A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin†
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics
Insa Klemt, Viktor Reshetnikov, Subrata Dutta, Galyna Bila, Rostyslav Bilyy, Itziar Cossío Cuartero, Andrés Hidalgo, Adrian Wünsche, Maximilian Böhm, Marit Wondrak, Leoni A. Kunz-Schughart, Rainer Tietze, Frank Beierlein, Petra Imhof, Sabrina Gensberger-Reigl, Monika Pischetsrieder, Marlies Körber, Tina Jost and Andriy Mokhir
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引用次数: 0
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.
期刊介绍:
Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry.
In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.