Controlled sequential in situ self-assembly and disassembly of a fluorogenic cisplatin prodrug for cancer theranostics

Xidan Wen, Rui Zhang, Yuxuan Hu, Luyan Wu, He Bai, Dongfan Song, Yanfeng Wang, Ruibing An, Jianhui Weng, Shuren Zhang, Rong Wang, Ling Qiu, Jianguo Lin, Guandao Gao, Hong Liu (), Zijian Guo () and Deju Ye ()
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Xidan Wen: Nanjing University
Rui Zhang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yuxuan Hu: Nanjing University
Luyan Wu: Nanjing University
He Bai: Nanjing University
Dongfan Song: Nanjing University
Yanfeng Wang: Nanjing University
Ruibing An: Nanjing University
Jianhui Weng: Nanjing University
Shuren Zhang: Nanjing University
Rong Wang: Nanjing University
Ling Qiu: Jiangsu Institute of Nuclear Medicine
Jianguo Lin: Jiangsu Institute of Nuclear Medicine
Guandao Gao: Nanjing University
Hong Liu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Zijian Guo: Nanjing University
Deju Ye: Nanjing University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Temporal control of delivery and release of drugs in tumors are important in improving therapeutic outcomes to patients. Here, we report a sequential stimuli-triggered in situ self-assembly and disassembly strategy to direct delivery and release of theranostic drugs in vivo. Using cisplatin as a model anticancer drug, we design a stimuli-responsive small-molecule cisplatin prodrug (P-CyPt), which undergoes extracellular alkaline phosphatase-triggered in situ self-assembly and succeeding intracellular glutathione-triggered disassembly process, allowing to enhance accumulation and elicit burst release of cisplatin in tumor cells. Compared with cisplatin, P-CyPt greatly improves antitumor efficacy while mitigates off-target toxicity in mice with subcutaneous HeLa tumors and orthotopic HepG2 liver tumors after systemic administration. Moreover, P-CyPt also produces activated near-infrared fluorescence (at 710 nm) and dual photoacoustic imaging signals (at 700 and 750 nm), permitting high sensitivity and spatial-resolution delineation of tumor foci and real-time monitoring of drug delivery and release in vivo. This strategy leverages the advantages offered by in situ self-assembly with those of intracellular disassembly, which may act as a general platform for the design of prodrugs capable of improving drug delivery for cancer theranostics.

Date: 2023
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DOI: 10.1038/s41467-023-36469-1

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