Tetraoxane-based tumor-activated prodrug strategy to target intracellular labile ferrous iron

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Publication . Magalhães e Silva, Diogo; Moreira, Rui Ferreira Alves; Lopes, Francisca da Conceição; Rodrigues, Cecília Maria Pereira

Iron is a critical component in many cellular functions including DNA replication and repair, essential for cell vitality. However, iron metabolism dysregulation is associated with infectious diseases and cancer. Despite clinical precedent for iron-dependent pharmacology in antimalarial therapy with endoperoxides, tumour targeting strategies designed to exploit changes in iron homeostasis remain poorly studied. In this work, two tetraoxane-based Fe(II)-activable drug conjugate (FeADC) systems were developed as targeted therapy. Type I FeADCs spontaneously releases the cytotoxic payload after reaction with Fe(II). Ten type I FeADCs were obtained with different cytotoxic payloads for malaria and cancer. Type I FeADCs coupled with antimalarials were potent on the nanomolar range in chloroquine-sensitive strain. Type I FeADCs conjugated with doxorubicin showed high efficiency in reducing cellular viability in Fe(II)-rich cancer cell lines. Importantly, this FeADC was significantly less toxic to non-tumorigenic cells than the parent drug. Type I FeADC activity against Fe(II)-rich cancer cell lines was abrogated when incubated with the iron chelator desferoxamine (DFO). Type II FeADCs, in addition to the Fe(II)-activable tetraoxane scaffold shared with the type I system, also contains an unique structural feature that enables reaction with another metabolite, which is elevated in cancer. This feature only becomes available after endoperoxide activation by Fe(II), thus increasing the potential for improved selectivity. We have prepared a type II FeADC that showed high efficiency in reducing cellular viability in Fe(II)-rich cancer cell lines. Type II FeADC selectivity was evaluated in AML12 cells, being 200-fold less toxic than the parent drug. Importantly, our results also demonstrate that type II FeADC induced cell death is iron-dependent. In summary, the tetraoxane scaffold was validated as a drug delivery system for diseases with iron metabolism dysregulation.

2022-09Tese de doutoramento

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

OE

Número da atribuição

SFRH/BD/132341/2017