抗非特异性蛋白吸附两性离子聚合物表面的制备、优化及应用
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摘要
蛋白质与表面相互作用是纳米技术、生物材料和生物技术中的基本问题。抗非特异性蛋白吸附表面已经成为如医用植入物材料,药物传递以及生物传感器等生物医学应用中的一个重要问题,但是目前能够满足实际需要的超低蛋白吸附材料并不是很多。本文系统的研究了一系列两性离子聚合物表面如硫代甜菜碱丙烯酸甲酯(SBMA),羧基甜菜碱丙烯酰胺(CBAA)和羧基甜菜碱丙烯酸甲酯(CBMA),对表面进行了优化,其目的是探索一种对血清和血浆都能够实现“零”吸附的表面,并进一步探索了其在生物传感器和癌症疾病诊断等领域的应用。
第一,通过原子转移自由基聚合反应(ATRP)得到了不同厚度的聚SBMA表面,并系统研究了不同厚度的表面与蛋白吸附的关系。实验结果表明,研究的所有聚合物表面都可以认为是超低的非特异性蛋白吸附表面。同时,对于复杂介质如未稀释血清和血浆的研究发现当聚合物厚度过薄或者过厚时,都可以看到较明显的蛋白吸附,只有当聚合物的厚度大约为62 nm时,可以观察到最低的蛋白吸附。
第二,研究了一种基于聚CBAA的表面平台,这个平台可以非常有效、灵敏以及特异性的检测血浆中的特定蛋白,同时还能提供非常稳定的超低蛋白吸附背景。抗体功能化之后的聚CBAA表面表现出对未稀释血浆有超低的蛋白吸附性质,表面等离子共振传感器(SPR)测量其吸附量低于3 ng/cm2。对未稀释血浆中一种癌症生物标记物(ALCAM)的检测表明其具有很高的灵敏度和特异性。同时,还研究了聚CBMA的金表面和二氧化硅表面的功能化。
第三,通过ATRP反应得到了不同厚度聚CBAA的表面,并且研究了这些表面与未稀释的老化血清,血清和血浆等多种蛋白在不同温度下的吸附关系。实验结果表明当聚CBAA表面的厚度为20 nm左右时,不管在25°C还是37°C下,表面对未稀释的老化血清、血清和血浆的蛋白吸附值都低于SPR的检测下限即0.3 ng/cm2。另外,功能化的实验结果表明聚CBAA表面在功能化之后能继续保持其良好的抗非特异性蛋白吸附的特性,并且可以对血清中的ALCAM抗原可以有效的进行检测。
第四,验证了一种适用于纳米颗粒的可功能化且超稳定的表面。结果表明聚CBAA包覆的纳米颗粒具有与传统的包覆层如聚乙二醇相比更稳定的特性,尽管聚乙二醇和甲基丙烯酸低聚乙二醇酯包覆的纳米颗粒在10%人血清中能稳定存在,但其在未稀释的血清中不能保持稳定。另外,生物识别因素如ALCAM可以通过氨基化学法非常简单且有效的连接到聚CBAA的表面。聚CBAA包覆的纳米颗粒表面的配体密度可以通过调整抗原/抗体的浓度而很容易的被调控。
Nonspecific protein adsorption has been a crucial issue for many biomedical applications, such as medical implants, drug delivery vehicles and biosensors. At present, there are a very limited number of effective nonfouling biomaterials available to meet the challenges of practical applications. Here, zwitterionic materials such as sulfobetaine methacrylate (SBMA), carboxybetaine acrylamide (CBAA) and carboxybetaine methacrylate (CBMA) were systematically introduced, optimized and investigated for their applications as biosensors.
Firstly, protein adsorption from single protein solutions and complex media such as 100% blood serum and plasma onto polySBMA-grafted surfaces via atom transfer radical polymerization (ATRP) at varying film thicknesses was investigated. It is interesting to observe that protein adsorption exhibits a minimum at a medium film thickness. Results show that the surface with 62 nm polySBMA brushes presents the best nonfouling character in 100% blood serum and plasma although all of these surfaces are highly resistant to nonspecific protein adsorption from single fibrinogen and lysozyme solutions. Surface resistance to 100% blood serum or plasma is necessary for many applications from blood-contacting devices to drug delivery. This work provides a new in vitro evaluation standard for the application of biomaterials in vivo.
Secondly, a zwitterionic polyCBAA biomimetic material was employed to create a unique biorecognition coating with an ultralow fouling background, enabling the sensitive and specific detection of proteins in blood plasma. Conditions for surface activation, protein immobilization, and surface deactivation of the carboxylate groups in the polyCBAA coating were determined. An antibody-functionalized polyCBAA surface platform was used to detect a target protein in blood plasma using a sensitive surface plasmon resonance (SPR) sensor. A cancer biomarker (ALCAM) was directly detected from 100% human blood plasma with extraordinary specificity and sensitivity. The total nonspecific protein adsorption on the functionalized polyCBAA surface was very low (<3 ng/cm2 for undiluted blood plasma). Furthermore, functionalization on polyCBMA-grafted gold or silicon dioxide surfaces was also investigated.
Thirdly, nonspecific protein adsorption from single protein solutions and complex media such as undiluted human blood serum and plasma onto polyCBAA-grafted surfaces was investigated. The polyCBAA grafting was done via ATRP with varying film thicknesses at different temperatures. The objective is to create a surface that experiences“zero”protein adsorption from complex undiluted human blood serum and plasma. Results show that protein adsorption from undiluted blood serum, plasma, and aged serum on the polyCBAA-grafted surface is undetectable at both 25°C and 37°C by a SPR sensor. This was achieved with a film thickness of ~20 nm. Further it is demonstrated that the polyCBAA surfaces after antibody immobilized maintain undetectable protein adsorption from undiluted human blood serum.
Finally, a new surface platform presenting an abundance of functional groups for ligand immobilization in an ultra-low fouling background necessary for targeted drug delivery and diagnostics was introduced. It is demonstrated that this surface platform, made from zwitterionic polyCBAA coated nanoparticles, is not only stable in undiluted human blood serum, but also can be conjugated to bio-molecules conveniently and effectively. In addition, a practical application was demonstrated by showing the amount of antibodies to a candidate cancer biomarker immobilized onto polyCBAA-coated nanoparticles can be easily adjusted. Results also indicate that 10% serum commonly used to evaluate the stability of nanoparticles is not sufficient and undiluted blood serum is recommended to screen nanoparticles before their in vivo experiments.
第一,通过原子转移自由基聚合反应(ATRP)得到了不同厚度的聚SBMA表面,并系统研究了不同厚度的表面与蛋白吸附的关系。实验结果表明,研究的所有聚合物表面都可以认为是超低的非特异性蛋白吸附表面。同时,对于复杂介质如未稀释血清和血浆的研究发现当聚合物厚度过薄或者过厚时,都可以看到较明显的蛋白吸附,只有当聚合物的厚度大约为62 nm时,可以观察到最低的蛋白吸附。
第二,研究了一种基于聚CBAA的表面平台,这个平台可以非常有效、灵敏以及特异性的检测血浆中的特定蛋白,同时还能提供非常稳定的超低蛋白吸附背景。抗体功能化之后的聚CBAA表面表现出对未稀释血浆有超低的蛋白吸附性质,表面等离子共振传感器(SPR)测量其吸附量低于3 ng/cm2。对未稀释血浆中一种癌症生物标记物(ALCAM)的检测表明其具有很高的灵敏度和特异性。同时,还研究了聚CBMA的金表面和二氧化硅表面的功能化。
第三,通过ATRP反应得到了不同厚度聚CBAA的表面,并且研究了这些表面与未稀释的老化血清,血清和血浆等多种蛋白在不同温度下的吸附关系。实验结果表明当聚CBAA表面的厚度为20 nm左右时,不管在25°C还是37°C下,表面对未稀释的老化血清、血清和血浆的蛋白吸附值都低于SPR的检测下限即0.3 ng/cm2。另外,功能化的实验结果表明聚CBAA表面在功能化之后能继续保持其良好的抗非特异性蛋白吸附的特性,并且可以对血清中的ALCAM抗原可以有效的进行检测。
第四,验证了一种适用于纳米颗粒的可功能化且超稳定的表面。结果表明聚CBAA包覆的纳米颗粒具有与传统的包覆层如聚乙二醇相比更稳定的特性,尽管聚乙二醇和甲基丙烯酸低聚乙二醇酯包覆的纳米颗粒在10%人血清中能稳定存在,但其在未稀释的血清中不能保持稳定。另外,生物识别因素如ALCAM可以通过氨基化学法非常简单且有效的连接到聚CBAA的表面。聚CBAA包覆的纳米颗粒表面的配体密度可以通过调整抗原/抗体的浓度而很容易的被调控。
Nonspecific protein adsorption has been a crucial issue for many biomedical applications, such as medical implants, drug delivery vehicles and biosensors. At present, there are a very limited number of effective nonfouling biomaterials available to meet the challenges of practical applications. Here, zwitterionic materials such as sulfobetaine methacrylate (SBMA), carboxybetaine acrylamide (CBAA) and carboxybetaine methacrylate (CBMA) were systematically introduced, optimized and investigated for their applications as biosensors.
Firstly, protein adsorption from single protein solutions and complex media such as 100% blood serum and plasma onto polySBMA-grafted surfaces via atom transfer radical polymerization (ATRP) at varying film thicknesses was investigated. It is interesting to observe that protein adsorption exhibits a minimum at a medium film thickness. Results show that the surface with 62 nm polySBMA brushes presents the best nonfouling character in 100% blood serum and plasma although all of these surfaces are highly resistant to nonspecific protein adsorption from single fibrinogen and lysozyme solutions. Surface resistance to 100% blood serum or plasma is necessary for many applications from blood-contacting devices to drug delivery. This work provides a new in vitro evaluation standard for the application of biomaterials in vivo.
Secondly, a zwitterionic polyCBAA biomimetic material was employed to create a unique biorecognition coating with an ultralow fouling background, enabling the sensitive and specific detection of proteins in blood plasma. Conditions for surface activation, protein immobilization, and surface deactivation of the carboxylate groups in the polyCBAA coating were determined. An antibody-functionalized polyCBAA surface platform was used to detect a target protein in blood plasma using a sensitive surface plasmon resonance (SPR) sensor. A cancer biomarker (ALCAM) was directly detected from 100% human blood plasma with extraordinary specificity and sensitivity. The total nonspecific protein adsorption on the functionalized polyCBAA surface was very low (<3 ng/cm2 for undiluted blood plasma). Furthermore, functionalization on polyCBMA-grafted gold or silicon dioxide surfaces was also investigated.
Thirdly, nonspecific protein adsorption from single protein solutions and complex media such as undiluted human blood serum and plasma onto polyCBAA-grafted surfaces was investigated. The polyCBAA grafting was done via ATRP with varying film thicknesses at different temperatures. The objective is to create a surface that experiences“zero”protein adsorption from complex undiluted human blood serum and plasma. Results show that protein adsorption from undiluted blood serum, plasma, and aged serum on the polyCBAA-grafted surface is undetectable at both 25°C and 37°C by a SPR sensor. This was achieved with a film thickness of ~20 nm. Further it is demonstrated that the polyCBAA surfaces after antibody immobilized maintain undetectable protein adsorption from undiluted human blood serum.
Finally, a new surface platform presenting an abundance of functional groups for ligand immobilization in an ultra-low fouling background necessary for targeted drug delivery and diagnostics was introduced. It is demonstrated that this surface platform, made from zwitterionic polyCBAA coated nanoparticles, is not only stable in undiluted human blood serum, but also can be conjugated to bio-molecules conveniently and effectively. In addition, a practical application was demonstrated by showing the amount of antibodies to a candidate cancer biomarker immobilized onto polyCBAA-coated nanoparticles can be easily adjusted. Results also indicate that 10% serum commonly used to evaluate the stability of nanoparticles is not sufficient and undiluted blood serum is recommended to screen nanoparticles before their in vivo experiments.
引文
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