In-cell Catalysis by Tethered Organo-Osmium Complexes Generates Selectivity for Breast Cancer Cells

Area of Science:

• Organometallic Chemistry
• Cancer Therapeutics
• Catalysis

Background:

• Drug resistance is a major challenge in cancer therapy.
• Catalytic anticancer agents offer multi-targeting strategies but face deactivation issues.
• Osmium-based catalysts show promise but require improved stability and targeted delivery.

Purpose of the Study:

• To synthesize a stable, potent osmium-based catalyst for cancer treatment.
• To investigate the catalyst's mechanism of action and cellular uptake.
• To evaluate the catalyst's efficacy against triple-negative breast cancer and tamoxifen resistance.

Main Methods:

• Synthesis of a tethered Os-based 16-electron half-sandwich catalyst.
• Antiproliferative activity assays against triple-negative breast cancer cells.
• Speciation and cellular accumulation studies (albumin binding, energy-dependent uptake).
• In-cell transfer hydrogenation catalysis with sodium formate.
• Reactive oxygen species (ROS) generation assays.

Main Results:

• The tethered Os catalyst demonstrated potent antiproliferative activity, comparable to cisplatin.
• The catalyst effectively overcame tamoxifen resistance in cancer cells.
• Osmium was primarily albumin-bound extracellularly and taken up via an energy-dependent, protein-mediated pathway.
• The catalyst remained intact upon cellular delivery and catalyzed in-cell transfer hydrogenation.
• The mechanism involved ROS generation, showing selectivity for cancer cells.

Conclusions:

• A stable, tethered Os-based catalyst offers a promising strategy for overcoming drug resistance in triple-negative breast cancer.
• The catalyst's efficacy is linked to its ability to perform in-cell catalysis and induce ROS.
• Albumin-mediated uptake and intracellular delivery are key to the catalyst's function.