胆红素水溶性分子吸附剂的制备及性能研究
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摘要
分子吸附再循环系统(Molecular Adsorbents Recycling System, MARS)是目前临床治疗重症肝病效果优良的非生物型人工肝支持系统。在以人血清白蛋白(Human serum albumin, HSA)为分子吸附剂的吸附透析过程中,添加到透析液中的HSA与血液中的蛋白质竞争性结合疏水性毒素并被透析液带走,从而有效、广谱去除患者血液中的蛋白质结合毒素及水溶性毒素,实现改善患者体内环境、促进肝脏功能恢复和为肝移植争取时间的目的。MARS的治疗效果已经得到医生和患者的广泛认可,在国外被推荐作为各类肝衰竭的标准治疗方案。由于HSA是MARS实现解毒功能的关键分子吸附剂,用量较大,而作为注射制剂的HSA来源有限,价格昂贵。HSA来源受限及其再生设备复杂等问题导致MARS临床治疗费用高昂,其应用人群范围受限。鉴于此,本论文设计合成了一种水溶性胆红素分子吸附剂替代HSA用于对肝病病人血液的吸附透析,该吸附剂在实现对胆红素等毒素高效去除的同时,可以简化治疗设备,显著降低治疗成本。
在本论文中,首先针对胆红素分子的结构特点,选择壳聚糖、右旋糖酐、聚乙烯亚胺(Polyethyleneimine, PEI)等水溶性高分子为载体,制备了带有不同吸附功能基的系列胆红素分子吸附剂。对其胆红素吸附能力评价的结果表明：以PEI为载体、以β-环糊精(β-cyclodextrin,β-CD)为功能基的水溶性吸附剂P-CD-PEI在相同条件下对胆红素的吸附透析能力最强。进一步以P-CD-PEI为研究对象,对其合成过程进行了优化。最终获得的β-CD-PEI的平均分子量约为157kD,平均每个β-CD-PEI分子上具有366个分枝点,偶联β-CD的数量约为51个。选择Nipro Sureflux-130G透析器,采用200mL含1%(w/v) p-CD-PEI的透析液对150mL含300mg／L胆红素的人血浆进行吸附透析,其对血浆中胆红素的1h吸附量达到3.55mg／g。
采用分子模拟的方法研究了分子吸附剂功能基p—CD与胆红素的结合方式以及结合能,并与α-CD、γ-CD及HSA与胆红素的相互作用进行了比较。研究结果表明：在环糊精家族中,α-CD由于疏水内腔太小,不能与胆红素形成包合物；β-CD及Y-CD与胆红素形成的2：1包合物比1：1包合物更稳定,其中p—CD胆红素2：1包合物稳定性高于HSA与胆红素的复合物,意味着β-CD与胆红素的结合能力强于HSA,有能力与HSA竞争结合胆红素。偶联反应对β-CD分子结构的改变不会减弱其与胆红素的结合能力。进一步通过将α、β、γ-CD分别偶联到PEI载体上合成了三种分子吸附剂,吸附透析实验结果表明β-CD-PEI对胆红素的结合能力最强；使用Benesi-Hildebrand法分析β-CD与胆红素包合后胆红素紫外可见光谱变化,进一步确认了β-CD与胆红素以2：1的比例形成包合物,从而证实了分子模拟研究的结果。
在吸附透析治疗中,对血浆胆红素的去除效果取决于透析膜的特性、血浆流速、透析液流速、血浆中的胆红素浓度、透析液中水溶性吸附剂的浓度以及吸附透析时间等因素。在吸附透析系统的参数优化中发现：当血浆及透析液流速分别为300和50mL/min时,β-CD-PEI吸附透析对血浆胆红素的去除效果最佳；超滤形成的跨膜液流产生的浓差极化现象增加了胆红素的传质阻力,降低了β-CD-PEI在透析膜内的分子扩散,不利于β-CD-PEI吸附透析对胆红素的去除；以聚醚砜为膜材质的Lengthen LST140透析器对于胆红素的传质效果强于以三醋酸纤维素为膜材质的Nipro Sureflux-130G透析器；透析膜表面及孔道中吸附的白蛋白能够对胆红素进行协助传递,进而提高透析膜对胆红素的传质效果。
在吸附透析过程中,β-CD-PEI的吸附量随着血浆中胆红素浓度的升高而增加,采用1L浓度为1%的β-CD-PEI透析液对200mL胆红素初始浓度分别为80.3、140.4、214.8、267.3、305.2mg／L的肝病病人血浆进行吸附透析,6h的总胆红素去除率均能达到30-40%,适用于不同患病程度的肝病病人。增加分子吸附剂β-CD-PEI的用量可以提高吸附透析对胆红素的去除效果。使用1L4%的β-CD-PEI透析液可以去除血浆中44.8%的胆红素(初始浓度140.4mg／L),比相同情况下4L1%分子吸附剂的胆红素去除率提高9个百分点。β-CD-PEI对血浆胆红素的清除率比相同质量分数的牛血清白蛋白高9.5个百分点,同时β-CD-PEI对血浆中的总胆汁酸、芳香族氨基酸等疏水毒素也具有明显的去除能力,说明β-CD-PEI具有替代白蛋白进行吸附透析的潜力。
通过基于物料衡算的数学模型描述了吸附透析过程中血浆胆红素浓度变化规律。通过实验数据回归,计算得到了Nipro Sureflux-130G血液透析膜对胆红素的总传质系数Dt为1.7L/min, p-CD-PEI与胆红素的吸附平衡常数Ka1为22.7L/μmoL。进一步使用该模型预测了同一体系中血浆胆红素初始浓度和吸附剂用量改变时胆红素的吸附透析效果,平均误差<5%。
上述研究结果证明,胆红素水溶性分子吸附剂β-CD-PEI对肝病患者血浆中的胆红素及其它疏水性毒素具有较高的清除能力,同时具有价格低廉、治疗设备简单的优势。具有替代白蛋白应用于临床治疗的潜力。
Albumin dialysis, known as Molecular Adsorbents Recycling System (MARS), is an effective and widely studied detoxification treatment for liver failure. Albumin dialysis is derived by adding albumin to the dialysate of extracorporeal hemodialysis. Both water-soluble and protein-bound toxins can be simultaneously removed by this treatment. The effectiveness of MARS in eliminating toxins has been confirmed by many clinical studies. Human serum albumin (HSA) is the key to the removal of protein-bound toxins by MARS, but HSA is isolated from human serum, and is therefore expensive as well as in short supply. To reduce the cost, limited dosage of HSA is used in MARS, and it has to be regenerated in situ. Due to the incomplete regeneration of HSA, the capacity and rates of MARS to remove protein-bound toxins decline over time. Furthermore, albumin regeneration system makes MARS very complicated and expensive, which has limited its clinical application, especially in developing countries. Thus developing an inexpensive water-soluble molecular adsorbent as an alternative to HSA is very attractive. This work represents the development of an efficient and inexpensive water-soluble molecular adsorbent for removing plasma bilirubin.
Seven bilirubin adsorbents were synthesized by grafting different ligands (quaternary ammonium, hydrophobic chain, β-CD) onto water-soluble polymers (chitosan, dextran, polyethyleneimine). Among the seven adsorbents, β-CD-PEI exhibited the highest adsorption capacity for bilirubin. In a plasma dialysis system,150mL plasma (with300mg/L bilirubin) was dialyzed with200mL of1%(w/v) adsorbent-spiked dialysate, bilirubin adsorption capacity of2.84mg/g was achieved by β-CD-PEI in1h. By optimizing the synthesis of β-CD-PEI, its bilirubin adsorption capacity further increased to3.55mg/g. Therefore, β-CD-PEI was chosen for subsequent studies.13C NMR results indicated that each β-CD-PEI has366branching points and51β-CD functional groups. The average molecular weight of β-CD-PEI was-157kD.
In order to understand the mechanism associated with the binding of bilirubin to β-CD at molecular level, dockings of bilirubin to α-, β-, γ-CD were carried out using AutoDock Vina1.1program. The results indicated that Bilirubin was too big to insert into α-CD, so its binding energy with bilirubin was the weakest among the CD family. Bilirubin-(β-CD)2complex was most favorable in term of binding energy. The structural change of β-CD caused by the grafting reaction did not hinder its binding with bilirubin. The best binding energy between bilirubin and HSA was higher than that of bilirubin-(β-CD)2complex. This result demonstrated that two β-CD molecules under the lowest binding energy could competitively bind bilirubin bound by HSA. The1:2binding model for bilirubin and β-CD was also confirmed by Benesi-Hildebrand experiments.
The highest bilirubin clearance (35.8%) was achieved by adopting the optimal flow rate of300mL/min for plasma and50mL/min for dialysate. Cross-membrane ultrafiltration enhanced concentration polarization in plasma during the dialysis, and increased bilirubin transfer resistance. The bilirubin clearance of Lengthen LST140dialyzer was stronger than Nipro Sureflux-130G dialyzer. The albumin adsorbed on the surface and pores of membrane can improve the transfer of bilirubin during dialysis. Bilirubin removal was fast in β-CD-PEI-spiked dialysis, with90%of total bilirubin removed in first4h.
β-CD-PEI-spiked dialysis could achieve high bilirubin clearance in plasma with different initial concentrations of bilirubin. Bilirubin clearance increased with increases in β-CD-PEI dosage, and high β-CD-PEI concentration was more favorable for bilirubin removal. About44.8%of bilirubin (140.4mg/L) was removed from200mL plasma by1L dialysate spiked with4%β-CD-PEI in6h. β-CD-PEI exhibited a significantly higher bilirubin clearance than BSA (P<0.05), which is an analogue of HSA, therefore demonstrating its strong bilirubin-binding ability. Both TBA and the three aromatic amino acids could be removed by β-CD-PEI-spiked dialysis without influencing the concentrations of plasma proteins and ions.
A quantitative description of bilirubin removal during β-CD-PEI-spiked dialysis was established by means of a mathematical model. Model development and validation are based on in vitro data of bilirubin concentration acquired in five sessions at different times during each session. The accuracy of the model in reproducing real data is high, and error of concentration of plasma bilirubin is less than5%. This model could be used to predict treatment outcomes in experiments with different initial concentrations of bilirubin and different dosages of β-CD-PEI.
To summarize, the water-soluble molecular adsorbent β-CD-PEI described in this study offers an efficient alternative to albumin for removing bilirubin from plasma. Since β-CD-PEI is much cheaper than HSA, it can reduce the economic burden for the patients. Almost unlimited ability to remove toxins could be achieved by continuously replacing the saturated adsorbent with new ones. No additional adsorbent regeneration devices are needed. Therefore, the equipment for the set up of β-CD-PEI-spiked dialysis can be greatly simplified compared with that of MARS. The results presented in this study demonstrate that β-CD-PEI, a water-soluble adsorbent, can effectively remove plasma bilirubin, and therefore may have potential application in a dialysis system.
在本论文中,首先针对胆红素分子的结构特点,选择壳聚糖、右旋糖酐、聚乙烯亚胺(Polyethyleneimine, PEI)等水溶性高分子为载体,制备了带有不同吸附功能基的系列胆红素分子吸附剂。对其胆红素吸附能力评价的结果表明：以PEI为载体、以β-环糊精(β-cyclodextrin,β-CD)为功能基的水溶性吸附剂P-CD-PEI在相同条件下对胆红素的吸附透析能力最强。进一步以P-CD-PEI为研究对象,对其合成过程进行了优化。最终获得的β-CD-PEI的平均分子量约为157kD,平均每个β-CD-PEI分子上具有366个分枝点,偶联β-CD的数量约为51个。选择Nipro Sureflux-130G透析器,采用200mL含1%(w/v) p-CD-PEI的透析液对150mL含300mg／L胆红素的人血浆进行吸附透析,其对血浆中胆红素的1h吸附量达到3.55mg／g。
采用分子模拟的方法研究了分子吸附剂功能基p—CD与胆红素的结合方式以及结合能,并与α-CD、γ-CD及HSA与胆红素的相互作用进行了比较。研究结果表明：在环糊精家族中,α-CD由于疏水内腔太小,不能与胆红素形成包合物；β-CD及Y-CD与胆红素形成的2：1包合物比1：1包合物更稳定,其中p—CD胆红素2：1包合物稳定性高于HSA与胆红素的复合物,意味着β-CD与胆红素的结合能力强于HSA,有能力与HSA竞争结合胆红素。偶联反应对β-CD分子结构的改变不会减弱其与胆红素的结合能力。进一步通过将α、β、γ-CD分别偶联到PEI载体上合成了三种分子吸附剂,吸附透析实验结果表明β-CD-PEI对胆红素的结合能力最强；使用Benesi-Hildebrand法分析β-CD与胆红素包合后胆红素紫外可见光谱变化,进一步确认了β-CD与胆红素以2：1的比例形成包合物,从而证实了分子模拟研究的结果。
在吸附透析治疗中,对血浆胆红素的去除效果取决于透析膜的特性、血浆流速、透析液流速、血浆中的胆红素浓度、透析液中水溶性吸附剂的浓度以及吸附透析时间等因素。在吸附透析系统的参数优化中发现：当血浆及透析液流速分别为300和50mL/min时,β-CD-PEI吸附透析对血浆胆红素的去除效果最佳；超滤形成的跨膜液流产生的浓差极化现象增加了胆红素的传质阻力,降低了β-CD-PEI在透析膜内的分子扩散,不利于β-CD-PEI吸附透析对胆红素的去除；以聚醚砜为膜材质的Lengthen LST140透析器对于胆红素的传质效果强于以三醋酸纤维素为膜材质的Nipro Sureflux-130G透析器；透析膜表面及孔道中吸附的白蛋白能够对胆红素进行协助传递,进而提高透析膜对胆红素的传质效果。
在吸附透析过程中,β-CD-PEI的吸附量随着血浆中胆红素浓度的升高而增加,采用1L浓度为1%的β-CD-PEI透析液对200mL胆红素初始浓度分别为80.3、140.4、214.8、267.3、305.2mg／L的肝病病人血浆进行吸附透析,6h的总胆红素去除率均能达到30-40%,适用于不同患病程度的肝病病人。增加分子吸附剂β-CD-PEI的用量可以提高吸附透析对胆红素的去除效果。使用1L4%的β-CD-PEI透析液可以去除血浆中44.8%的胆红素(初始浓度140.4mg／L),比相同情况下4L1%分子吸附剂的胆红素去除率提高9个百分点。β-CD-PEI对血浆胆红素的清除率比相同质量分数的牛血清白蛋白高9.5个百分点,同时β-CD-PEI对血浆中的总胆汁酸、芳香族氨基酸等疏水毒素也具有明显的去除能力,说明β-CD-PEI具有替代白蛋白进行吸附透析的潜力。
通过基于物料衡算的数学模型描述了吸附透析过程中血浆胆红素浓度变化规律。通过实验数据回归,计算得到了Nipro Sureflux-130G血液透析膜对胆红素的总传质系数Dt为1.7L/min, p-CD-PEI与胆红素的吸附平衡常数Ka1为22.7L/μmoL。进一步使用该模型预测了同一体系中血浆胆红素初始浓度和吸附剂用量改变时胆红素的吸附透析效果,平均误差<5%。
上述研究结果证明,胆红素水溶性分子吸附剂β-CD-PEI对肝病患者血浆中的胆红素及其它疏水性毒素具有较高的清除能力,同时具有价格低廉、治疗设备简单的优势。具有替代白蛋白应用于临床治疗的潜力。
Albumin dialysis, known as Molecular Adsorbents Recycling System (MARS), is an effective and widely studied detoxification treatment for liver failure. Albumin dialysis is derived by adding albumin to the dialysate of extracorporeal hemodialysis. Both water-soluble and protein-bound toxins can be simultaneously removed by this treatment. The effectiveness of MARS in eliminating toxins has been confirmed by many clinical studies. Human serum albumin (HSA) is the key to the removal of protein-bound toxins by MARS, but HSA is isolated from human serum, and is therefore expensive as well as in short supply. To reduce the cost, limited dosage of HSA is used in MARS, and it has to be regenerated in situ. Due to the incomplete regeneration of HSA, the capacity and rates of MARS to remove protein-bound toxins decline over time. Furthermore, albumin regeneration system makes MARS very complicated and expensive, which has limited its clinical application, especially in developing countries. Thus developing an inexpensive water-soluble molecular adsorbent as an alternative to HSA is very attractive. This work represents the development of an efficient and inexpensive water-soluble molecular adsorbent for removing plasma bilirubin.
Seven bilirubin adsorbents were synthesized by grafting different ligands (quaternary ammonium, hydrophobic chain, β-CD) onto water-soluble polymers (chitosan, dextran, polyethyleneimine). Among the seven adsorbents, β-CD-PEI exhibited the highest adsorption capacity for bilirubin. In a plasma dialysis system,150mL plasma (with300mg/L bilirubin) was dialyzed with200mL of1%(w/v) adsorbent-spiked dialysate, bilirubin adsorption capacity of2.84mg/g was achieved by β-CD-PEI in1h. By optimizing the synthesis of β-CD-PEI, its bilirubin adsorption capacity further increased to3.55mg/g. Therefore, β-CD-PEI was chosen for subsequent studies.13C NMR results indicated that each β-CD-PEI has366branching points and51β-CD functional groups. The average molecular weight of β-CD-PEI was-157kD.
In order to understand the mechanism associated with the binding of bilirubin to β-CD at molecular level, dockings of bilirubin to α-, β-, γ-CD were carried out using AutoDock Vina1.1program. The results indicated that Bilirubin was too big to insert into α-CD, so its binding energy with bilirubin was the weakest among the CD family. Bilirubin-(β-CD)2complex was most favorable in term of binding energy. The structural change of β-CD caused by the grafting reaction did not hinder its binding with bilirubin. The best binding energy between bilirubin and HSA was higher than that of bilirubin-(β-CD)2complex. This result demonstrated that two β-CD molecules under the lowest binding energy could competitively bind bilirubin bound by HSA. The1:2binding model for bilirubin and β-CD was also confirmed by Benesi-Hildebrand experiments.
The highest bilirubin clearance (35.8%) was achieved by adopting the optimal flow rate of300mL/min for plasma and50mL/min for dialysate. Cross-membrane ultrafiltration enhanced concentration polarization in plasma during the dialysis, and increased bilirubin transfer resistance. The bilirubin clearance of Lengthen LST140dialyzer was stronger than Nipro Sureflux-130G dialyzer. The albumin adsorbed on the surface and pores of membrane can improve the transfer of bilirubin during dialysis. Bilirubin removal was fast in β-CD-PEI-spiked dialysis, with90%of total bilirubin removed in first4h.
β-CD-PEI-spiked dialysis could achieve high bilirubin clearance in plasma with different initial concentrations of bilirubin. Bilirubin clearance increased with increases in β-CD-PEI dosage, and high β-CD-PEI concentration was more favorable for bilirubin removal. About44.8%of bilirubin (140.4mg/L) was removed from200mL plasma by1L dialysate spiked with4%β-CD-PEI in6h. β-CD-PEI exhibited a significantly higher bilirubin clearance than BSA (P<0.05), which is an analogue of HSA, therefore demonstrating its strong bilirubin-binding ability. Both TBA and the three aromatic amino acids could be removed by β-CD-PEI-spiked dialysis without influencing the concentrations of plasma proteins and ions.
A quantitative description of bilirubin removal during β-CD-PEI-spiked dialysis was established by means of a mathematical model. Model development and validation are based on in vitro data of bilirubin concentration acquired in five sessions at different times during each session. The accuracy of the model in reproducing real data is high, and error of concentration of plasma bilirubin is less than5%. This model could be used to predict treatment outcomes in experiments with different initial concentrations of bilirubin and different dosages of β-CD-PEI.
To summarize, the water-soluble molecular adsorbent β-CD-PEI described in this study offers an efficient alternative to albumin for removing bilirubin from plasma. Since β-CD-PEI is much cheaper than HSA, it can reduce the economic burden for the patients. Almost unlimited ability to remove toxins could be achieved by continuously replacing the saturated adsorbent with new ones. No additional adsorbent regeneration devices are needed. Therefore, the equipment for the set up of β-CD-PEI-spiked dialysis can be greatly simplified compared with that of MARS. The results presented in this study demonstrate that β-CD-PEI, a water-soluble adsorbent, can effectively remove plasma bilirubin, and therefore may have potential application in a dialysis system.
引文
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