2026-05-08T19:56:54Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/199332024-09-27T08:01:34Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Klemt, Insa author Reshetnikov, Viktor author Dutta, Subrata author Bila, Galyna author Bilyy, Rostyslav author Cuartero, Itziar Cossío author Hidalgo, Andres author Wünsche, Adrian author Böhm, Maximilian author Wondrak, Marit author Kunz-Schughart, Leoni A author Tietze, Rainer author Beierlein, Frank author Imhof, Petra author Gensberger-Reigl, Sabrina author Pischetsrieder, Monika author Körber, Marlies author Jost, Tina author Mokhir, Andriy author 2024-04-24 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. RSC Med Chem. 2024 Jan 31;15(4):1189-1197. 10.1039/d3md00609c 2632-8682 RSC medicinal chemistry 38665843 http://hdl.handle.net/20.500.12105/19933 A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin.