CN107693803A - 一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法 - Google Patents
一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法 Download PDFInfo
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- CN107693803A CN107693803A CN201711067707.4A CN201711067707A CN107693803A CN 107693803 A CN107693803 A CN 107693803A CN 201711067707 A CN201711067707 A CN 201711067707A CN 107693803 A CN107693803 A CN 107693803A
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- Prior art keywords
- sodium alginate
- pei
- manganese oxide
- hydridization
- solution
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- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 title claims abstract description 105
- 239000000661 sodium alginate Substances 0.000 title claims abstract description 39
- 235000010413 sodium alginate Nutrition 0.000 title claims abstract description 39
- 229940005550 sodium alginate Drugs 0.000 title claims abstract description 39
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000011068 loading method Methods 0.000 title claims abstract description 6
- 239000011572 manganese Substances 0.000 claims abstract description 61
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- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 50
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- 238000003756 stirring Methods 0.000 claims description 16
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 15
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- VNNDVNZCGCCIPA-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;manganese Chemical compound [Mn].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O VNNDVNZCGCCIPA-FDGPNNRMSA-N 0.000 claims description 3
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- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
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- IKULXUCKGDPJMZ-UHFFFAOYSA-N sodium manganese(2+) oxygen(2-) Chemical compound [O-2].[Mn+2].[Na+] IKULXUCKGDPJMZ-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
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- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 3
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- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 2
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- 239000011734 sodium Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- AEMOLEFTQBMNLQ-SYJWYVCOSA-N (2s,3s,4s,5s,6r)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-SYJWYVCOSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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- 101100028791 Caenorhabditis elegans pbs-5 gene Proteins 0.000 description 1
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
- A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1803—Semi-solid preparations, e.g. ointments, gels, hydrogels
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
- C08J2329/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal, or ketal radical; Hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Derivatives of such polymer
- C08J2329/02—Homopolymers or copolymers of unsaturated alcohols
- C08J2329/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
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- 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
- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
- C08J2405/04—Alginic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/18—Oxygen-containing compounds, e.g. metal carbonyls
- C08K3/20—Oxides; Hydroxides
- C08K3/22—Oxides; Hydroxides of metals
- C08K2003/2262—Oxides; Hydroxides of metals of manganese
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
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- C08K2201/011—Nanostructured additives
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
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Abstract
本发明涉及一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,包括:将海藻酸钠经EDC/NHS活化、双乳化处理后得到W/O/W聚合物乳液,然后将聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI‑Mn3O4的溶液作为交联剂加入到乳液中,通过化学交联得到负载氧化锰的杂化海藻酸钠纳米凝胶。本发明的方法简单,易于操作分离,成本低廉,原料来源广泛、价廉、生物可降解,具有良好的发展前景;制备得到的负载氧化锰的杂化海藻酸钠纳米凝胶粒径较小,分布均匀,具有良好的水溶性、胶体稳定性、细胞相容性,对生物体无不良影响,r1弛豫率高,造影效果强,在磁共振成像造影剂领域具有潜在的应用价值。
Description
技术领域
本发明属于磁共振成像造影剂领域,特别涉及一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法。
背景技术
磁共振成像(MRI)技术是七十年代发展起来的一种先进医学成像诊断技术,已广泛用于人体多种疾病的检测和早期诊断。MRI具有较高的分辨率,较高的空间和断层成像能力,无放射引起的电离损害,同时可获得解剖及生理信息,具有其他医学成像无可比拟的优点。MRI在疾病监测领域发挥越来越重要的作用。但MRI的弱点是其敏感性较低,而且不同器官或肿瘤组织的弛豫时间相互重叠使MRI诊断困难。近年来,通过注射MRI造影剂的方法可以有效解决MRI敏感性较低的问题,显著提高成像的对比度和清晰度。因此选择合适的MRI造影剂就显得尤为重要。常用的MRI造影剂的可分为T1阳性和T2阴性造影剂。由于在人体血液中、钙离子富集区、金属离子沉积以及人体组织损伤部位在T2成像过程中会出现信号减弱现象而得到负造影图像干扰临床诊断,限制了以氧化铁纳米颗粒为代表的T2阴性造影剂的应用。临床上常用的T1阳性造影剂为钆基小分子造影剂。然而这类小分子造影剂往往存在着较短的血液循环时间,对肾功能不全患者的明显肾脏毒性等缺陷。为了解决这些问题,许多研究者开始将目光转向一些其他的无机纳米颗粒(如氧化锰纳米颗粒等)并研究其作为T1阳性造影剂的潜能。本课题组前期专利成果(史向阳,罗宇,于智博。一种聚乙烯亚胺介导的多功能四氧化三锰纳米颗粒核磁共振造影剂的制备方法。中国发明专利,授权公告号:CN104274842B)显示溶剂热法制备得到PEI修饰的Mn3O4纳米颗粒(PEI-Mn3O4)尺寸较小,颗粒分布均匀,且其表面存在大量的氨基活性基团,可作为T1阳性MRI造影剂。但是PEI-Mn3O4的r1弛豫率较低,仅为0.56-0.59mM-1s-1,明显低于临床钆基小分子造影剂r1弛豫率。
纳米凝胶是由亲水性或两亲性的高分子链通过物理或者化学交联的方式组成的三维网状结构的水凝胶颗粒,它是一种纳米尺度的软体材料。纳米凝胶具有许多优良的特性,如良好的胶体稳定性、生物相容性、高负载能力、易于多功能化、易进入肿瘤组织等,促进了其在诸多领域尤其是在分子影像学的应用。同时有文献报道(J.Mater.Res.2014,29(15),1626-1634;Biomater.Sci.2016,4(10),1422-1430),以纳米凝胶作为载体负载MRI造影元素,可显著提高r1或r2弛豫率。AG是一种天然多糖类物质,具有良好的生物相容性和生物可降解性,同时价廉易得,广泛用于合成纳米凝胶。它是从褐藻类的海带或马尾藻中提取碘和甘露醇之后的副产物,是由β-D-甘露糖醛酸和α-L-古洛糖醛酸以1,4-糖苷键连接而成的线性聚合物,每个糖醛酸单元上含有一个羧基。海藻酸钠的分子式为(C6H7O6Na)n,相对分子量为2000-200000。海藻酸钠具有无毒,良好的水溶性、生物相容性和生物降解性等优点,已广泛用于生物医学领域。
检索国内外文献尚没有发现关于用溶剂热法合成的PEI-Mn3O4为交联剂制备海藻酸钠纳米凝胶作为MRI造影剂研究的相关报道。
发明内容
本发明所要解决的技术问题是提供一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,该方法简单,易于操作分离,成本低廉,原料来源广泛、价廉、生物可降解,具有良好的发展前景。
本发明的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,包括:
(1)将海藻酸钠溶解于溶剂中形成溶液,然后用1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDC和N-羟基琥珀酰亚胺NHS活化,加入到磺基琥珀酸二辛酯钠AOT溶液中,搅拌,再加入到聚乙烯醇PVA溶液中,继续搅拌,得到W/O/W聚合物乳液,其中海藻酸钠、EDC和NHS的摩尔比为1:1:1-1:3:3,海藻酸钠溶液的浓度为1wt%-3wt%,海藻酸钠溶液、AOT溶液和PVA溶液的体积比为1:1:10-1:2:15;
(2)将聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4的溶液作为交联剂加入到步骤(1)中W/O/W聚合物乳液中,搅拌过夜,继续反应,分离洗涤,即得负载氧化锰的杂化海藻酸钠纳米凝胶,其中,步骤(1)中海藻酸钠与PEI-Mn3O4的质量比为1:1-1:3。
所述步骤(1)中溶剂为水;磺基琥珀酸二辛酯钠AOT溶液的溶剂为二氯甲烷;聚乙烯醇PVA溶液的溶剂为水。
所述步骤(1)中磺基琥珀酸二辛酯钠AOT溶液的浓度为2.5wt%;聚乙烯醇PVA溶液的浓度为2wt%。
所述步骤(1)中活化时间为2-3h;搅拌、继续搅拌的时间均为20-30min。
所述步骤(1)中搅拌、继续搅拌和步骤(2)中搅拌转速均为1000rpm。
所述步骤(2)中聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4的制备方法为:将聚乙烯亚胺PEI分散在二甘醇DEG中,得到聚乙烯亚胺溶液,然后将乙酰丙酮锰Mn(acac)2分散在聚乙烯亚胺溶液中,50-60℃搅拌0.5-1h,然后转移至高压反应釜中,搅拌至混匀,在150-180℃反应12-24h,冷却,离心,透析,冷却干燥,即得聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4,其中,乙酰丙酮锰Mn(acac)2、二甘醇DEG、聚乙烯亚胺PEI的比例为0.4227g:12mL:0.12g。
所述步骤(2)中聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4的溶液为水溶液;反应时间为24h。
所述步骤(2)中分离洗涤的具体步骤为:先使用截留分子量100000的透析袋对水溶液透析2-3天,然后15000rpm离心水洗3-5次。
所述步骤(2)中负载氧化锰的杂化海藻酸钠纳米凝胶颗粒分布均匀,具有较高的r1弛豫率,用作磁共振成像的造影剂,可用于肿瘤模型的磁共振成像造影诊断。
本发明的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,以海藻酸钠为载体,同时以溶剂热法合成的PEI-Mn3O4作为化学交联剂构建杂化纳米凝胶;先将海藻酸钠(Alginate,AG)经EDC/NHS活化和双乳化过程后,加入溶剂热法制备的PEI-Mn3O4作为交联剂,发生化学交联反应形成负载氧化锰的杂化海藻酸钠纳米凝胶。
本发明使用Zeta电势及动态光散射分析(DLS)、热重分析(TGA)、透射电子显微镜(TEM)、傅里叶变换红外光谱(FTIR)、电感耦合等离子体原子发射光谱法(ICP-AES)和磁共振(MR)成像分析等手段表征制备的负载氧化锰的杂化海藻酸钠纳米凝胶(AG/PEI-Mn3O4)。然后利用CCK-8法评价纳米凝胶的细胞毒性,并用相差显微镜获取与材料共培养后的细胞的形貌。最后进行体外细胞、裸鼠体内肿瘤模型的磁共振成像实验,考察AG/PEI-Mn3O4纳米凝胶的体外、体内MR成像效果。此外,通过组织分布实验研究AG/PEI-Mn3O4纳米凝胶在生物体内的代谢情况。
有益效果
(1)本发明的方法简单,易于操作分离,成本低廉,原料来源广泛、价廉、生物可降解,具有良好的发展前景;
(2)本发明制备得到的负载氧化锰的杂化海藻酸钠纳米凝胶粒径较小,分布均匀,具有良好的水溶性、胶体稳定性、细胞相容性,对生物体无不良影响,r1弛豫率高,造影效果强,在磁共振成像造影剂领域具有潜在的应用价值。
附图说明
图1为实施例1制备的AG/PEI-Mn3O4纳米凝胶的TEM图(a)和粒径分布柱状图(b);
图2为实施例1制备的AG/PEI-Mn3O4纳米凝胶、PEI-Mn3O4纳米颗粒及AG的FTIR图谱;
图3为实施例1制备的AG/PEI-Mn3O4纳米凝胶和PEI-Mn3O4纳米颗粒的TGA分析曲线;
图4为实施例2中AG/PEI-Mn3O4纳米凝胶在不同储存时间的水动力学直径变化图;
图5为实施例3中AG/PEI-Mn3O4纳米凝胶在锰浓度为0.016-0.26mM的MR T1加权成像图(a)及T1弛豫时间倒数与锰浓度的线性关系图(b);
图6为实施例4中U87MG细胞经实施例1制备的AG/PEI-Mn3O4纳米凝胶(纳米凝胶浓度为20、50、100、200和500μg/mL)和纯PBS处理24h后的CCK-8细胞活力分析结果图;
图7为实施例4中U87MG细胞经过PBS缓冲液(空白对照,a)和实施例1制备的AG/PEI-Mn3O4纳米凝胶(纳米凝胶浓度为b:20μg/mL、c:50μg/mL、d:100μg/mL、e:200μg/mL和f:500μg/mL)处理24小时后的细胞形态;
图8为实施例5中U87MG细胞经过PBS缓冲液、对照材料PEI.Ac-Mn3O4纳米颗粒和实施例1制备的AG/PEI-Mn3O4纳米凝胶(锰浓度为0.5μM和1μM)处理4小时后的细胞T1MR成像图片(a:PEI.Ac-Mn3O4纳米颗粒,b:AG/PEI-Mn3O4纳米凝胶)和相应的MR信号强度变化(c);
图9为实施例6中AG/PEI-Mn3O4纳米凝胶和对照材料PEI.Ac-Mn3O4纳米颗粒的PBS溶液(100μL,[Mn]=1mM)经尾静脉注射前和注射后不同时间点小鼠肿瘤的MR成像(a:AG/PEI-Mn3O4纳米凝胶,c:PEI.Ac-Mn3O4纳米颗粒)和相应的信噪比变化(b:AG/PEI-Mn3O4纳米凝胶,d:PEI.Ac-Mn3O4纳米颗粒);
图10为实施例7中尾静脉注射实施例1制备的AG/PEI-Mn3O4纳米凝胶PBS溶液(100μL,[Mn]=1mM)后不同时间点,Mn元素在小鼠主要器官(心、肝、脾、肺、肾)和肿瘤的组织分布图。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
(1)取5mL浓度为1wt%AG(50mg)水溶液,先用88.7mgEDC和53.25mg NHS活化3h,然后逐滴加入到10mL 2.5wt%AOT的二氯甲烷溶液中,搅拌30min,形成W/O乳液,然后将该W/O乳液逐滴加入到75mL2wt%PVA的水溶液中,搅拌30min,得到W/O/W聚合物乳液。
(2)将聚乙烯亚胺PEI(120mg)分散在二甘醇DEG(12mL)中,得到聚乙烯亚胺溶液,然后将乙酰丙酮锰Mn(acac)2(422.7mg)分散在聚乙烯亚胺溶液中,50℃下搅拌1h,然后转移至高压反应釜中,搅拌至混匀,在180℃反应24h,冷却,离心,透析,冷却干燥,即得聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4。
(3)将步骤(2)中聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4(100mg,5mg/mL)水溶液作为交联剂加入到步骤(1)中W/O/W聚合物乳液中,搅拌过夜,继续敞口反应24h,蒸发除去有机溶剂,然后使用截留分子量100000的透析袋对水溶液透析3天(2L/次,3次/天),最后15000rpm离心水洗3次,即得AG/PEI-Mn3O4纳米凝胶。
图1表明:AG/PEI-Fe3O4纳米凝胶的形貌呈球形或准球形,尺寸均匀,凝胶直径大小约为141.6nm,没有明显的团聚现象,在溶液中分散良好而且不发生聚集。
图2表明:在1414cm-1和1610cm-1处吸收峰减弱或消失,在1734cm-1处出现一个新的吸收峰,说明PEI-Mn3O4与AG成功地发生了化学交联反应,形成了新的化学键酰胺键。
图3表明:AG/PEI-Fe3O4纳米凝胶中AG的含量为13.01%。
实施例2
取实施例1制备的AG/PEI-Mn3O4纳米凝胶(1mg),将其用超纯水稀释至50μg/mL后,用于测表面电势和水动力直径。Zeta电势测定结果表明AG/PEI-Mn3O4纳米凝胶的表面电势为-17.8mV,交联剂PEI-Mn3O4的表面电势为+40.7mV,证明了AG和PEI-Mn3O4的成功交联。其水动力学直径为216.2nm,粒径分布均一,且水动力直径能长时间保持几乎不变(图4),从而说明AG/PEI-Mn3O4纳米凝胶具有良好的胶体稳定性。
实施例3
通过ICP-AES测试法测定实施例1制备的AG/PEI-Mn3O4纳米凝胶中Mn元素的含量。分别配制Mn浓度为0.016、0.0325、0.065、0.13、0.26mM的AG/PEI-Mn3O4纳米凝胶水溶液2mL,通过磁共振成像分析仪测定材料在不同Mn浓度下的T1弛豫效应(如图5)。弛豫率测试结果表明AG/PEI-Mn3O4纳米凝胶的弛豫时间倒数随着Mn浓度的增加(在0.016~0.26mM浓度范围内)具有良好的线性关系。通过计算得出AG/PEI-Mn3O4纳米凝胶的r1值为26.12mM-1s-1,是常规马根维显(Gd-DTPA)的5.7倍。因此,实施例1制备的AG/PEI-Mn3O4纳米凝胶可以作为MR分子影像诊断中的优良T1阳性造影剂。
实施例4
收集对数生长期U87MG细胞,按照10000细胞每孔的密度接种在96孔细胞培养板上,置于5%CO2,37℃条件下孵育24小时。弃掉培养基后,每孔更换180μL培养基,并添加20μL含不同浓度的AG/PEI-Mn3O4纳米凝胶(最终凝胶浓度为20、50、100、200、500μg/mL)或纯PBS(对照组)。将细胞培养板继续放置在5%CO2,37℃继续孵育24小时。随后弃掉原培养基,加入含10μL CCK-8的新鲜培养基溶液,继续培养2h后,放置在多功能酶标仪中于测试波长450nm下测试吸光值,结果如图6所示。与PBS对照组相比,AG/PEI-Mn3O4纳米凝胶在试验浓度范围内对U87MG细胞没有明显细胞毒性,细胞存活率均在85%以上,说明AG/PEI-Mn3O4纳米凝胶具有良好的生物相容性。同时,通过相差显微镜观察法进一步验证了AG/PEI-Mn3O4纳米凝胶对细胞形貌的影响。如图7所示,纯PBS和不同浓度AG/PEI-Mn3O4纳米凝胶(最终凝胶浓度为20、50、100、200、500μg/mL)在37℃下与细胞共培养24小时后,细胞形貌与PBS处理的细胞没有明显的变化,进一步说明了AG/PEI-Mn3O4纳米凝胶具有良好的细胞相容性。
实施例5
在体内实验之前,评价了实施例1制备的AG/PEI-Mn3O4纳米凝胶的细胞MR成像效果。取U87MG细胞与实施例1制备的AG/PEI-Mn3O4纳米凝胶和对照材料(乙酰化后的PEI-Mn3O4纳米颗粒PEI.Ac-Mn3O4)(Mn浓度为0.5μM和1μM)在5%CO2,37℃下共培养4小时,并且以PBS处理的细胞作为空白组,在培养结束后细胞用PBS清洗5次,再用胰酶消化、离心、过滤,最后分散在1mL PBS(含0.5%琼脂糖)中,用核磁共振成像仪测量各细胞样品的T1弛豫效应(如图8)。在图8a和8b中,在随着Mn浓度的增加,两组材料处理后的细胞都表现出MR信号增强的趋势。定量MR成像信号值分析(图8c)也验证了这一结果。但是在较高浓度下,与对照材料相比,AG/PEI-Mn3O4纳米凝胶体现出较高的MR成像信号值。这些结果说明实施例1制备的AG/PEI-Mn3O4纳米凝胶具有很好的细胞MR成像效果。
对照材料(乙酰化后的PEI-Mn3O4纳米颗粒PEI.Ac-Mn3O4)的制备方法为:取30mg实施例1中PEI-Mn3O4分散于10mL水中,然后向其中加入287.3μL三乙胺,混合搅拌30min后,再向反应液中滴入233.8μL乙酸酐,之后继续反应12h。反应结束后,以截留分子量8000-14000的透析袋用蒸馏水透析3天,然后冷冻干燥得到乙酰化后的PEI-Mn3O4纳米颗粒(PEI.Ac-Mn3O4)。
实施例6
在裸鼠体内构建U87MG皮下瘤模型,通过尾静脉注射实施例1制备的AG/PEI-Mn3O4纳米凝胶和对照材料(实施例5制备得到的PEI.Ac-Mn3O4)的PBS溶液(100μL,[Mn]=1mM)来评价肿瘤部位MR成像效果(参见附图9)。与注射前的空白组相比较,在注射后40min内,注射AG/PEI-Mn3O4纳米凝胶的小鼠肿瘤部位信号增强,然后逐渐开始恢复,120min时基本完全恢复,说明纳米凝胶可以随着血液流通从肿瘤部位逐渐代谢出去。同时MRI信号值定量分析结果显示,注射前肿瘤部位信噪比SNR为20.4,注射AG/PEI-Mn3O4纳米凝胶40min后肿瘤部位信噪比SNR为30.7,ΔSNR为10.3。注射对照材料PEI.Ac-Mn3O4的实验组,小鼠肿瘤部位信号增强不明显,注射后40min,肿瘤部位信噪比SNR从22.2增长到25.1,ΔSNR为2.9,明显小于注射AG/PEI-Mn3O4纳米凝胶组。肿瘤MR成像结果说明实施例1制备的AG/PEI-Fe3O4纳米凝胶可以作为造影剂应用于增强的体内肿瘤MR成像诊断。
实施例7
以实施例6构建的U87MG肿瘤模型裸鼠来研究实施例1制备的AG/PEI-Mn3O4纳米凝胶在生物体内各组织的分布代谢情况。向裸鼠尾静脉注射实施例1制备的AG/PEI-Mn3O4纳米凝胶的PBS溶液(100μL,[Mn]=1mM),分别在注射20、40、60、90、120min后,处死小鼠,取出各个主要器官和肿瘤部位并称重,然后切成小片段,并加入3mL王水浸泡2天,用ICP-AES测定各个组织样品中Mn的含量。如图10所示,在注射后,肺中Mn的含量较高然后随时间增加逐渐降低,肝脏和脾脏中Mn含量随时间增加逐渐升高。肿瘤部位Mn含量在注射40min后达到最高,然后逐渐降低,与体内肿瘤MR成像结果相对应。说明实施例1制备的AG/PEI-Mn3O4纳米凝胶能在小鼠体内正常的代谢清除。
Claims (9)
1.一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,包括:
(1)将海藻酸钠溶解于溶剂中形成溶液,然后用1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDC和N-羟基琥珀酰亚胺NHS活化,加入到磺基琥珀酸二辛酯钠AOT溶液中,搅拌,再加入到聚乙烯醇PVA溶液中,继续搅拌,得到W/O/W聚合物乳液,其中海藻酸钠、EDC和NHS的摩尔比为1:1:1-1:3:3,海藻酸钠溶液的浓度为1wt%-3wt%,海藻酸钠溶液、AOT溶液和PVA溶液的体积比为1:1:10-1:2:15;
(2)将聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4的溶液作为交联剂加入到步骤(1)中W/O/W聚合物乳液中,搅拌过夜,继续反应,分离洗涤,即得负载氧化锰的杂化海藻酸钠纳米凝胶,其中,步骤(1)中海藻酸钠与PEI-Mn3O4的质量比为1:1-1:3。
2.按照权利要求1所述的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,其特征在于,所述步骤(1)中溶剂为水;磺基琥珀酸二辛酯钠AOT溶液的溶剂为二氯甲烷;聚乙烯醇PVA溶液的溶剂为水。
3.按照权利要求1所述的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,其特征在于,所述步骤(1)中磺基琥珀酸二辛酯钠AOT溶液的浓度为2.5wt%;聚乙烯醇PVA溶液的浓度为2wt%。
4.按照权利要求1所述的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,其特征在于,所述步骤(1)中活化时间为2-3h;搅拌、继续搅拌的时间均为20-30min。
5.按照权利要求1所述的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,其特征在于,所述步骤(1)中搅拌、继续搅拌和步骤(2)中搅拌转速均为1000rpm。
6.按照权利要求1所述的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,其特征在于,所述步骤(2)中聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4的制备方法为:将聚乙烯亚胺PEI分散在二甘醇DEG中,得到聚乙烯亚胺溶液,然后将乙酰丙酮锰Mn(acac)2分散在聚乙烯亚胺溶液中,50-60℃搅拌0.5-1h,然后转移至高压反应釜中,搅拌至混匀,在150-180℃反应12-24h,冷却,离心,透析,冷却干燥,即得聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4,其中,乙酰丙酮锰Mn(acac)2、二甘醇DEG、聚乙烯亚胺PEI的比例为0.4227g:12mL:0.12g。
7.按照权利要求1所述的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,其特征在于,所述步骤(2)中聚乙烯亚胺PEI修饰的氧化锰纳米颗粒PEI-Mn3O4的溶液为水溶液;反应时间为24h。
8.按照权利要求1所述的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,其特征在于,所述步骤(2)中分离洗涤的具体步骤为:先使用截留分子量100000的透析袋对水溶液透析2-3天,然后15000rpm离心水洗3-5次。
9.按照权利要求1所述的一种负载氧化锰的杂化海藻酸钠纳米凝胶的制备方法,其特征在于,所述步骤(2)中负载氧化锰的杂化海藻酸钠纳米凝胶用作磁共振成像的造影剂。
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