基于发光聚合物纳米颗粒的葡萄糖传感器及活体监测研究

糖尿病是一种以持续的高血糖水平为疾病特征的代谢类疾病。长期的高血糖会导致如心脏病、高血压、肾衰竭和失明等多种并发症。因此，严格的血糖控制成为糖尿病治疗中最为关键的一环。指尖采血法是临床上应用最广泛的葡萄糖检测方法。虽然检测精度较高，但仅能间歇性地提供葡萄糖浓度信息。相比之下，连续监测血糖技术可实时测量血糖的变化，并在血糖异常时及时发出警告，有助于使患者在饮食和用药方面做出更明智的决策。

目前市售的连续血糖监测设备多为植入皮下的电化学传感器，虽能够量化组织液中葡萄糖的浓度，但其电极在生理环境中容易退化导致灵敏度下降，造成传感器需频繁更换，对患者造成了更大的经济负担和更高的感染风险。近些年，光学传感器由于其高灵敏度与良好的生物相容性等优点，在生命科学与临床研究中表现出极大的应用潜力，为开发新型的连续血糖监测技术提供了全新的视野。

聚合物纳米颗粒（Polymer nanoparticles，NPs）具有高荧光亮度、良好的稳定性和优异的生物相容性，近年来被广泛应用于生物医学领域。本论文开发了一类基于聚合物纳米颗粒的光学葡萄糖传感器，用于小鼠体内葡萄糖水平的连续监测。具体成果如下：

本文首先设计了一种在近红外区发射的光学聚合物纳米颗粒葡萄糖传感器，该传感器能够在实现体内葡萄糖连续监测的同时，实现小鼠的脑部葡萄糖摄取的定量检测。使用尼罗红（Nile Red）和铂卟啉染料构建氧敏感磷光探针，随后将该探针与葡萄糖氧化酶（Glucose oxidase，GOx）共价结合，产生对葡萄糖浓度高度敏感的近红外磷光。该葡萄糖传感器不仅在体内长期连续血糖监测中具有较好的检测准确度，其平均绝对相对差值（Mean absolute relative difference，MARD）达到10.7%，而且能够量化小鼠脑部葡萄糖的摄取率，检测转基因脑瘤小鼠脑部葡萄糖代谢的异常，实现正常小鼠与脑瘤小鼠的区分。

为了提高葡萄糖传感器的稳定性和制备可重复性，进一步开发了卟啉共价的聚合物纳米颗粒葡萄糖传感器进行体内连续血糖监测研究。与传统的染料掺杂的方式不同，该传感器中金属卟啉被共价连接在聚合物骨架中。该方法可以提高粒子内能量转移效率，同时克服聚合物纳米颗粒制备和贮存过程中染料聚集的问题。与金属卟啉掺杂的纳米颗粒相比，金属卟啉共价连接的纳米颗粒具有更小的批次间差异，更高的磷光量子效率和更好的稳定性。金属卟啉共价连接的纳米颗粒传感器在小鼠体内的长期连续血糖监测中也表现出了更高的葡萄糖检测准确度，其MARD值达到4.4%。

对葡萄糖氧化酶催化过程中的副产物过氧化氢对传感器性能的影响进行了探究。验证了过氧化氢对传感器的发光猝灭作用，同时能够降低葡萄糖氧化酶的催化效率，进而影响传感器的性能。对偶联的过氧化氢酶（Catalase，CAT）的活性及长期稳定性进行了表征。细胞毒性实验的结果表明，同时偶联葡萄糖氧化酶和过氧化氢酶可以显著提高纳米颗粒传感器的生物相容性。系统探究了葡萄糖、氧气和激光对传感器细胞毒性的影响。最后，证明与未偶联过氧化氢酶的葡萄糖传感器相比，过氧化氢酶可以大幅提高传感器在长期连续血糖监测中的灵敏度。偶联过氧化氢的葡萄糖传感器在植入小鼠体内28天后其灵敏度与未偶联过氧化氢的传感器相比提高了1.8倍。

综上所述，本研究首先制备了一种具有较大穿透深度的光学纳米颗粒葡萄糖传感器，用于体内长期葡萄糖连续监测和小鼠脑部葡萄糖摄取的动态成像和定量分析。为了进一步改善传感器的光学性能，将卟啉染料共价连接在共轭聚合物骨架中以提升传感器的稳定性和制备可重复性。随后系统研究了过氧化氢对基于葡萄糖氧化酶的葡萄糖传感系统的影响。证实了过氧化氢酶的偶联能够通过分解过氧化氢从而大幅提高传感器的稳定性、灵敏度和生物相容性，最终实现更优异的体内长期连续血糖监测性能。

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