Safe delivery of a highly toxic anthracycline derivative through liposomal nanoformulation achieves complete cancer regression

Füredi, András and Tóth, Szilárd and Hegedüs, Kristóf and Szabó, Pál Tamás and Gaál, Anikó and Barta, Gergő and Naszályi, Lívia N. and Kiss, Krisztina and Bölcskei, Kata and Szeltner, Zoltán and Bajtai, Eszter and Gombos, Balázs and Kiss, Dániel and Cserepes, Tamás Mihály and Kiss, Attila and Pokreisz, Peter and Kenner, Lukas and Högler, Sandra and Magyar, Csaba and Cowles, Jamie D. and Csiszar, Agnes and Tóvári, József and Szüts, Dávid and Helyes, Zsuzsanna and Varga, Zoltán and Mező, Gábor and Szakács, Gergely (2025) Safe delivery of a highly toxic anthracycline derivative through liposomal nanoformulation achieves complete cancer regression. MOLECULAR CANCER, 24 (1). No. 269. ISSN 1476-4598

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Abstract

Background: Chemotherapy remains the cornerstone of cancer treatment despite its well-documented challenges, including toxic side effects and drug resistance. Here, we demonstrate that a novel, highly toxic, daunosamine-modified derivative of daunorubicin (2-pyrrolino-daunorubicin, PyDau) can be safely administered to mice when encapsulated in liposome. Methods: PyDau was synthesized from daunorubicin in a one-step reaction. Its increased in vitro cytotoxicity was confirmed across 42 human cell lines representing 12 cancer types, including multidrug resistant cells. The activity profile of this new derivative was analyzed in the context of 13 commonly used cancer drugs across a panel of lymphoblast cell lines missing individual components of DNA-repair enzymes. To enable in vivo application, PyDau was encapsulated in pegylated liposome, resulting in liposomal PyDau (LiPyDau). In vivo efficacy of LiPyDau was evaluated in three allograft models (melanoma, breast, lung), a xenograft model (uterine sarcoma), a patient-derived xenograft model (lung), and a genetically engineered mouse model of mammary cancer, including two models of drug resistance. Results: While PyDau exhibited up to 1000-fold greater cytotoxicity than daunomycin and doxorubicin against cancer cell lines, its in vivo application was hindered by an extremely narrow therapeutic window. Liposomal nanoformulation mitigated the limiting toxicity, allowing LiPyDau to be tested in preclinical allograft and xenograft mouse models. LiPyDau demonstrated robust efficacy across all models including multidrug-resistant cancer, completely eradicating tumors in a genetically engineered mouse model of triple-negative breast cancer. LiPyDau exerts its anticancer effect through a unique mechanism involving the crosslinking of complementary DNA strands, resulting in irreversible DNA damage. Conclusion: Liposomal formulations of extremely cytotoxic anthracycline analogs, such as LiPyDau, represent a promising and highly effective therapeutic approach for combating drug resistant cancer.

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