Novel Type-I Carbazole/Benz[cd]indolium Photosensitizers for High-Efficient Chemo/Photodynamic/Immune Multimodal Therapy of Hypoxic Tumor

  • Bioconjug Chem. 2026 May 20;37(5):1047-1057. doi: 10.1021/acs.bioconjchem.6c00147.
Weiwei Gong  1 ,  Yangyang Jiang  1  2 ,  Dongliang Ji  2  3  4 ,  Ke Xu  2 ,  Yifan Ma  2 ,  Jiayang Cai  2 ,  Kang Yuan  2 ,  Yingxue Chang  2 ,  Dongwei Liu  2 ,  Pengbo Wang  2 ,  Tao Yang  4 ,  Yong Ling  2  3  4 ,  Xiao Liu  1  2  3
Affiliations
  • 1. Department of Pharmacy, Nantong First People's Hospital, Nantong 226001, Jiangsu Province, China.
  • 2. School of Pharmacy, Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu Province, China.
  • 3. School of Medical, Nantong University, Nantong 226001, Jiangsu Province, China.
  • 4. Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China.
PMID: 42012870 DOI: 10.1021/acs.bioconjchem.6c00147
Abstract

Photodynamic therapy (PDT) represents a promising therapeutic strategy for Cancer management, yet developing highly efficient photosensitizers (PSs) remains a significant challenge. Herein, a series of novel carbazole/benz[cd]indolium PSs (3a-c) were designed and synthesized through incorporating a strong electron-accepting benz[cd]indolium group with the carbazole, and their photodynamic Anticancer activities and associated mechanisms were evaluated. All compounds effectively induced the generation of Reactive Oxygen Species (ROS), while compound 3a was chiefly associated with a type-I pathway, leading mainly to the formation of superoxide anions (O2•-) and hydroxyl radicals (•OH), effectively mitigating oxygen dependence in PDT. The increased generation of type-I ROS in 3a is attributed to its higher intersystem crossing rate constant (kISC) compared to 3b and 3c. 3a exhibited significant antiproliferative activity in both normoxic and hypoxic environments (IC50s,light = 1.8-6.3 μM), underscoring its low-oxygen-dependent chemo/photodynamic therapeutic potential. In vivo experiments showed that 3a significantly inhibited breast Cancer tumor growth, achieving a 93.1% inhibition rate. Importantly, 3a triggered immunogenic cell death (ICD) in Cancer cells by enhancing oxidative stress, promoting dendritic cell (DC) maturation, and boosting T cell infiltration. Consequently, novel carbazole/benz[cd]indolium PSs, as low-oxygen-dependent type-I PSs, may show promise for chemo/photodynamic/immune multitherapy and warrant further preclinical investigation.

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