GSH/pH双响应有机半导体纳米诊疗剂用于药物释放实时追踪与肿瘤高效联合治疗

doi:10.6023/A26020043

摘要/Abstract

如何实现纳米药物在肿瘤微环境释放过程的实时监测对肿瘤精准治疗具有重要意义. 本工作构建了一种具有谷胱甘肽(GSH)/pH双响应特性的有机半导体聚合物纳米诊疗剂, 实现了模拟肿瘤微环境响应下药物释放的实时监测及光热-化疗协同增强治疗. 纳米体系以双(2-甲基丙烯)乙氧基二硫(BMOD)为交联剂, N-异丙基丙烯酰胺(NIPAM)和丙烯酸(AA)为共聚单体, 采用半互穿网络交联策略构建GSH/pH双响应型有机半导体纳米诊疗剂(PDPP3T NSs). 在此基础上, 将近红外荧光染料Cy5作为药物释放示踪分子, 与化疗药物阿霉素(Doxorubicin, DOX)共负载于PDPP3T NSs, 构建出有机半导体纳米诊疗剂PDPP3T@Cy5@DOX NSs. 在PDPP3T@Cy5@DOX NSs中, Cy5的荧光信号处于“屏蔽”状态, 当PDPP3T@Cy5@DOX NSs在肿瘤微环境中受到低pH和高GSH条件触发后, 引起DOX与Cy5的同步释放, Cy5荧光信号逐渐恢复并与DOX的释放量呈现良好的相关性, 从而实现对药物释放过程的实时监测. 此外, PDPP3T NSs具有优异的近红外光热转换性能, 与DOX化疗产生协同作用, 从而有效增强肿瘤治疗效果. 本研究通过将药物释放监测、肿瘤微环境响应和光热-化疗协同治疗集成于同一有机半导体纳米平台中, 为纳米诊疗一体化体系的构建提供了一种新的思路.

关键词: 有机半导体聚合物, pH/GSH双响应, 实时监测, 联合治疗

Real-time monitoring of drug release from nanomedicines is significantly important for precise cancer therapy. Herein, we developed a glutathione (GSH)/pH dual-responsive organic semiconducting polymer-based nanotheranostic agent. This agent enables real-time tracking of drug release and enhances synergistic photothermal-chemotherapy under tumor microenvironmental conditions. We used Bis(2-methacryloyl)oxyethyl disulfide (BMOD) as a crosslinker and N-isopropylacrylamide (NIPAM) and acrylic acid (AA) as comonomers. The GSH/pH dual-responsive organic semiconducting nanotheranostic agent (PDPP3T NSs) was then formed via a semi-interpenetrating network (semi-IPN) crosslinking strategy. The near-infrared fluorescent dye Cy5, serving as a drug-release tracking probe, and the chemotherapeutic agent doxorubicin (DOX) were co-loaded into the PDPP3T NSs to fabricate the organic semiconducting nanotheranostic agent PDPP3T@Cy5@DOX NSs. In the intact PDPP3T@Cy5@DOX NSs, the fluorescence of Cy5 was initially in a “quenched” state. Upon exposure to the acidic and GSH-rich tumor microenvironment, the dual-responsive behavior of the nanoplatform triggered the synchronous release of DOX and Cy5, leading to a gradual recovery of Cy5 fluorescence that correlated well with the amount of DOX released, thereby enabling real-time monitoring of the drug-release process. In addition, PDPP3T NSs exhibited excellent near-infrared photothermal conversion performance, which synergized with DOX chemotherapy to effectively enhance antitumor therapeutic efficacy. By integrating drug-release monitoring, tumor microenvironment responsiveness, and synergistic photothermal-chemotherapy within a single organic semiconducting nanoplatform, this study provides a promising strategy for the development of advanced nanotheranostic systems for precise cancer therapy.

Key words: organic semiconducting polymer, pH/GSH dual-responsive, real-time monitoring, combination therapy

引用此文

鲍碧清, 李欣珂, 李思雨, 李智烁, 张晶晶. GSH/pH双响应有机半导体纳米诊疗剂用于药物释放实时追踪与肿瘤高效联合治疗[J]. 化学学报, 2026, 84(7): 1057-1066.

Biqing Bao, Xinke Li, Siyu Li, Zhishuo Li, Jingjing Zhang. GSH/pH Dual-Responsive Organic Semiconducting Nanotheranostics for Real-Time Tracking of Drug Release and Efficient Combination Cancer Therapy[J]. Acta Chimica Sinica, 2026, 84(7): 1057-1066.

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图/表 9

图1. PDPP3T@Cy5@DOX NSs的制备及其对DOX释放过程的实时监测示意图

Figure 1. Schematic mechanism of PDPP3T@Cy5@DOX NSs for real-time monitoring of DOX release

图2. (A) PDPP3T NSs的粒径分布图; (B) PDPP3T NSs的透射电子显微镜(TEM)图像; (C) PDPP3T NPs和PDPP3T NSs的紫外吸收光谱; (D) PDPP3T NSs在不同溶液中尺寸随时间变化情况

Figure 2. (A) DLS data of PDPP3T NSs. (B) Transmission electron microscopy (TEM) image of PDPP3T NSs. (C) UV-Vis absorption spectra of PDPP3T NPs and PDPP3T NSs. (D) The hydrodynamic diameter of PDPP3T NSs as a function of storage time

图3. (A) PDPP3T NSs的光热升温图像; (B)不同浓度和(C)不同激光功率照射下PDPP3T NSs的光热升温曲线; (D) PDPP3T NSs的光热循环稳定性. 数据以均值±标准差表示(n=3)

Figure 3. (A) IR thermal images of PDPP3T NSs and water with 808 nm laser irradiation. Temperature elevation of PDPP3T NSs (B) at various concentrations under 808 nm irradiation at 1 W/cm2 and (C) with different laser power densities at 40 μg/mL. (D) Photothermal stability of PDPP3T NSs with 808 nm laser irradiation at 20 μg/mL. Data are presented as means±SD (n=3)

图4. (A)不同pH条件下阿霉素(DOX)的释放行为; (B)谷胱甘肽(GSH)处理下阿霉素(DOX)的释放行为

Figure 4. (A) Dox release behavior of PDPP3T@Cy5@DOX NSs in different pH values of PBS buffer respectively. (B) GSH-triggered DOX release of PDPP3T@Cy5@DOX NSs at PBS (pH 7.4)

图5. (A) GSH处理不同时间下PDPP3T@Cy5@DOX NSs的荧光发射光谱. (B) GSH处理后不同时间点PDPP3T@Cy5@DOX NSs在675 nm处的荧光发射峰强度变化. (C) GSH处理后不同时间点PDPP3T@Cy5@DOX NSs中DOX的累积释放曲线. (D)在GSH存在条件下, DOX释放百分比与Cy5荧光强度增加倍数之间的线性关系拟合

Figure 5. (A) Fluorescence emission spectrum of PDPP3T@Cy5@DOX NSs in PBS after the addition of GSH. (B) Intensity of the 675 nm emission peak of PDPP3T@Cy5@DOX NSs in the presence of GSH at diﬀerent times. (C) Time-dependent proﬁle of cumulative release of DOX from PDPP3T@Cy5@DOX NSs in the presence of GSH measured by UV-vis spectrophotometer. (D) Linear curve fitting between the percentage of released DOX and the increased fluorescence intensity of Cy5 in the presence of GSH

图6. (A) PDPP3T@Cy5@DOX NSs在pH 5.4缓冲液中的荧光发射光谱. (B)不同时间点PDPP3T@Cy5@DOX NSs溶液在675 nm处的荧光发射峰强度变化(pH 5.4). (C) PDPP3T@Cy5@DOX NSs中DOX的累积释放曲线(pH 5.4). (D) DOX释放百分比与Cy5荧光强度增加倍数之间的线性关系拟合(pH 5.4)

Figure 6. (A) Fluorescence emission spectrum of PDPP3T@Cy5@DOX NSs in PBS buffer (pH 5.4). (B) Intensity of the 675 nm emission peak of PDPP3T@Cy5@DOX NSs in PBS buffer (pH 5.4) at diﬀerent times. (C) Time-dependent proﬁle of cumulative release of DOX from PDPP3T@Cy5@DOX NSs in PBS buffer (pH 5.4). (D) Linear curve fitting between the percentage of released DOX and the increased fluorescence intensity of Cy5 in PBS buffer (pH 5.4)

图7. (A) GSH处理后, PDPP3T@Cy5@DOX NSs PBS溶液(pH 5.4)的荧光发射光谱. (B) GSH处理后不同时间点PDPP3T@Cy5@DOX NSs在675 nm处的荧光发射峰强度变化(pH 5.4). (C) GSH处理后不同时间点PDPP3T@Cy5@DOX NSs中DOX的累积释放曲线(pH 5.4). (D)在GSH存在条件下, DOX释放百分比与Cy5荧光强度增加倍数之间的线性关系拟合

Figure 7. (A) Fluorescence emission spectrum of PDPP3T@Cy5@DOX NSs in PBS after the addition of GSH (pH 5.4). (B) Intensity of the 675 nm emission peak of PDPP3T@Cy5@DOX NSs in the presence of GSH at diﬀerent times (pH 5.4). (C) Time-dependent proﬁle of cumulative release of DOX from PDPP3T@Cy5@DOX NSs in the presence of GSH measured by UV-vis spectrophotometer (pH 5.4). (D) Linear curve fitting between the percentage of released DOX and the increased fluorescence intensity of Cy5 in the presence of GSH

图8. (A) PDPP3T NSs对4T1细胞的毒性; (B) PDPP3T@Cy5@DOX NSs的光热效果

Figure 8. (A) Cytotoxicity of PDPP3T NSs on 4T1 cells. (B) Photothermal effect of PDPP3T@Cy5@DOX NSs on 4T1 cells

图9. (A) 4T1细胞与PDPP3T@Cy5@DOX NSs孵育不同时间的共聚焦荧光图像; (B) 4T1细胞与PDPP3T@Cy5@DOX NSs孵育不同时间的荧光强度曲线图

Figure 9. (A) Fluorescence images of 4T1 cells incubated with PDPP3T@Cy5@DOX NSs for different times at 37 ℃. (B) Quantitative data of the fluorescence signal in 4T1 cells incubated with PDPP3T@Cy5@DOX NSs

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