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Peer-reviewedCC BY-NC-ND 4.0JACS Au

On-Demand Drug Release under Ultrasound Irradiation

  • Shiyang Chen1
  • Shirui Wang2
  • Raymond Tio2
  • Xiaolu Zhu1
  • Mengyao Liang1
  • Huitao Liu1
  • Teck-Peng Loh1,2
  • Peng Chen1
  • Zhenhua Jia3
  1. 1Henan University of Technology , , ,
  2. 2Nanyang Technological University , , ,
  3. 3Fudan University , , ,
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Abstract

Achieving precise, on-demand release of therapeutic agents remains a central challenge in pharmacology and chemical biology. In this work, we reported a modular prodrug release platform that employed low-intensity medical ultrasound (1 MHz, 2.5 W cm–2) to trigger the cleavage of carbamate and thiocarbamate linkers in aqueous media, enabling on-demand release of hydrophilic drug payloads. The linker was designed to couple drug release with the concurrent release of methylene blue (MB), allowing fluorescence measurements to track ultrasound-triggered linker cleavage and cargo release from the same molecular construct. Mechanistic studies including radical probes, EPR spectroscopy, Fenton validation, and intracellular DCFH-DA imaging supported the crucial role of cavitation-generated •OH and O2•– for the cleavage of the linkers. Furthermore, we evaluated payload compatibility using topotecan (TPT), an FDA-approved anticancer drug, and N-acetyl-l-cysteine as representative hydroxyl- and thiol-containing prodrugs, respectively. Ultrasound irradiation triggered TPT release and restored the cytotoxic activity of the masked prodrug in HeLa cells, whereas the nonactivated prodrug maintained >86% MCF-10A cell viability. Ex vivo studies also showed that ultrasound-triggered MB and TPT release remained detectable through porcine tissue barriers of 2.0 cm thickness, enabling controlled drug release with fluorescence-based monitoring and tissue-penetrating delivery.

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Cite

BibTeXRIS
BibTeX
@article{chen2026ondemand,
  title = {{On-Demand Drug Release under Ultrasound Irradiation}},
  author = {Shiyang Chen and Shirui Wang and Raymond Tio and Xiaolu Zhu and Mengyao Liang and Huitao Liu and Teck-Peng Loh and Peng Chen and Zhenhua Jia},
  journal = {JACS Au},
  year = {2026},
  month = nov,
  doi = {10.1021/jacsau.6c01395},
  url = {https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01395/5462552/On-Demand-Drug-Release-under-Ultrasound},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - On-Demand Drug Release under Ultrasound Irradiation
AU  - Shiyang Chen
AU  - Shirui Wang
AU  - Raymond Tio
AU  - Xiaolu Zhu
AU  - Mengyao Liang
AU  - Huitao Liu
AU  - Teck-Peng Loh
AU  - Peng Chen
AU  - Zhenhua Jia
PY  - 2026
DA  - 2026/11/03
JO  - JACS Au
DO  - 10.1021/jacsau.6c01395
UR  - https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01395/5462552/On-Demand-Drug-Release-under-Ultrasound
AB  - Achieving precise, on-demand release of therapeutic agents remains a central challenge in pharmacology and chemical biology. In this work, we reported a modular prodrug release platform that employed low-intensity medical ultrasound (1 MHz, 2.5 W cm–2) to trigger the cleavage of carbamate and thiocarbamate linkers in aqueous media, enabling on-demand release of hydrophilic drug payloads. The linker was designed to couple drug release with the concurrent release of methylene blue (MB), allowing fluorescence measurements to track ultrasound-triggered linker cleavage and cargo release from the same molecular construct. Mechanistic studies including radical probes, EPR spectroscopy, Fenton validation, and intracellular DCFH-DA imaging supported the crucial role of cavitation-generated •OH and O2•– for the cleavage of the linkers. Furthermore, we evaluated payload compatibility using topotecan (TPT), an FDA-approved anticancer drug, and N-acetyl-l-cysteine as representative hydroxyl- and thiol-containing prodrugs, respectively. Ultrasound irradiation triggered TPT release and restored the cytotoxic activity of the masked prodrug in HeLa cells, whereas the nonactivated prodrug maintained >86% MCF-10A cell viability. Ex vivo studies also showed that ultrasound-triggered MB and TPT release remained detectable through porcine tissue barriers of 2.0 cm thickness, enabling controlled drug release with fluorescence-based monitoring and tissue-penetrating delivery.
SN  - 2691-3704
ER  -