2. Academic Validation
  3. Novel chlorin e6-based conjugates of tyrosine kinase inhibitors: Synthesis and photobiological evaluation as potent photosensitizers for photodynamic therapy

Novel chlorin e6-based conjugates of tyrosine kinase inhibitors: Synthesis and photobiological evaluation as potent photosensitizers for photodynamic therapy

  • Eur J Med Chem. 2023 Sep 5:261:115787. doi: 10.1016/j.ejmech.2023.115787.
Fei Huang 1,  Yu Li 1,  Xing-Jie Zhang 1,  Mei-Yu Lin 1,  Gui-Yan Han 2,  Hui-Ying Lin 3,  Hui-Yun Lin 3,  Zhenyuan Miao 1,  Bu-Hong Li 4,  Chun-Quan Sheng 5,  Jian-Zhong Yao 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
  • 2 Qingdao Special Servicemen Recuperation Center of PLA Navy, Qingdao, 266000, China.
  • 3 Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fujian Normal University, Fuzhou, 350007, China.
  • 4 School of Science, Hainan University, 58 Renmin Avenue, Haikou, 570228, China. Electronic address: [email protected].
  • 5 School of Pharmacy, Second Military Medical University, Shanghai, 200433, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Second Military Medical University, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 37690263 DOI: 10.1016/j.ejmech.2023.115787
Abstract

Since tyrosine kinase inhibitor (TKI) could reverse ABCG2-mediated drug-resistance, novel chlorin e6-based conjugates of Dasatinib and Imatinib as photosensitizer (PS) were designed and synthesized. The results demonstrated that conjugate 10b showed strongest phototoxicity against HepG2 and B16-F10 cells, which was more phototoxic than chlorin e6 and Talaporfin. It could reduce efflux of intracellular PS by inhibiting ABCG2 in HepG2 cells, and localize in mitochondria, lysosomes, golgi and ER, resulting in higher cell Apoptosis rate and ROS production than Talaporfin. Moreover, it could induce cell Autophagy and block cell cycle in S phase, and significantly inhibit tumor growth and prolong survival time on BALB/c nude mice bearing HepG2 xenograft tumor to a greater extent than chlorin e6. Consequently, compound 10b could be applied as a promising candidate PS due to its good water-solubility and stability, low drug-resistance, high quantum yield of 1O2 and excellent antitumor efficacy in vitro and in vivo.

Keywords

ABCG2; Chlorin e(6); Photodynamic therapy (PDT); Photosensitizer; Tyrosine kinase inhibitors (TKI).

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