低聚壳聚糖衍生物的制备及其修饰的磁共振成像造影剂体内外弛豫性能研究
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摘要
壳聚糖是自然界中第二大类丰产资源甲壳素脱乙酰化的产物,也是食品工业中的重要原料之一。壳聚糖后加工产品的进一步开发与应用是避免自然资源浪费、扩大壳聚糖应用范围的途径之一,尤其是在具有高附加值的生物医药领域的拓展应用。临床常用的造影剂Gd-DTPA (马根维显,Magnevist(?))在生物体内的对比时间短、弛豫率低、无靶向性,具有一定的毒性,甚至会引起生物体肾细胞的纤维化。利用天然零毒性、可生物降解、具有良好生物相容性的低聚壳聚糖对商用造影剂进行修饰改性,以提高造影剂的弛豫率和体内安全性。本论文的研究内容主要分为以下3个部分：
1.通过微波辅助双氧水降解法制备不同聚合度的水溶性低聚壳聚糖并合成了3种低聚壳聚糖衍生物。研究了低聚壳聚糖及其衍生物作为亲水药物载体模型的潜能。
1.1通过核磁氢谱(1H NMR)、凝胶过滤色谱(GFC)、红外光谱(IR)等表征了低聚壳聚糖及其衍生物的结构。结果表明壳聚糖在降解过程中只是发生了β-1,4糖苷键的断裂,不存在开环等副反应。当降解得到的低聚壳聚糖的聚合度在20以下时,其分子量分布指数(PDI)大大降低。
1.2研究了牛血清白蛋白(BSA)在低聚壳聚糖及其衍生物溶液中的紫外(UV)和荧光光谱。结果表明低聚壳聚糖及其衍生物与BSA结合的主要作用力是疏水和氢键作用。BSA的构象在低聚壳聚糖及其衍生物溶液的微环境中没有大的改变,天然活性没有受到影响,说明低聚壳聚糖及其衍生物具有成为良好的水溶性药物载体的潜力。
1.3通过等温滴定微量热仪(ITC)研究了低聚壳聚糖及其衍生物与活性医药蛋白BSA之间的热力学作用。结果表明,低聚壳聚糖及其衍生物与BSA的作用过程均是放热的,且是自发进行的。低聚壳聚糖与BSA作用的主要驱动力是氢键。低聚壳聚糖衍生物与BSA作用的主要驱动力是氢键和疏水作用。这一结论与紫外和荧光光谱的结果一致。
2.将不同聚合度的低聚壳聚糖对DTPA进行修饰得到新的配体(DTPA(低聚壳聚糖)),再分别与顺磁性Mn(Ⅱ)、Gd(Ⅲ)络合得到新型的功能配合物作为潜在的MRI造影剂,并研究了锰基和钆基配合物的体外弛豫性能。
2.1通过反转恢复序列研究了DTPA(低聚壳聚糖)锰基和钆基配合物的纵向弛豫率。结果发现钆基配合物的弛豫率不仅高于商业化的造影剂Gd-DTPA,同时也高于锰基配合物。一定条件下配合物的纵向弛豫率均随着修饰的低聚壳聚糖聚合度的增加而增加。DTPA(低聚壳聚糖)锰基和钆基配合物在BSA溶液中的纵向弛豫率均略高于在水溶液中的弛豫率,说明配合物与BSA之间存在相互作用,除了自由态的配合物之外,还形成了配合物-BSA的复合模式。
2.2通过多层自旋回波序列研究了DTPA(低聚壳聚糖)锰基和钆基配合物的体外T1加权成像。结果表明锰基和钆基配合物的体外T1加权成像所得到的FLASH图像的亮度和对比度与配合物的浓度有一定的线性相关性,同等浓度下DTPA(低聚壳聚糖)钆基配合物的体外成像效果最优。另外研究发现体外T1加权成像的效果与修饰的低聚壳聚糖的聚合度也有一定的关系。
2.3通过ITC研究了DTPA(低聚壳聚糖)锰基和钆基配合物与BSA之间的热力学作用。结果表明这两类配合物与BSA之间的作用均是自发进行的,熵驱动的,且作用力以疏水作用为主。
3.以DTPA(低聚壳聚糖)钆基配合物为主要研究对象,研究了其在小鼠体内的安全性和大鼠体内核磁成像情况。
3.1小鼠急性毒性实验结果表明, DTPA(低聚壳聚糖)钆基配合物在注射入小鼠体内一星期后,小鼠仍健康存活,体重正常增加,未见明显的毒性反应。
3.2小鼠骨髓中嗜多染红细胞(PCE)微核实验结果呈阴性,表明DTPA(低聚壳聚糖)钆基配合物对小鼠的染色体没有危害,没有致突变副作用。
3.3金属Gd(Ⅲ)在小鼠体内的残留量分析结果表明,Gd(Ⅲ)在小鼠的肝脏和肾脏内的残留量是先增后减的趋势,一天后残留量逐渐减少。Gd(Ⅲ)在小鼠其它脏器内的残留量呈现逐渐降低的趋势,且残留量不大于Gd-DTPA。
3.4大鼠体内核磁成像研究结果表明,DTPA(低聚壳聚糖)钆基配合物在大鼠体内的保留时间及靶向部位与修饰的低聚壳聚糖的聚合度有关。聚合度为11的低聚壳聚糖修饰的钆基配合物在大鼠肝脏部位的保留时间最长,并且在一定时间内信号强度不降低,有利于肝靶向成像。但是6聚合度的低聚壳聚糖修饰的钆基配合物在肝脏部位没有此效果,其会很快进入肾脏并代谢出体外。
Chitosan is the deacetylated product of chitin, which is the second largest high-yield resource in nature. Chitsan is one of the important raw materials in food industry. The further development and application of chitosan processing products is one of the ways to avoid wastage of natural resources and expand the application of chitosan, especially in the biomedical field with high value. The common contrast agent Gd-DTPA (Magnevist(?)) was found that the contrast time in body was short and the relaxivity was relatively low. In addition, Gd-DTPA is non-targeted and has toxicity, even lead to nephrogenic systemic fibrosis (NSF) of organism renal cells. The commercial contrast agent was modified with chitosan with low degree of polymerization, which was non-toxic, biodegradable and biocompatible. The final goal was to improve the relaxivity of contrast agent and the safety in body. The contents of this paper are divided into the following three parts.
1. Water-soluble low molecular weight chitosan with various degrees of polymerization were prepared with the method of microwave-assisted hydrogen peroxide degradation. The three derivatives were also synthesized. The potential of low molecular weight chitosan and its derivatives as hydrophilic drug carrier model was studied.
1.1The structures of low molecular weight chitosan and its derivatives were characterized through'H NMR, Gel filtration chromatography (GFC), IR, etc. The results showed that only β-1,4glucoside bond was fractured in the degradation process. There was no side reaction such as ring-opening. The polydispersity index was greatly lowed when the degree of polymerization of low molecular weight chitosan was below20.
1.2The UV and fluorescence spectra of bovine serum albumin (BSA), which was in low molecular weight chitosan and its derivatives solution, were studied. The results showed that the main binding force was hydrophobic and hydrogen bonding effect. The conformation of BSA was not changed in the microenvironment of low molecular weight chitosan and its derivatives solution. Besides, the natural activity of BSA was not affected. It was concluded that they have the potential to be good hydrophilic drug carrier model.
1.3The thermodynamic effect between low molecular weight chitosan and its derivatives and active pharmaceutical BSA was studied by isothermal titration calorimetry (ITC). The results indicated that the binding process was exothermic and spontaneous. The main binding force between low molecular weight chitosan and BSA was hydrogen bonding effect. The main binding force between its derivatives and BSA was hydrogen bonding and hydrophobic effect. The conclusion was consistent with the results of UV and fluorescence spectra.
2. The new ligand was modified with low molecular weight chitosan at various degrees of polymerization and then chelated with paramagnetic Mn(Ⅱ) as well as Gd(Ⅲ) to prepare new functional complexes as potential MRI contrast agents. The relaxation property of Mn(Ⅱ) and Gd(Ⅲ) complexes was studied.
2.1The longitudinal relaxivity of Mn(Ⅱ) and Gd(Ⅲ) complexes modified with low molecular weight chitosan was measured with inversion recovery sequence. The results showed that the relaxivity of Gd(Ⅲ) complex was not only higher than that of commercial Gd-DTPA but also Mn(Ⅱ) complex. Under certain condition, the longitudinal relaxivity was increased with the increase of degree of polymerization of low molecular weight chitosan. The longitudinal relaxivity in BSA solution was higher than that in aqueous solution, which suggested that the interaction between the complexes and BSA occurred. The compound model of complexes-BSA was formed.
2.2Ti-weighted imaging in vitro of Mn(Ⅱ) and Gd(Ⅲ) complex was measured with multislice spin echo sequence. It was found that there was a correlation between lightness and imaging contrast of FLASH images and the concentration of the complexes. The results of Ti-weighted imaging in vitro of Gd(Ⅲ) complex were optimal at the equivalent concentration. It was also found that the imaging result was related to the degree of polymerization of low molecular weight chitosan.
2.3The thermodynamic effect between the Mn(Ⅱ) and Gd(Ⅲ) complexes and BSA was measured with ITC. The results showed that the binding process was both spontaneous and entropy-driven. The main binding force was hydrophobic effect.
3. The Gd(Ⅲ) complex modified with low molecular weight chitosan was chosen as a main study object. The safety in mice and MR imaging in vivo in the rat of Gd(Ⅲ) complex were studied.
3.1The results of acute toxicity study showed that the mice remained healthy one week after the injection of Gd(Ⅲ) complex, and normal weight was gained. There was no significant toxicity.
3.2The micronucleus result of polychromatic erythrocyte (PCE) in mice marrow was negative, which indicated that there is no harm on mice chromosome. Gd(Ⅲ) complex would not lead to mutagenesis side effects.
3.3The results of Gd(Ⅲ) residual analysis showed that Gd(Ⅲ) residue in mice liver and kidney was firstly increased and then decreased. The residues were promptly decreased after one day. However, Gd(Ⅲ) in other organs were gradually decreased, and Gd(Ⅲ) was metabolized out of the body.
3.4The results of MR imaging in vivo showed that the length of retention time of Gd(Ⅲ) complex persisted in rat liver, and the target site were related to the degree of polymerization of low molecular weight chitosan for modification. The retention time of Gd(Ⅲ) complex modified with low molecular weight chitosan with11degree of polymerization in rat liver was longest and the signal strength was not reduced within a certain time, which was advantageous for liver target. However, the Gd(Ⅲ) complex modified with low molecular weight chitosan with6degree of polymerization had no effect in the rat liver, and it reached the kidney and metabolized out of the body.
1.通过微波辅助双氧水降解法制备不同聚合度的水溶性低聚壳聚糖并合成了3种低聚壳聚糖衍生物。研究了低聚壳聚糖及其衍生物作为亲水药物载体模型的潜能。
1.1通过核磁氢谱(1H NMR)、凝胶过滤色谱(GFC)、红外光谱(IR)等表征了低聚壳聚糖及其衍生物的结构。结果表明壳聚糖在降解过程中只是发生了β-1,4糖苷键的断裂,不存在开环等副反应。当降解得到的低聚壳聚糖的聚合度在20以下时,其分子量分布指数(PDI)大大降低。
1.2研究了牛血清白蛋白(BSA)在低聚壳聚糖及其衍生物溶液中的紫外(UV)和荧光光谱。结果表明低聚壳聚糖及其衍生物与BSA结合的主要作用力是疏水和氢键作用。BSA的构象在低聚壳聚糖及其衍生物溶液的微环境中没有大的改变,天然活性没有受到影响,说明低聚壳聚糖及其衍生物具有成为良好的水溶性药物载体的潜力。
1.3通过等温滴定微量热仪(ITC)研究了低聚壳聚糖及其衍生物与活性医药蛋白BSA之间的热力学作用。结果表明,低聚壳聚糖及其衍生物与BSA的作用过程均是放热的,且是自发进行的。低聚壳聚糖与BSA作用的主要驱动力是氢键。低聚壳聚糖衍生物与BSA作用的主要驱动力是氢键和疏水作用。这一结论与紫外和荧光光谱的结果一致。
2.将不同聚合度的低聚壳聚糖对DTPA进行修饰得到新的配体(DTPA(低聚壳聚糖)),再分别与顺磁性Mn(Ⅱ)、Gd(Ⅲ)络合得到新型的功能配合物作为潜在的MRI造影剂,并研究了锰基和钆基配合物的体外弛豫性能。
2.1通过反转恢复序列研究了DTPA(低聚壳聚糖)锰基和钆基配合物的纵向弛豫率。结果发现钆基配合物的弛豫率不仅高于商业化的造影剂Gd-DTPA,同时也高于锰基配合物。一定条件下配合物的纵向弛豫率均随着修饰的低聚壳聚糖聚合度的增加而增加。DTPA(低聚壳聚糖)锰基和钆基配合物在BSA溶液中的纵向弛豫率均略高于在水溶液中的弛豫率,说明配合物与BSA之间存在相互作用,除了自由态的配合物之外,还形成了配合物-BSA的复合模式。
2.2通过多层自旋回波序列研究了DTPA(低聚壳聚糖)锰基和钆基配合物的体外T1加权成像。结果表明锰基和钆基配合物的体外T1加权成像所得到的FLASH图像的亮度和对比度与配合物的浓度有一定的线性相关性,同等浓度下DTPA(低聚壳聚糖)钆基配合物的体外成像效果最优。另外研究发现体外T1加权成像的效果与修饰的低聚壳聚糖的聚合度也有一定的关系。
2.3通过ITC研究了DTPA(低聚壳聚糖)锰基和钆基配合物与BSA之间的热力学作用。结果表明这两类配合物与BSA之间的作用均是自发进行的,熵驱动的,且作用力以疏水作用为主。
3.以DTPA(低聚壳聚糖)钆基配合物为主要研究对象,研究了其在小鼠体内的安全性和大鼠体内核磁成像情况。
3.1小鼠急性毒性实验结果表明, DTPA(低聚壳聚糖)钆基配合物在注射入小鼠体内一星期后,小鼠仍健康存活,体重正常增加,未见明显的毒性反应。
3.2小鼠骨髓中嗜多染红细胞(PCE)微核实验结果呈阴性,表明DTPA(低聚壳聚糖)钆基配合物对小鼠的染色体没有危害,没有致突变副作用。
3.3金属Gd(Ⅲ)在小鼠体内的残留量分析结果表明,Gd(Ⅲ)在小鼠的肝脏和肾脏内的残留量是先增后减的趋势,一天后残留量逐渐减少。Gd(Ⅲ)在小鼠其它脏器内的残留量呈现逐渐降低的趋势,且残留量不大于Gd-DTPA。
3.4大鼠体内核磁成像研究结果表明,DTPA(低聚壳聚糖)钆基配合物在大鼠体内的保留时间及靶向部位与修饰的低聚壳聚糖的聚合度有关。聚合度为11的低聚壳聚糖修饰的钆基配合物在大鼠肝脏部位的保留时间最长,并且在一定时间内信号强度不降低,有利于肝靶向成像。但是6聚合度的低聚壳聚糖修饰的钆基配合物在肝脏部位没有此效果,其会很快进入肾脏并代谢出体外。
Chitosan is the deacetylated product of chitin, which is the second largest high-yield resource in nature. Chitsan is one of the important raw materials in food industry. The further development and application of chitosan processing products is one of the ways to avoid wastage of natural resources and expand the application of chitosan, especially in the biomedical field with high value. The common contrast agent Gd-DTPA (Magnevist(?)) was found that the contrast time in body was short and the relaxivity was relatively low. In addition, Gd-DTPA is non-targeted and has toxicity, even lead to nephrogenic systemic fibrosis (NSF) of organism renal cells. The commercial contrast agent was modified with chitosan with low degree of polymerization, which was non-toxic, biodegradable and biocompatible. The final goal was to improve the relaxivity of contrast agent and the safety in body. The contents of this paper are divided into the following three parts.
1. Water-soluble low molecular weight chitosan with various degrees of polymerization were prepared with the method of microwave-assisted hydrogen peroxide degradation. The three derivatives were also synthesized. The potential of low molecular weight chitosan and its derivatives as hydrophilic drug carrier model was studied.
1.1The structures of low molecular weight chitosan and its derivatives were characterized through'H NMR, Gel filtration chromatography (GFC), IR, etc. The results showed that only β-1,4glucoside bond was fractured in the degradation process. There was no side reaction such as ring-opening. The polydispersity index was greatly lowed when the degree of polymerization of low molecular weight chitosan was below20.
1.2The UV and fluorescence spectra of bovine serum albumin (BSA), which was in low molecular weight chitosan and its derivatives solution, were studied. The results showed that the main binding force was hydrophobic and hydrogen bonding effect. The conformation of BSA was not changed in the microenvironment of low molecular weight chitosan and its derivatives solution. Besides, the natural activity of BSA was not affected. It was concluded that they have the potential to be good hydrophilic drug carrier model.
1.3The thermodynamic effect between low molecular weight chitosan and its derivatives and active pharmaceutical BSA was studied by isothermal titration calorimetry (ITC). The results indicated that the binding process was exothermic and spontaneous. The main binding force between low molecular weight chitosan and BSA was hydrogen bonding effect. The main binding force between its derivatives and BSA was hydrogen bonding and hydrophobic effect. The conclusion was consistent with the results of UV and fluorescence spectra.
2. The new ligand was modified with low molecular weight chitosan at various degrees of polymerization and then chelated with paramagnetic Mn(Ⅱ) as well as Gd(Ⅲ) to prepare new functional complexes as potential MRI contrast agents. The relaxation property of Mn(Ⅱ) and Gd(Ⅲ) complexes was studied.
2.1The longitudinal relaxivity of Mn(Ⅱ) and Gd(Ⅲ) complexes modified with low molecular weight chitosan was measured with inversion recovery sequence. The results showed that the relaxivity of Gd(Ⅲ) complex was not only higher than that of commercial Gd-DTPA but also Mn(Ⅱ) complex. Under certain condition, the longitudinal relaxivity was increased with the increase of degree of polymerization of low molecular weight chitosan. The longitudinal relaxivity in BSA solution was higher than that in aqueous solution, which suggested that the interaction between the complexes and BSA occurred. The compound model of complexes-BSA was formed.
2.2Ti-weighted imaging in vitro of Mn(Ⅱ) and Gd(Ⅲ) complex was measured with multislice spin echo sequence. It was found that there was a correlation between lightness and imaging contrast of FLASH images and the concentration of the complexes. The results of Ti-weighted imaging in vitro of Gd(Ⅲ) complex were optimal at the equivalent concentration. It was also found that the imaging result was related to the degree of polymerization of low molecular weight chitosan.
2.3The thermodynamic effect between the Mn(Ⅱ) and Gd(Ⅲ) complexes and BSA was measured with ITC. The results showed that the binding process was both spontaneous and entropy-driven. The main binding force was hydrophobic effect.
3. The Gd(Ⅲ) complex modified with low molecular weight chitosan was chosen as a main study object. The safety in mice and MR imaging in vivo in the rat of Gd(Ⅲ) complex were studied.
3.1The results of acute toxicity study showed that the mice remained healthy one week after the injection of Gd(Ⅲ) complex, and normal weight was gained. There was no significant toxicity.
3.2The micronucleus result of polychromatic erythrocyte (PCE) in mice marrow was negative, which indicated that there is no harm on mice chromosome. Gd(Ⅲ) complex would not lead to mutagenesis side effects.
3.3The results of Gd(Ⅲ) residual analysis showed that Gd(Ⅲ) residue in mice liver and kidney was firstly increased and then decreased. The residues were promptly decreased after one day. However, Gd(Ⅲ) in other organs were gradually decreased, and Gd(Ⅲ) was metabolized out of the body.
3.4The results of MR imaging in vivo showed that the length of retention time of Gd(Ⅲ) complex persisted in rat liver, and the target site were related to the degree of polymerization of low molecular weight chitosan for modification. The retention time of Gd(Ⅲ) complex modified with low molecular weight chitosan with11degree of polymerization in rat liver was longest and the signal strength was not reduced within a certain time, which was advantageous for liver target. However, the Gd(Ⅲ) complex modified with low molecular weight chitosan with6degree of polymerization had no effect in the rat liver, and it reached the kidney and metabolized out of the body.
引文
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