由自组装构筑蛋白酶响应性近红外/磁共振双显影微球

郭和泽; 宋晟; 戴婷婷; 李圣利; 窦红静

doi:10.11777/j.issn1000-3304.2018.18079

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由自组装构筑蛋白酶响应性近红外/磁共振双显影微球

研究论文 | 更新时间：2021-01-26

- 由自组装构筑蛋白酶响应性近红外/磁共振双显影微球
- Trypsin-responsive Near-infrared Fluorescent/Magnetic Resonance Dual-imaging Composite Nanospheres Based on Self-assembly
- 高分子学报 2018年0卷第8期页码：1127-1140
- 作者机构：
  
  1.上海交通大学材料科学与工程学院金属基复合材料国家重点实验室　上海 200240
  2.上海交通大学医学院附属第九人民医院上海市组织工程重点实验室　上海 200011
- 作者简介：
  
  E-mail: hjdou@sjtu.edu.cn Dou Hongjing, hjdou@sjtu.edu.cn
- 基金信息：
  
  国家自然科学基金(基金号 21374061，81501571和81371700)、上海高校特聘教授(东方学者)计划(项目号 SHDP201802)和上海市教委“曙光计划”(项目号 12SG12)资助()
- DOI：10.11777/j.issn1000-3304.2018.18079
  中图分类号：
- 纸质出版日期：2018-8，
  
  收稿日期：2018-3-12，
  
  修回日期：2018-4-16，
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郭和泽, 宋晟, 戴婷婷, 李圣利, 窦红静. 由自组装构筑蛋白酶响应性近红外/磁共振双显影微球[J]. 高分子学报, 2018,0(8):1127-1140.

He-ze Guo, Sheng Song, Ting-ting Dai, Sheng-li Li, Hong-jing Dou. Trypsin-responsive Near-infrared Fluorescent/Magnetic Resonance Dual-imaging Composite Nanospheres Based on Self-assembly[J]. Acta Polymerica Sinica, 2018,0(8):1127-1140.
郭和泽, 宋晟, 戴婷婷, 李圣利, 窦红静. 由自组装构筑蛋白酶响应性近红外/磁共振双显影微球[J]. 高分子学报, 2018,0(8):1127-1140. DOI： 10.11777/j.issn1000-3304.2018.18079.

He-ze Guo, Sheng Song, Ting-ting Dai, Sheng-li Li, Hong-jing Dou. Trypsin-responsive Near-infrared Fluorescent/Magnetic Resonance Dual-imaging Composite Nanospheres Based on Self-assembly[J]. Acta Polymerica Sinica, 2018,0(8):1127-1140. DOI： 10.11777/j.issn1000-3304.2018.18079.

摘要

由分子侧链上修饰近红外荧光分子的聚赖氨酸及表面聚丙烯酸修饰的磁共振显影磁性纳米颗粒为组装单元，采用自组装法构筑了在近红外、磁共振双重显影中均具有蛋白酶响应性的纳米尺度自组装微球. 微球形成的组装驱动力为聚赖氨酸侧链氨基与磁性纳米颗粒表面羧基在水相中的静电相互作用，两类组装前驱体在静电力作用下组装为纳米尺度团聚体，再通过戊二醛对氨基的适度交联来构筑胰蛋白酶响应的双显影复合微球. 该复合微球处于自组装聚集状态时，微球内近红外荧光分子间的距离减小从而发生荧光共振能量转移，导致荧光分子的自淬灭；而在胰蛋白酶活化后的解组装状态，微球内聚赖氨酸重复单元间的酰胺键被胰蛋白酶切断，荧光分子间距扩大，共振能量转移现象消失，从而导致复合微球在胰蛋白酶存在下释放荧光，荧光释放强度/淬灭强度的比值最高可达18. 此外，自组装微球的磁共振显影同样具有胰蛋白酶敏感性，这与组装—解组装过程导致微球内磁性纳米颗粒的局部浓度及聚集状态发生变化有关. 细胞和动物实验研究表明，复合微球呈现低细胞毒性，并可特异性地对胰蛋白酶阳性的细胞和组织进行近红外/磁共振双显影，在胰蛋白酶的生物影像学检测中具有潜在的应用前景.

Abstract

The trypsin-responsive near-infrared fluorescent/magnetic resonance dual-imaging composite nanospheres

which consist of PAA-decorated Fe

magnetic nanoparticles (MNPs) that serve as the magnetic resonance imaging (MRI) agents and Cy5.5-modified poly-L-lysine (Cy5.5-PLL) as the trypsin-responsive substrate and fluorescent carrier

were successfully fabricated

via

self-assembly method. The MNPs present negatively charge due to the carboxyl groups from PAA on their surface and the Cy5.5-PLL present positively charge due to the amino groups in PLL chains. The construction of the composite nanospheres was initially performed

via

the self-assembly driven by the electrostatic interactions between the above mentioned oppositely charged precursors. Subsequently

glutaraldehyde (GA) was introduced to partially crosslink the amino groups in PLL and stabilize the nanospheres. The fluorescent and magnetic characterization of the two precursors of the composite nanospheres

Cy5.5-PLL and MNPs

indicated that Cy5.5-PLL chains showed obvious fluorescent signal and the MNPs displayed the superparamagnetism property. However

the notable fluorescent signal from Cy5.5-PLL in native soluble state was self-quenched thanks to the short distance among the Cy5.5 fluorescent molecules after the construction of the nanospheres. Additionally

the structure of the as-prepared self-assembled nanospheres was stable

resulting from the almost unchanged results of the hydrodynamic size and fluorescence intensity of nanospheres in different buffer solutions. Nevertheless

because of the sensitivity of PLL chains to trypsin

the nanospheres were selectively disintegrated into fragmented segments under the hydrolysis by trypsin

leading to 18-fold amplification of fluorescent intensity in comparison with the self-assembled nanospheres in quenched state. Moreover

the magnetic resonance imaging enhancement was also related to the disintegration of the nanospheres. As expected

the trypsin-positive cells incubated with nanospheres exhibited remarkable fluorescent imaging due to the disintegration of the nanospheres into debris

whereas this disintegration did not take place for the trypsin-negative cells.

In vivo

fluorescent images of the composite nanospheres in normal nude mice further verified the trypsin-triggered fluorescent imaging. Cytotoxicity study demonstrated that the composite nanospheres presented low toxicity to several cell lines

and exhibited remarkable near-infrared fluorescent/magnetic resonance imaging capabilities

which were sensitive to the presence of trypsin and thus provided excellent opportunity to serve as dual-imaging agents.

关键词

聚赖氨酸蛋白酶响应性磁性纳米颗粒自组装近红外荧光/磁共振双显影

Keywords

Poly-L-lysineTrypsin-responsivityMagnetite nanoparticleSelf-assemblyNear-infrared fluorescent/MRI dual imaging

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