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

João Franco Machado1,2, Marco Sá1, Inês Pires3

  • 1Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal. tsmorais@fc.ul.pt.

Dalton Transactions (Cambridge, England : 2003)
|April 4, 2024
PubMed

Insights

We developed novel ruthenium-peptide conjugates (RuPCs) that selectively target Fibroblast Growth Factor Receptors (FGFRs) in breast cancer cells. These RuPCs release cytotoxic ruthenium complexes in acidic tumor environments, enhancing efficacy against FGFR-expressing cancers.

Area of Science:

  • Bioconjugation Chemistry
  • Cancer Therapeutics
  • Molecular Targeted Therapy

Background:

  • Dysregulated Fibroblast Growth Factor Receptors (FGFRs) signaling is linked to breast cancer development.
  • Targeted delivery systems for cytotoxic agents in breast cancer remain underexplored.
  • Ruthenium complexes offer potential as anticancer agents but require targeted delivery.

Purpose of the Study:

  • To design and synthesize novel bi-functional ruthenium-peptide conjugates (RuPCs) for FGFR-targeted breast cancer therapy.
  • To evaluate the FGFR-targeting and pH-dependent drug release capabilities of RuPCs.
  • To assess the antiproliferative activity of RuPCs in breast cancer cell lines with varying FGFR expression levels.

Main Methods:

  • Synthesis of four new bi-functional ruthenium-peptide conjugates (RuPCs).
  • In vitro antiproliferative assays using breast cancer cell lines (SKBR-3, MDA-MB-134-VI, MCF-7, MDA-MB-231) and human dermal fibroblasts (HDF) at pH 6.8 and 7.4.
  • Evaluation of ruthenium complex release profiles from RuPCs.
  • Molecular dynamic simulations and computational calculations for mechanistic insights.

Main Results:

  • RuPCs demonstrated enhanced cytotoxicity against FGFR-expressing breast cancer cells, particularly at acidic pH (6.8).
  • Activity was significantly higher (up to 6-fold) in FGFR-positive breast cancer lines compared to normal fibroblasts.
  • Cytotoxicity and drug release were dependent on the peptide conjugation site within the ruthenium complex.
  • Ruthenium release profiles correlated with observed antiproliferative effects.

Conclusions:

  • A lead bi-functional RuPC was identified as a promising FGFR-targeted chemotherapeutic agent for breast cancer.
  • The developed RuPCs offer selective delivery and controlled activation in the tumor microenvironment.
  • Peptide conjugation strategy is critical for optimizing the efficacy of these targeted ruthenium-based therapeutics.

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