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

Klemt I, Reshetnikov V, Dutta S, Bila G, Bilyy R, Cuartero IC, Hidalgo A, Wünsche A, Böhm M, Wondrak M, Kunz-Schughart LA, Tietze R, Beierlein F, Imhof P, Gensberger-Reigl S, Pischetsrieder M, Körber M, Jost T, Mokhir A (2024)

Publication Type: Journal article, Original article

Publication year: 2024

Journal

RSC Medicinal Chemistry Royal Society of Chemistry

DOI: 10.1039/d3md00609c

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.

Authors with CRIS profile

Insa Klemt Lehrstuhl für Organische Chemie II Viktor Reshetnikov Lehrstuhl für Organische Chemie II Subrata Dutta Lehrstuhl für Organische Chemie II Adrian Wünsche Lehrstuhl für Organische Chemie II Maximilian Böhm Lehrstuhl für Organische Chemie II Rainer Tietze Department of Otorhinolaryngology – Head and Neck Surgery (HNO-Klinik) Frank Beierlein Erlangen National High Performance Computing Center (NHR@FAU) Petra Imhof Professur für Computational Chemistry Sabrina Gensberger-Reigl Lehrstuhl für Lebensmittelchemie (Henriette-Schmidt-Burkhardt Lehrstuhl) Monika Pischetsrieder Lehrstuhl für Lebensmittelchemie (Henriette-Schmidt-Burkhardt Lehrstuhl) Marlies Körber Lehrstuhl für Organische Chemie II Tina Jost Department of Radiation Oncology Andriy Mokhir Professur für Organische Chemie

Additional Organisation(s)

FAU Forschungszentrum Neue Wirkstoffe (FAU NeW)

Involved external institutions

Spanish National Center for Cardiovascular Research / Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) ES Spain (ES) Danylo Halytsky Lviv National Medical University / Львiвський Національний Медичний Унiверситет iм. Данила Галицького UA Ukraine (UA) Nationales Zentrum für Strahlenforschung in der Onkologie / National Center for Radiation Research in Oncology (NCRO- OncoRay) DE Germany (DE)

How to cite

APA:

Klemt, I., Reshetnikov, V., Dutta, S., Bila, G., Bilyy, R., Cuartero, I.C.,... Mokhir, A. (2024). A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin. RSC Medicinal Chemistry. https://doi.org/10.1039/d3md00609c

MLA:

Klemt, Insa, et al. "A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin." RSC Medicinal Chemistry (2024).

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