Novel tris-bipyridine based Ru(II) complexes as type-I/-II photosensitizers for antitumor photodynamic therapy through ferroptosis and immunogenic cell death

  • Eur J Med Chem. 2024 Sep 24:279:116909. doi: 10.1016/j.ejmech.2024.116909.
Hongwei Zheng  1 ,  Kai Wang  2 ,  Dongliang Ji  1 ,  Xiao Liu  1 ,  Chen Wang  1 ,  Yangyang Jiang  2 ,  Zihan Jia  2 ,  Biao Xiong  3 ,  Yong Ling  4 ,  Jiefei Miao  5
Affiliations
  • 1. Department of Oncology, Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong 226001, China; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China.
  • 2. School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China.
  • 3. School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China. Electronic address: [email protected].
  • 4. Department of Oncology, Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong 226001, China; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China. Electronic address: [email protected].
  • 5. Department of Oncology, Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong 226001, China; School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong Key Laboratory of Small Molecular Drug Innovation, Nantong University, Nantong 226001, China. Electronic address: [email protected].
PMID: 39357314 DOI: 10.1016/j.ejmech.2024.116909
Abstract

Ru(II) complexes have attracted attention as photosensitizers for their promising photodynamic properties. Herein, novel tris-bipyridine based Ru(II) complexes (6a-e) were synthesized by introducing saturated heterocycles to improve photodynamic properties and lipid-water partition coefficients. Among them, 6d demonstrated significant phototoxicity towards three Cancer cells, with IC50 values of 5.66-7.17 μM, exceeding values in dark (IC50s > 100 μM). Under hypoxic conditions, 6d maintained excellent photodynamic activity in A549 cells, with PI values exceeding 24, highlighting its potential for highly effective type-I/-II photodynamic therapy by inducing ROS generation, oxidative stress, and mitochondrial damage. Additionally, it induced Ferroptosis and immunogenic cell death of A549 cells by regulating the expression of relevant markers. Finally, 6d remarkably inhibited the growth of A549 transplanted tumor growth by 95.4 %. This Ru(II) complex shows great potential for Cancer treatment with its potent photodynamic activity and diverse mechanisms of tumor cell death.

Keywords
Antitumor activity; Ferroptosis; Photodynamic therapy (PDT); Ru(II) complexes; Tris-bipyridine.
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