分子のための担体としての生物分解性微小球 | |
US20130142763A1 (en) | Crosslinked cellulosic polymers | |
CN111072997B (zh) | 一种基于改性透明质酸的高强自愈合水凝胶及其制备方法 | |
Işıklan et al. | Synthesis and characterization of pH-and temperature-sensitive materials based on alginate and poly (N-isopropylacrylamide/acrylic acid) for drug delivery | |
CN108484797B (zh) | 烷氧醚树枝化壳聚糖、其水凝胶材料及其制备方法 | |
CN109251451B (zh) | 一种pH敏感型黄原胶/聚乙烯醇水凝胶的制备方法 | |
CN111592618A (zh) | 一种透明质酸水凝胶及其制备方法和应用 | |
CN111363168A (zh) | 具有抗凝作用的混合凝胶、其制备方法及应用 | |
CN113197843A (zh) | 一种多巴胺涂覆的纤维素纳米晶-琼脂糖载药水凝胶及其制备方法 | |
CN112915064A (zh) | 一种药物缓释载体水凝胶的制备方法及其应用 | |
Chatterjee et al. | A detailed discussion on interpenetrating polymer network (IPN) based drug delivery system for the advancement of health care system | |
CN112142932B (zh) | 一种具有调控药物相反释放行为的pH响应UV交联壳聚糖水凝胶的制备方法 | |
CN111378152B (zh) | 一种水凝胶材料催化氧化与功能化修饰的方法 | |
CN112442193B (zh) | 一种兼具韧性与粘附性的自修复仿生水凝胶的制备方法 | |
CN103333272A (zh) | 一种可快速uv固化且能溶于水的壳聚糖衍生物及其合成方法 | |
CN108421042B (zh) | 一种光控降解水凝胶的制备方法 | |
US20240245604A1 (en) | Polymeric compound of glucuronic acid with phenolic groups, gel-forming composition comprising such a compound and method for producing the same | |
CN113736131B (zh) | 一种海藻酸钠离子凝胶及其制备方法 | |
CN115887772A (zh) | 一种明胶/海藻酸钠水凝胶基3d打印生物墨水及其应用 | |
CN111533927B (zh) | 一种pH和温度双响应UV交联壳聚糖可注射水凝胶的制备方法 | |
CN115073770A (zh) | 一种基于两性离子改性多糖的物理凝胶及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220524 |