Inducing ferroptosis in cancer cells using drug-metal coordination complexes

Inducing ferroptosis in cancer cells using drug-metal coordination complexes

The fast-growing cancer incidence and mortality worldwide have raised great challenges for the currently available anticancer options, which warrants the development of new therapeutic modalities based on novel antitumor mechanisms. Ferroptosis, a recently discovered form of non-apoptotic cell death, is one such candidate and has already demonstrated immense potential in clinical oncology as it provides alternative therapeutic opportunities for the management of treatment-resistant tumors.

In a research study published on Science Advances, lead author reported a novel strategy to induce ferroptosis in target cancer cells and further amplify the ferroptotic damage for efficient tumor therapy. The nanoformulation was designed to be exclusively activated in the tumor microenvironment, which has demonstrated potent inhibition effect against multiple types of tumors while sparing healthy cells and tissues.

"Overloading tumor cells with ferrous ions could readily initiate the ferroptotic death cascade, and the complexed doxorubicin may further amplify the ferroptotic damage by providing additional reactive oxygen species to sustain the lipid peroxidation." Says the lead. "The benefit of coordinating Fe2+ ions with doxorubicin is manifold. It could not only enhance the stability of Fe2+ ions in biological environment, but also facilitate the subsequent lipid peroxidation process to promote ferroptosis. Moreover, doxorubicin is an FDA-approved anticancer drug capable of inhibiting the topoisomerase 2 in tumor cells to prevent DNA replication, leading to complementary ferroptosis/apoptosis effect against a broad spectrum of tumor indications." Says another author.

The underlying molecular mechanism for the synergy between Fe2+ and doxorubicin is that doxorubicin could generate high level of intracellular ROS by activating the intracellular NADPH oxidase 4 (NOX4) in tumor cells, which may supply H2O2 to sustain the Fe2+-catalyzed lipid peroxidation.

Inspired by the recent advances in self-assembly technology, researchers from the two groups developed an intricate self-assembly-based nanoplatform for the tumor-targeted cytosolic delivery of the Fe2+-doxorubicin complex. The Fe2+-doxorubicin complex were efficiently encapsulated into amorphous calcium carbonate nanospheres in a simple one-step co-condensation process, and the surface of the drug-loaded amorphous calcium nanoparticles was modified with polyamidoamine (PAMAM) dendrimer-based tumor-microenvironment-activatable multifunctional ligands, which would remain bioinert during circulation but switch to a tumor-affinitive state upon entering the matrix metalloproteinase-2 (MMP-2)-rich tumor microenvironment. Thanks to the acid sensitivity of the amorphous calcium carbonate contents, the nanoparticle could be readily degraded in the acidic tumor lysosomes to release the Fe2+-doxorubicin complex, which could be further reverted into free doxorubicin and Fe2+ through the protonation-induced dissociation. Meanwhile, the PAMAM dendrimers could disrupt the lysosomal membrane via "proton sponge" effect and release doxorubicin and Fe2+ to the cytosol, where the H2O2 produced during doxorubicin metabolism could stimulate the ferroptotic toxicity of Fe2+ ions to tumor cells.

In the future, the authors hope to further simplify the synthesis procedures of the amorphous calcium carbonate-based nanoplatform and thoroughly investigate their efficacy and safety in a clinically relevant context.