GSH/pH Dual-Responsive Organic Semiconducting Nanotheranostics for Real-Time Tracking of Drug Release and Efficient Combination Cancer Therapy

doi:10.6023/A26020043

Abstract

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

Cite this article

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.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 9

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

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

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)

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)

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

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)

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

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

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

References 32

[1]	Jain, R. K.; Stylianopoulos, T. Nat. Rev. Clin. Oncol. 2010, 7, 653. doi: 10.1038/nrclinonc.2010.139
[2]	Shi, J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Nat. Rev. Cancer 2017, 17, 20. doi: 10.1038/nrc.2016.108
[3]	Gomerdinger, V. F.; Nabar, N.; Hammond, P. T. Nat. Rev. Cancer 2025, 25, 657. doi: 10.1038/s41568-025-00847-2 pmid: 40751005
[4]	Chen, X.; Chen, F. Y.; Lu, Y.; Liu, Z.; Wang, L.-H. Adv. Sci. 2024, 11, 2404731. doi: 10.1002/advs.v11.36
[5]	Li, X.; Bottini, M.; Zhang, L.; Zhang, Z. ACS Nano 2019, 13, 176. doi: 10.1021/acsnano.8b05136
[6]	Roy, S.; Bag, N.; Bardhan, S.; Das, P. K. Adv. Drug Delivery Rev. 2023, 197, 114821. doi: 10.1016/j.addr.2023.114821
[7]	Luo, D.; Goel, S.; Liu, H. J.; Cai, W. ACS Nano 2017, 11, 12482. doi: 10.1021/acsnano.7b06578
[8]	Jiang, Q.; Nie, Y.; Chen, X.; He, Y. Adv. Funct. Mater. 2017, 27, 1701571. doi: 10.1002/adfm.v27.26
[9]	Mei, R.; Wang, Y.; Zhao, X.; Liu, G. Anal. Chem. 2021, 93, 16590. doi: 10.1021/acs.analchem.1c03949
[10]	Spiekhout, S.; Abeid, B. A.; Estrada, J. B.; Sharma, N. Ultrason. Sonochem. 2026, 128, 107806. doi: 10.1016/j.ultsonch.2026.107806
[11]	Zhao, Z.; He, Y.; Shi, C.; Li, X. Coord. Chem. Rev. 2026, 547, 217118. doi: 10.1016/j.ccr.2025.217118
[12]	Huang, X.; Lu, Y.; Guo, M.; Zhang, Y. Theranostics 2021, 11, 7546. doi: 10.7150/thno.56482
[13]	Wang, Y.; Meng, H. M.; Song, G.; Li, Z. ACS Appl. Polym. Mater. 2020, 2, 4258. doi: 10.1021/acsapm.0c00680
[14]	Li, W.; Yang, J.; Luo, L.; Zhang, H. Nat. Commun. 2019, 10, 3349. doi: 10.1038/s41467-019-11269-8
[15]	Hou, X.; Tao, Y.; Pang, Y.; Liu, Y. Int. J. Cancer 2018, 143, 3050. doi: 10.1002/ijc.v143.12
[16]	Ma, G. C.; Guo, C. X.; Wang, B. Acta Chim. Sinica 2021, 79, 967 (in Chinese). doi: 10.6023/A21040173
	(马光彩, 郭彩霞, 王博, 化学学报, 2021, 79, 967.) doi: 10.6023/A21040173
[17]	Tang, D.; Cui, M.; Karges, J.; Xiao, H. Adv. Mater. 2026, 38, e16008. doi: 10.1002/adma.v38.8
[18]	Yang, D. C.; Wen, L. F.; Du, L.; Wang, H. ACS Appl. Mater. Interfaces 2022, 14, 40546. doi: 10.1021/acsami.2c09071
[19]	Ma, M.; Zhang, Y.; Pu, K.; Tang, W. Chem. Soc. Rev. 2025, 54, 653. doi: 10.1039/D4CS00679H
[20]	Liu, Y.; Li, W.; Xu, M.; Zhang, Q. Nano Lett. 2026, 26, 2103. doi: 10.1021/acs.nanolett.5c05422
[21]	Marzuoli, C.; Pianetti, A.; Mancinelli, E.; Rossi, F. Adv. Sci. 2026, 13, e22894. doi: 10.1002/advs.v13.30
[22]	Xu, C.; Zhang, Y.; Liang, G.; Pu, K. Nat. Mater. 2025, 24, 1694. doi: 10.1038/s41563-025-02338-z
[23]	Xu, C.; Pu, K. Chem. Soc. Rev. 2021, 50, 1111. doi: 10.1039/D0CS00664E
[24]	Huang, Y. Q.; Li, J. Q.; Ding, G. C.; Zhang, R.; Liu, X. F.; Fan, Q. L.; Huang, W. Acta Chim. Sinica 2025, 83, 1324 (in Chinese). doi: 10.6023/A25050141
	(黄艳琴, 李佳启, 丁桂策, 张瑞, 刘兴奋, 范曲立, 黄维, 化学学报, 2025, 83, 1324.) doi: 10.6023/A25050141
[25]	Xu, Y.; Chen, J.; Tong, L.; Wang, H. J. Control. Release 2019, 293, 94. doi: 10.1016/j.jconrel.2018.11.016
[26]	Zhang, T.; Han, C.; Wei, C.; Li, Y. Chin. Chem. Lett. 2025, 37, 111566. doi: 10.1016/j.cclet.2025.111566
[27]	Liu, C.; Gu, X.; Li, L.; Wang, J. Adv. Funct. Mater. 2026, 36, e25442. doi: 10.1002/adfm.v36.26
[28]	Xu, Y.; Zhai, X.; Su, P.; Liu, Y. Theranostics 2020, 10, 5966. doi: 10.7150/thno.43090
[29]	Liang, J. N.; Fu, K. Q.; Zhou, R.; Zhang, L. Chem. J. Chin. Univ. 2025, 46, 58 (in Chinese).
	(梁家宁, 符开奇, 周瑞, 张林, 高等学校化学学报, 2025, 46, 58.)
[30]	Zhang, J.; Yang, C.; Zhang, R.; Chen, X. Adv. Funct. Mater. 2017, 27, e1605094.
[31]	Li, R.; Peng, F.; Cai, J.; Xu, L. Asian J. Pharm. Sci. 2020, 15, 311.
[32]	Ma, T.; Li, W.; Ye, J.; Zhang, Y. Nanoscale 2023, 15, 16947. doi: 10.1039/D3NR03881E

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