Fe_3O_4纳米颗粒及其靶向药物研究
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摘要
磁性靶向药物能有效减小化疗药物的毒副作用，提高药效，减少用药量，在治疗恶性肿瘤方面表现出十分广阔的前景。目前作为药物载体的磁性纳米颗粒的制备工艺需要进一步简化，磁性靶向药物的载药量、靶向性能、药物控制释放等特性还需要深入研究。
本文以铁盐、NaOH和聚乙二醇4000(PEG)为原料，采用共沉淀法和超临界流体干燥技术(SCFD)制备了磁性Fe_3O_4纳米颗粒(MNP)，简化了制备方法和工艺，通过FTIR、XRD、SEM、BET和VSM等手段表征了Fe_3O_4纳米颗粒的组成、结构和特性。进行了一系列条件实验，研究了制备条件(物料加入顺序、铁盐浓度、Fe~(2+)／Fe~(3+)比例、NaOH过量比、PEG加入量和反应温度)对Fe_3O_4纳米颗粒的性能评价指标(比表面积、水悬液的悬浮稳定性和磁响应性)的作用方式和作用机理；进行了一组L~3(4)正交试验，对正交试验结果进行了灰色关联分析。结果表明，本文设计的制备方法和工艺可以得到性能良好的Fe_3O_4纳米颗粒，颗粒表面吸附了PEG高分子，有丰富的羟基，能作为药物载体；制备条件对Fe_3O_4纳米颗粒性能影响程度的大小排序为：NaOH过量比＞PEG加入量＞反应温度＞Fe~(2+)／Fe~(3+)比例；控制制备条件：铁盐浓度0.036～0.072mol／L，NaOH过量比0～0.5，PEG加入量50～100mg／ml，反应温度50～70℃，Fe~(2+)／Fe~(3+)比例1～2，制备的Fe_3O_4纳米颗粒比表面积达到83.21m~2／g，5分钟内水悬液不沉降，磁响应性达到9s／0.22T·cm。
本文以牛血清白蛋白(BSA)、MNP和氟尿嘧啶(5-Fu)为原料，采用乳化包覆法制备了磁性靶向药物，设计了药物含量和药物缓释性能的测试表征方法，通过FTIR、SEM、AAS、分光光度法等手段表征了磁性靶向药物的组成、结构、粒径、形貌、载药量和药物缓释性能；自制了体外靶向性能测试仪，并研究了磁性靶向药物的体外靶向性与MNP含量、流速和磁场强度的关系。结果表明，磁性靶向药物为核壳式结构，BSA对MNP的包覆完整，并且BSA与MNP形成了一定程度的化学结合；磁性靶向药物是球形颗粒，固化过程中形成二次颗粒是导致粒径分布变宽的重要原因；5-Fu加入量越大，磁性靶向药物的载药量越大，固化温度越高，BSA固化程度越大，药物缓释性能越好；磁性靶向药物的体外靶向性随MNP含量的增大而增强，随流速增大而减弱，随磁场强度增强而增强；控制制备条件：混悬液(5-Fu7～14％，Fe_3O_4磁性纳米颗粒18～30％，BSA56～75％)、乳液中水／油相比例1／30～3／30、固化温度90～130℃，得到的磁性靶向药物的粒径达到3.3μm，药物含量达到7.93％，药物释放50％的时间为79.3min，体外靶向性可达到100％。
Magnetic targeted drugs (MTD) could provide the opportunity to limit side effects created from nonspecific systemic exposure, by reducing the total amount of drug administered as well as limiting circulation of the drug throughout the body, while still achieving an efficacious concentration at the desired site in the body. Therefore, MTD have got great and wide attention in the field of cancer treatment. However, at present the process preparing magnetic nanosized particles (MNP) for antitumor drug carrier demands simplification, and drug content, drug control release and magnetic targeting activity to tumor of MTD demands thorough investigation and substantial promotion.
In this thesis magnetic Fe3O4 nano-particles (MNP) were synthesized from molysite, sodium hydrate and polyethylene glycol (PEG), by the method of co-precipitation and supercritical fluid drying technique (SCFD). The preparing technique and processes were simplified. The composition, structure and properties of MNP were investigated by the methods of FTIR, XRD, SEM, BET and VSM. A series of conditional experiments and a group of L3(4) orthogonal experiments were carried out. The ways and mechanisms of preparing conditions (the sequences of introduction of materials, molysite concentrations, the ratio of Fe2+/Fe3+, the ratio of overdosage of sodium hydrate, the quantity of introduction of PEG and reaction temperature) affecting evaluation indicaters of properties (the specific surface area, the suspending stabilization and magnetic respondence of aqueous suspensions of MNP) were studied. The results of the orthogonal experiments were analyzed with the gray relationship systemic method. The main conclusions wer
e as follows:
(1) MNP could be prepared with the simplified technique and processes, absorbed a little of PEG with abundant hydroxyl groups in the surface of MNP particles, and could be used as drug carrier.
(2) the order of the extent of the preparing conditions affecting properties of MNP was the ratio of overdosage of sodium hydrate > the quantity of introduction of PEG> reaction temperature> the ratio of ferrous salt to ferric salt.
(3) the specific surface area of MNP could reach 83.21m2/g, and the aqueous suspensions of MNP could be stable against precipitation in 5 minutes, and magnetic respondence could reach 9s/0.22T-cm, with the molysite concentrations in the range of 0.036-0.072 mol/L, the ratio of overdosage of sodium hydrate in the range of 0.0-0.5, the quantity of introduction of PEG in the range of 50-100 mg/ml, reaction
temperature in the range of 50-70 ℃.
Magnetic targeted drugs (MTD) were synthesized from bovine serum albumin (BSA), MNP and fluorouracil (5-Fu), by the technique of emulsion-cladding. The methods of test and characterization of drug content and drug control release of MTD were designed. The composition, structure, diameters and morphology of MTD particles was investigated by the methods of FTIR, SEM and AAS. The relationships between targeting activity in vitro and MNP content, velocity of flow and magnetic field intensity were studied with the designed tester of targeting activity in vitro. The main findings were as follows:
(1) the MTD particles were formed with a magnetic nucleus coated by a integrated BSA layer, so-called core/shell structure, and the coating was of integrity, a kind of chemical bonds were formed between the nucleus and the coatings.
(2) The analysis of morphology showed that the MTD particles was spheric, the formation of so-called secondary particle in the course of BSA curing played an important roll of the broaden of the diameter distributions.
(3) the drug content of MTD increased with the quantity of introduction of 5-Fu increasing, the extent of BSA curing and the effect of the drug control release was enhanced with the curing temperature elevated.
(4) the targeting activity in vitro was enhanced with the MNP content of MTD increasing, played down with the velocity of flow getting bigger, and promoted with the magnetic field intensity i
本文以铁盐、NaOH和聚乙二醇4000(PEG)为原料，采用共沉淀法和超临界流体干燥技术(SCFD)制备了磁性Fe_3O_4纳米颗粒(MNP)，简化了制备方法和工艺，通过FTIR、XRD、SEM、BET和VSM等手段表征了Fe_3O_4纳米颗粒的组成、结构和特性。进行了一系列条件实验，研究了制备条件(物料加入顺序、铁盐浓度、Fe~(2+)／Fe~(3+)比例、NaOH过量比、PEG加入量和反应温度)对Fe_3O_4纳米颗粒的性能评价指标(比表面积、水悬液的悬浮稳定性和磁响应性)的作用方式和作用机理；进行了一组L~3(4)正交试验，对正交试验结果进行了灰色关联分析。结果表明，本文设计的制备方法和工艺可以得到性能良好的Fe_3O_4纳米颗粒，颗粒表面吸附了PEG高分子，有丰富的羟基，能作为药物载体；制备条件对Fe_3O_4纳米颗粒性能影响程度的大小排序为：NaOH过量比＞PEG加入量＞反应温度＞Fe~(2+)／Fe~(3+)比例；控制制备条件：铁盐浓度0.036～0.072mol／L，NaOH过量比0～0.5，PEG加入量50～100mg／ml，反应温度50～70℃，Fe~(2+)／Fe~(3+)比例1～2，制备的Fe_3O_4纳米颗粒比表面积达到83.21m~2／g，5分钟内水悬液不沉降，磁响应性达到9s／0.22T·cm。
本文以牛血清白蛋白(BSA)、MNP和氟尿嘧啶(5-Fu)为原料，采用乳化包覆法制备了磁性靶向药物，设计了药物含量和药物缓释性能的测试表征方法，通过FTIR、SEM、AAS、分光光度法等手段表征了磁性靶向药物的组成、结构、粒径、形貌、载药量和药物缓释性能；自制了体外靶向性能测试仪，并研究了磁性靶向药物的体外靶向性与MNP含量、流速和磁场强度的关系。结果表明，磁性靶向药物为核壳式结构，BSA对MNP的包覆完整，并且BSA与MNP形成了一定程度的化学结合；磁性靶向药物是球形颗粒，固化过程中形成二次颗粒是导致粒径分布变宽的重要原因；5-Fu加入量越大，磁性靶向药物的载药量越大，固化温度越高，BSA固化程度越大，药物缓释性能越好；磁性靶向药物的体外靶向性随MNP含量的增大而增强，随流速增大而减弱，随磁场强度增强而增强；控制制备条件：混悬液(5-Fu7～14％，Fe_3O_4磁性纳米颗粒18～30％，BSA56～75％)、乳液中水／油相比例1／30～3／30、固化温度90～130℃，得到的磁性靶向药物的粒径达到3.3μm，药物含量达到7.93％，药物释放50％的时间为79.3min，体外靶向性可达到100％。
Magnetic targeted drugs (MTD) could provide the opportunity to limit side effects created from nonspecific systemic exposure, by reducing the total amount of drug administered as well as limiting circulation of the drug throughout the body, while still achieving an efficacious concentration at the desired site in the body. Therefore, MTD have got great and wide attention in the field of cancer treatment. However, at present the process preparing magnetic nanosized particles (MNP) for antitumor drug carrier demands simplification, and drug content, drug control release and magnetic targeting activity to tumor of MTD demands thorough investigation and substantial promotion.
In this thesis magnetic Fe3O4 nano-particles (MNP) were synthesized from molysite, sodium hydrate and polyethylene glycol (PEG), by the method of co-precipitation and supercritical fluid drying technique (SCFD). The preparing technique and processes were simplified. The composition, structure and properties of MNP were investigated by the methods of FTIR, XRD, SEM, BET and VSM. A series of conditional experiments and a group of L3(4) orthogonal experiments were carried out. The ways and mechanisms of preparing conditions (the sequences of introduction of materials, molysite concentrations, the ratio of Fe2+/Fe3+, the ratio of overdosage of sodium hydrate, the quantity of introduction of PEG and reaction temperature) affecting evaluation indicaters of properties (the specific surface area, the suspending stabilization and magnetic respondence of aqueous suspensions of MNP) were studied. The results of the orthogonal experiments were analyzed with the gray relationship systemic method. The main conclusions wer
e as follows:
(1) MNP could be prepared with the simplified technique and processes, absorbed a little of PEG with abundant hydroxyl groups in the surface of MNP particles, and could be used as drug carrier.
(2) the order of the extent of the preparing conditions affecting properties of MNP was the ratio of overdosage of sodium hydrate > the quantity of introduction of PEG> reaction temperature> the ratio of ferrous salt to ferric salt.
(3) the specific surface area of MNP could reach 83.21m2/g, and the aqueous suspensions of MNP could be stable against precipitation in 5 minutes, and magnetic respondence could reach 9s/0.22T-cm, with the molysite concentrations in the range of 0.036-0.072 mol/L, the ratio of overdosage of sodium hydrate in the range of 0.0-0.5, the quantity of introduction of PEG in the range of 50-100 mg/ml, reaction
temperature in the range of 50-70 ℃.
Magnetic targeted drugs (MTD) were synthesized from bovine serum albumin (BSA), MNP and fluorouracil (5-Fu), by the technique of emulsion-cladding. The methods of test and characterization of drug content and drug control release of MTD were designed. The composition, structure, diameters and morphology of MTD particles was investigated by the methods of FTIR, SEM and AAS. The relationships between targeting activity in vitro and MNP content, velocity of flow and magnetic field intensity were studied with the designed tester of targeting activity in vitro. The main findings were as follows:
(1) the MTD particles were formed with a magnetic nucleus coated by a integrated BSA layer, so-called core/shell structure, and the coating was of integrity, a kind of chemical bonds were formed between the nucleus and the coatings.
(2) The analysis of morphology showed that the MTD particles was spheric, the formation of so-called secondary particle in the course of BSA curing played an important roll of the broaden of the diameter distributions.
(3) the drug content of MTD increased with the quantity of introduction of 5-Fu increasing, the extent of BSA curing and the effect of the drug control release was enhanced with the curing temperature elevated.
(4) the targeting activity in vitro was enhanced with the MNP content of MTD increasing, played down with the velocity of flow getting bigger, and promoted with the magnetic field intensity i
引文
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