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 Full article

Journal

European Journal of Medicinal Chemistry
ISSN: 1768-3254 , E-ISSN: 0223-5234

Output data

Year: 2024, Volume: 269, Article number : 116283, Pages count : DOI: 10.1016/j.ejmech.2024.116283

Authors

Otvagin Vasilii F. ¹ , Krylova Lubov V. ¹ , Peskova Nina N. ¹ , Kuzmina Natalia S. ¹ , Fedotova Ekaterina A. ¹ , Nyuchev Alexander V. ¹ , Romanenko Yuliya V. ² , Koifman Oscar I. ² , Vatsadze Sergey Z. ³ , Schmalz Hans-Günther ⁴ , Balalaeva Irina V. ¹ , Fedorov Alexey Yu ¹

Affiliations

1	Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation
2	Research Institute of Macroheterocycles, Ivanovo State University of Chemical Technology, 153000, Ivanovo, Russian Federation
3	N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow, 119991, Russian Federation
4	Department of Chemistry, University of Cologne, Greinstrasse 4, 50939, Cologne, Germany

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.

Otvagin V.F. , Krylova L.V. , Peskova N.N. , Kuzmina N.S. , Fedotova E.A. , Nyuchev A.V. , Romanenko Y.V. , Koifman O.I. , Vatsadze S.Z. , Schmalz H-G. , Balalaeva I.V. , Fedorov A.Y.
A first-in-class β-glucuronidase responsive conjugate for selective dual targeted and photodynamic therapy of bladder cancer
European Journal of Medicinal Chemistry. 2024. V.269. 116283 . DOI: 10.1016/j.ejmech.2024.116283 WOS Scopus OpenAlex

Web of science:	WOS:001222292200001
Scopus:	2-s2.0-85186966396
OpenAlex:	W4392462824

DB	Citing
OpenAlex	12
Scopus	12
Web of science	10