Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/19933
Title
A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin.
Author(s)
Klemt, Insa | Reshetnikov, Viktor | Dutta, Subrata | Bila, Galyna | Bilyy, Rostyslav | Cuartero, Itziar Cossío | Hidalgo, Andres CNIC | Wünsche, Adrian | Böhm, Maximilian | Wondrak, Marit | Kunz-Schughart, Leoni A | Tietze, Rainer | Beierlein, Frank | Imhof, Petra | Gensberger-Reigl, Sabrina | Pischetsrieder, Monika | Körber, Marlies | Jost, Tina | Mokhir, Andriy
Date issued
2024-04-24
Citation
RSC Med Chem. 2024 Jan 31;15(4):1189-1197.
Language
Inglés
Document type
journal article
Abstract
Many known chemotherapeutic anticancer agents exhibit neutropenia as a dose-limiting side effect. In this paper we suggest a prodrug concept solving this problem for camptothecin (HO-cpt). The prodrug is programmed according to Boolean "AND" logic. In the absence of H2O2 (trigger T1), e.g. in the majority of normal cells, it exists as an inactive oligomer. In cancer cells and in primed neutrophils (high H2O2), the oligomer is disrupted forming intermediate (inactive) lipophilic cationic species. These are accumulated in mitochondria (Mit) of cancer cells, where they are activated by hydrolysis at mitochondrial pH 8 (trigger T2) with formation of camptothecin. In contrast, the intermediates remain stable in neutrophils lacking Mit and therefore a source of T2. In this paper we demonstrated a proof-of-concept. Our prodrug exhibits antitumor activity both in vitro and in vivo, but is not toxic to normal cell and neutrophils in contrast to known single trigger prodrugs and the parent drug HO-cpt.
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