2. Academic Validation
  3. A first-in-class β-glucuronidase responsive conjugate for selective dual targeted and photodynamic therapy of bladder cancer

A first-in-class β-glucuronidase responsive conjugate for selective dual targeted and photodynamic therapy of bladder cancer

  • Eur J Med Chem. 2024 Apr 5:269:116283. doi: 10.1016/j.ejmech.2024.116283.
Vasilii F Otvagin 1,  Lubov V Krylova 2,  Nina N Peskova 2,  Natalia S Kuzmina 2,  Ekaterina A Fedotova 2,  Alexander V Nyuchev 2,  Yuliya V Romanenko 3,  Oscar I Koifman 3,  Sergey Z Vatsadze 4,  Hans-Günther Schmalz 5,  Irina V Balalaeva 6,  Alexey Yu Fedorov 7
Affiliations

Affiliations

  • 1 Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation. Electronic address: votvagin@yandex.ru.
  • 2 Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation.
  • 3 Research Institute of Macroheterocycles, Ivanovo State University of Chemical Technology, 153000, Ivanovo, Russian Federation.
  • 4 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow, 119991, Russian Federation.
  • 5 Department of Chemistry, University of Cologne, Greinstrasse 4, 50939, Cologne, Germany.
  • 6 Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation. Electronic address: irin-b@mail.ru.
  • 7 Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation. Electronic address: afedorovnn@yandex.ru.
PMID: 38461680 DOI: 10.1016/j.ejmech.2024.116283
Abstract

In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder Cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e6 photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a β-glucuronidase-responsive linker. Upon activation by β-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells. This activation was accompanied by the recovery of its fluorescence and the generation of Reactive Oxygen Species. Investigation of photodynamic and dark toxicity in vitro revealed that the novel conjugate had an excellent safety profile and was able to inhibit tumor cells proliferation at submicromolar concentrations. Additionally, combined therapy effects were also observed in 3D models of tumor growth, demonstrating synergistic suppression through the activation of both photodynamic and targeted therapy.

Keywords

Bladder cancer; Cabozantinib; Chlorin-e(6); Combination therapy; Photodynamic therapy; β-glucuronidase.

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