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

Autor: Otvagin VF; Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation. Electronic address: votvagin@yandex.ru., Krylova LV; Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation., Peskova NN; Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation., Kuzmina NS; Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation., Fedotova EA; Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation., Nyuchev AV; Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation., Romanenko YV; Research Institute of Macroheterocycles, Ivanovo State University of Chemical Technology, 153000, Ivanovo, Russian Federation., Koifman OI; Research Institute of Macroheterocycles, Ivanovo State University of Chemical Technology, 153000, Ivanovo, Russian Federation., Vatsadze SZ; N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow, 119991, Russian Federation., Schmalz HG; Department of Chemistry, University of Cologne, Greinstrasse 4, 50939, Cologne, Germany., Balalaeva IV; Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation. Electronic address: irin-b@mail.ru., Fedorov AY; Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation. Electronic address: afedorovnn@yandex.ru.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Apr 05; Vol. 269, pp. 116283. Date of Electronic Publication: 2024 Mar 05.
DOI: 10.1016/j.ejmech.2024.116283
Abstrakt: 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-e 6 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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