Anticancer Agents: Does a Phosphonium Behave Like a Gold(I) Phosphine Complex? Let a "Smart" Probe Answer!

Area of Science:

• Inorganic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Gold phosphine complexes, like auranofin, are known antirheumatic drugs with potential anticancer and anti-HIV applications.
• The precise mechanism of action and in vivo behavior of gold phosphine complexes remain unclear, particularly regarding their stability and target interactions.
• Investigating whether gold complexes act as prodrugs or maintain gold-ligand integrity during treatment is crucial.

Purpose of the Study:

• To synthesize and characterize novel gold phosphine complexes with a fluorescent smart probe ligand.
• To compare the in vitro biological activity, in vivo biodistribution, and toxicity of these new gold complexes against auranofin and a phosphonium analogue.
• To elucidate the cellular targets and stability of the gold complexes using advanced imaging techniques.

Main Methods:

• Synthesis and characterization of novel gold phosphine complexes and a phosphonium analogue.
• In vitro biological assays to determine cytotoxicity (IC50 values) in cancer cell lines.
• In vivo studies in zebrafish larvae for biodistribution and toxicity assessment.
• Two-photon microscopy to visualize cellular localization and target interactions.

Main Results:

• The novel gold complexes demonstrated stability in vitro and in vivo, distinct from auranofin and the phosphonium analogue.
• Two-photon microscopy revealed different cellular targets for the gold complexes compared to the phosphonium analogue.
• Despite comparable in vitro anticancer activity in some cell lines, the gold complexes exhibited significantly lower in vivo toxicity than the phosphonium salt.

Conclusions:

• The studied gold phosphine complexes are stable and possess unique biological properties.
• Their distinct cellular targets and low in vivo toxicity suggest potential for development as therapeutic agents.
• These findings support further in vivo investigation of gold phosphine complexes for anticancer applications.