Multitargeting Prodrugs that Release Oxaliplatin, Doxorubicin and Gemcitabine are Potent Inhibitors of Tumor Growth and Effective Inducers of Immunogenic Cell Death

Amrita Sarkar, Vojtech Novohradsky, Moumita Maji, Tomer Babu, Lenka Markova, Hana Kostrhunova, Jana Kasparkova, Valentina Gandin*, Viktor Brabec*, Dan Gibson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

A multitargeting prodrug (2) that releases gemcitabine, oxaliplatin, and doxorubicin in their active form in cancer cells is a potent cytotoxic agent with nM IC50s; it is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells facilitating more efficient phagocytosis by J774 macrophages than the FDA drugs or their co-administration. The viability of CT26 cells co-cultured with J774 macrophages and treated with 2 was reduced by 32 % compared to the non-treated cells, suggesting a synergistic antiproliferative effect between the chemical and immune reactions. 2 inhibited in vivo tumor growth in two murine models (LLC and CT26) better than the FDA drugs or their co-administration with significantly lower body weight loss. Mice inoculated with CT26 cells treated with 2 showed slightly better tumor free survival than doxorubicin.

Original languageEnglish
Article numbere202310774
JournalAngewandte Chemie - International Edition
Volume62
Issue number42
DOIs
StatePublished - 16 Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Keywords

  • Doxorubicin
  • Gemcitabine
  • Immunogenic Cell Death
  • Multi-Targeting Prodrugs
  • Oxaliplatin

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