A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin

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 H O (trigger T1), in th...

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Published inMedChemComm Vol. 15; no. 4; pp. 1189 - 1197
Main Authors Klemt, Insa, Reshetnikov, Viktor, Dutta, Subrata, Bila, Galyna, Bilyy, Rostyslav, Cuartero, Itziar Cossío, Hidalgo, Andrés, 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
Format Journal Article
LanguageEnglish
Published England Royal Society of Chemistry 24.04.2024
RSC
Subjects
Anticancer properties
Antineoplastic drugs
Antitumor activity
Antitumour agents
Biocompatibility
Camptothecin
Cancer
Cations
Chemistry
Drugs
Hydrogen peroxide
Intermediates
Leukocytes (neutrophilic)
Lipophilic
Neutropenia
Neutrophils
Oligomerization
Oligomers
Prodrugs
Side effects
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Summary: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 H O (trigger T1), in the majority of normal cells, it exists as an inactive oligomer. In cancer cells and in primed neutrophils (high H O ), 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 and , 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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These authors contributed equally.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d3md00609c