Dual FGFR-targeting and pH-activatable ruthenium–peptide conjugates for targeted therapy of breast cancer

João Franco Machado; Marco Sá; Inês Pires; Miguel Tarita da Silva; Fernanda Marques; Jaime A. S. Coelho; Filipa Mendes; M. Fátima M. Piedade; Miguel Machuqueiro; María Angeles Jiménez; Maria Helena Garcia; João D. G. Correia; Tânia S. Morais

doi:10.1039/D4DT00497C

Dual FGFR-targeting and pH-activatable ruthenium–peptide conjugates for targeted therapy of breast cancer†

João Franco Machado,

^ab Marco Sá,‡^a Inês Pires,‡^c Miguel Tarita da Silva,^b Fernanda Marques,

^bd Jaime A. S. Coelho,^a Filipa Mendes,

^bd M. Fátima M. Piedade,^ef Miguel Machuqueiro,

^ce María Angeles Jiménez,

^g Maria Helena Garcia,^ae João D. G. Correia

*^bd and Tânia S. Morais

*^ae

Author affiliations

* Corresponding authors

^a Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
E-mail: tsmorais@fc.ul.pt

^b Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139, 7), 2695-066 Bobadela LRS, Portugal
E-mail: jgalamba@ctn.tecnico.ulisboa.pt

^c BioISI – Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal

^d Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139, 7), 2695-066 Bobadela LRS, Portugal

^e Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal

^f Centro de Química Estrutural, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal

^g Institute of Physical Chemistry Blas Cabreras (IQF-CSIC), Serrano 119, E-28006 Madrid, Spain

Abstract

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium–peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.

Dalton Transactions

Dual FGFR-targeting and pH-activatable ruthenium–peptide conjugates for targeted therapy of breast cancer†

Abstract

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Dual FGFR-targeting and pH-activatable ruthenium–peptide conjugates for targeted therapy of breast cancer

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