基于聚合物纳米颗粒的光学离子传感器的构建及其性能研究

各类离子的定性与定量分析在生物化学、临床诊断、环境科学、法医学物证检验和工业生产等领域均具有重要意义。在众多的离子检测工具中，基于聚合物纳米颗粒的光学离子传感器因其在微小空间（如细胞内）能够实现无创检测而备受关注。该传感器具有灵敏度高、响应速度快、生物相容性好、化学稳定性高以及可兼容生物成像等特点。尽管如此，相关分析方法的开发仍面临许多技术挑战。例如，许多传感器的测试结果可信度较差，这是由于其线性响应范围无法覆盖目标离子的宽分布浓度，或是其选择性无法应对成分复杂且动态变化的实际样品所造成的。本论文针对不同目标离子的分析方法的局限性，开发了新型传感策略、设计与合成了一种可兼容于聚合物纳米颗粒的高选择性新型离子探针并且构建了一系列基于聚合物纳米颗粒的光学离子传感器，详细研究了它们的性能与传感机理，并对其应用进行了探索与拓展。主要研究内容和结果如下：

通过在聚合物纳米颗粒中仅负载单一组分亲脂性pH指示剂（生色离子载体III，CH3）制备了荧光自比率型纳米传感器，其线性响应区间（pH 3.0–7.0）可完全覆盖细胞内吞途径中核内体-溶酶体的氢离子浓度范围。该传感器具有独特的pH响应特性，在纳米尺度的有机相-液相界面上，光谱重叠与染料堆积引起了颗粒内部多种Förster共振能量转移过程（FRET）。这种能量转移不仅发生在CH3质子化和去质子化状态之间（hetero-FRET），还发生在其自身之间（homo-FRET）。界面响应机制模拟的pH响应表明了响应的动态范围依赖于纳米颗粒的尺寸（半径，r）与染料的分布情况（分配系数，Kp）。因此，通过调整传感器的尺寸与局部染料浓度即可产生一系列不同的动态传感范围（仅基于单一指示剂表观pKa在4.4–9.6可调）。作为概念验证，该纳米传感器被成功递送于HeLa细胞用于核内体-溶酶体中的亚细胞pH监测，确定了溶酶体的平均pH约为4.7，并成功可视化了溶酶体膜通透性（LMP）与液泡型H+-ATP酶抑制引起的pH中性化过程。

提出了一种在平衡模式下快速（10 s以内）检测聚离子鱼精蛋白与肝素的光学检测方法，通过将带电生色离子载体与离子交换剂负载于乳化聚合物纳米颗粒中，进一步将pH指示剂（生色离子载体）开发成可在界面上检测聚离子的工具。该方法具有高灵敏度、可调的线性传感范围（0–4.0 mg/L，i.e.，0.68 unit/mL，检测限为0.1 mg/L）且响应平衡时间较传统基于膜型或纸基型的方法（10 h以上）显著缩短。作为概念验证，肝素纳米传感器在十倍稀释的血清中高灵敏度比色检测的线性响应范围（1.0–13.0 mg/L，i.e.，0.17–2.21 unit/mL）可完全覆盖肝素的临床相关浓度（10–100 mg/L）。这些改进的特性主要归功于该传感器的小尺寸效应以及在纳米尺度液-液界面上的可逆识别机制。

设计了一种可兼容于聚合物纳米颗粒的新型Cu2+探针（HTI-Q），该探针具有高选择性、高灵敏度且检测限（LOD）约为0.02 μM。HTI-Q以半硫靛蓝和8-羟基喹啉为骨架，其设计受可见光响应的光开关启发。HTI-Q的中心碳-碳双键在Z和E构型之间可在470 nm光照下进行光致异构，但是当与Cu2+以2:1的结合比络合时易旋转的中心碳-碳双键会被锁定在E构型，并伴随吸收光谱102 nm的大红移与比率型荧光变化，其等吸收点为481 nm。此外，其在470 nm光照下的吸光度变化也受Cu2+浓度影响。HTI-Q可兼容于多种传感模式，包括混合溶剂、含离子交换剂的两相传感体系以及含参比染料的荧光纳米传感器。作为概念验证，基于HTI-Q的传感器被成功应用于实际水样中Cu2+监测并具有良好的回收率（97–102 %）；负载HTI-Q的荧光纳米传感器实现了在外部刺激下RAW264.7细胞核内体-溶酶体中Cu2+浓度变化的可视化。

The qualitative and quantitative analysis of various ions is in high demand and of great importance in biochemistry, clinical diagnostics, environmental science, forensic evidence testing and industrial production. Among the tools for ion detection, optical ion sensors based on polymeric nanoparticles, which can be used for non-invasive detection in tiny spaces such as cells, have attracted much attention for their high sensitivity, fast response time, biocompatibility and chemical stability, as well as compatibility with bioimaging, but the development of relevant analytical methods still faces many technical challenges. For example, the linear response range of many sensors cannot cover a wide distribution of target ion concentrations or their selectivity cannot cope with the complex and dynamic composition of real samples, making the reliability of the results questionable. In this thesis, novel sensing strategies are developed to address the limitations of different target ion analysis methods, a new highly selective ion probe compatible with polymer nanoparticles is designed and synthesised, and a series of optical ion sensors based on polymeric nanoparticles are constructed, their performance and sensing mechanisms are investigated in detail, and their applications are explored and extended. The main research contents and results are summarized as follows:

Nanosensors with a linear response range (pH 3.0–7.0) covering the full range of hydrogen ion concentrations in the endolysosomal pathway were prepared by encapsulating polymeric nanoparticles with only a single component of a lipophilic pH indicator (chromoionophore III, CH3). The sensor has unique pH response at the aqueous-organic interface, where spectral overlap and dye accumulation caused multiple Förster resonance energy transfer processes (FRET) within the nanoparticle that occur not only between the protonated and deprotonated CH3 (hetero-FRET), but also between themselves (homo-FRET). The pH response was simulated according to an interfacial response mechanism and the dynamic range was found to depend on the

size of the nanoparticles and dye distribution(K_p). Therefore, adjusting the size of the nanoparticles and the local dye concentration gave rise to a series of dynamic sensing ranges with apparent pKa values from 4.4 to 9.6 based on a single indicator. As a proof of concept, the nanosensors were successfully delivered to HeLa cells to monitor subcellular pH values in the endosomes and lysosomes. Based on cellular calibrations, the average pH in the organelles were determined to be ca. 4.7. Moreover, the pH neutralization process during lysosome membrane permeabilization (LMP) and vesicular H⁺-ATPase inhibition was also successfully visualized with the nanosensors.

An optical detection method based on emulsified polymer nanospheres encapsulated with charged chromoionophores and ion exchangers is proposed for the rapid (within 10 s) equilibrated detection of protamine and heparin, further developing the pH indicator (chromoionophores) as a tool for detecting polyions at the aqueous-organic interface. The method has a tunable linear sensing range (0–4.0 mg/L, i.e., 0.68 unit/mL, limit of detection 0.1 mg/L), high sensitivity and significantly shorter response times than previous membrane-based or paper-based methods (10 h+). As a proof of concept, the linear response range of the heparin nanosensors for highly sensitive colorimetric detection in serum (1.0–13.0 mg/L, i.e., 0.17–2.21 unit/mL) takes into account that ten-fold dilutions can fully cover clinically relevant concentrations of heparin (10–100 mg/L). The improved characteristics are attributable to the small size of the nanospheres as well as the reversible recognition at the nanoscale liquid−liquid interface.

A new Cu²⁺ probe (HTI-Q) with a hemithioindigo and 8-hydroxyquinoline backbone compatible with polymeric nanoparticles was designed with excellent selectivity, high sensitivity, and a limit of detection (LOD) of ca. 0.02 μM. The design of the probe was inspired by a family of visible light responsive photoswitchable compounds. While the central carbon-carbon double bond of HTI-Q is photoisomerizable between the Z and E configurations at 470 nm light, it is locked upon binding with Cu²⁺ in a 2:1 stoichiometry into the E configuration, resulting in a large bathochromic shift (102 nm) and ratiometric fluorescence changes with an isosbestic point at 481 nm. The absorbance change of HTI-Q upon 470 nm light illumination also depended on the concentration of Cu²⁺. Different sensing modes were demonstrated including in mixed solvents, a two-phase sensing system containing cation exchanger, and fluorescent nanoprobes containing a reference dye. As a proof of concept, HTI-Q-based sensors were successfully applied to determine Cu²⁺ in real water samples with excellent recovery (97–102 %). Further, fluorescent nanoprobes incorporating HTI-Q were successfully applied to image endolysosomal Cu²⁺ changes upon external stimulation.

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