2. Academic Validation
  3. Peripheral structural engineering of quinoline-malononitrile-triphenylamine (QM-TPA) core enhances Anti-tumor PDT efficacy through necroptosis

Peripheral structural engineering of quinoline-malononitrile-triphenylamine (QM-TPA) core enhances Anti-tumor PDT efficacy through necroptosis

  • Eur J Med Chem. 2026 Oct 5:315:118962. doi: 10.1016/j.ejmech.2026.118962.
Linjun Fang 1,  Fengkai Qiu 2,  You Wu 3,  Haifeng Li 3,  Shizhen Zhang 4,  Shi-Yu Liu 1,  Jiaan Shao 5,  Yong Shen 6,  Wenteng Chen 7
Affiliations

Affiliations

  • 1 Hangzhou Lin'an Traditional Chinese Medicine Hospital, Affiliated Hospital, Hangzhou City University, Hangzhou, 311300, China.
  • 2 School of Medicine, Hangzhou City University, Hangzhou, 310015, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 3 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 4 Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
  • 5 Hangzhou Lin'an Traditional Chinese Medicine Hospital, Affiliated Hospital, Hangzhou City University, Hangzhou, 311300, China; School of Medicine, Hangzhou City University, Hangzhou, 310015, China. Electronic address: [email protected].
  • 6 Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. Electronic address: [email protected].
  • 7 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. Electronic address: [email protected].
PMID: 42142454 DOI: 10.1016/j.ejmech.2026.118962
Abstract

To circumvent the limitations of aggregation-caused quenching (ACQ) associated with conventional photosensitizers (PSs), we sought to develop PSs based on aggregation-induced emission luminogens (AIEgens). Through molecular hybridization of a quinoline-malononitrile (QM) acceptor and a triphenylamine (TPA) unit, along with systematic SAR exploration of N-atom substitutions on the QM core, we generated a series of AIE-active PSs. Among these, A04 emerged as the lead, exhibiting potent Type I ROS generation, a high safety profile (selectivity index >158), and remarkable specificity for the endoplasmic reticulum (ER) (Pearson correlation coefficient = 0.91). Critically, this subcellular localization underpins its mechanism of action: by generating ROS within the ER, A04 induces Necroptosis. Consequently, A04 demonstrates robust antitumor PDT activity both in vitro and in a 4T1 murine model. This study thus validates A04 as a therapeutically promising, rationally designed AIEgen-PS.

Keywords

AIE photosensitizer; Endoplasmic reticulum accumulation; Necroptosis; Quinoline–malononitrile; Structural engineering.

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