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Metal-Drug Complexes Trigger Synergistic Ferroptosis-Apoptosis in Cancer Cells

Fe2+-doxorubicin complexes, delivered specifically to tumours via encapsulation in amorphous calcium carbonate (ACC)-based nanospheres, confer severe damage by inducing ferroptosis and apoptosis.

Ferroptosis is a recently discovered mode of non-apoptotic cell death activated by the iron-dependent accumulation of cytotoxic lipid hydroperoxides; increasing intracellular iron levels is an effective approach to induce ferroptosis in tumour cells. Nevertheless, reports on ferroptosis-based tumour therapy are still rare due to the relative high oxidation susceptibility of Fe2+ ions and regulation of the ferroptosis process.

In a study published in Science Advances, lead author Professor Shu-Hong Yu from the University of Science and Technology of China and his collaborator Professor Zhong Luo in Chongqing University designed a tumour-targeted amorphous calcium carbonate (ACC)-based nano-formulation with complementary ferroptosis/apoptosis-inducing capability involving Fe2+ and doxorubicin (DOX).

“We two groups have been collaborating closely on the synthesis and functionalization of biocompatible inorganic nanomaterials,” said Luo. “Amorphous calcium carbonate nanoparticle is a very promising inorganic nanomaterial for biomedical applications. It’s easy to synthesize and has tunable drug loading capability. It could also be rapidly degraded in human body and the degradation products are all non-toxic.”

In the design, DOX first chelates with Fe2+ ions and then co-condenses with calcium-containing precursors to produce ACC-encapsulated Fe2+-DOX cores in a one-step approach. The complexation of DOX and Fe2+ ions not only allows for their efficient loading into the ACC-based nanoparticles but also minimizes the susceptibility of Fe2+ ions to be oxidized before their intracellular release. The surfaces of the drug-loaded cores were then conjugated with PEGylated polyamidoamine (PAMAM) dendrimers, which recognises tumour cells.

After successful internalization by tumour cells, the ACC-based nanospheres would be readily degraded in the acidic tumour lysosomes to release the Fe2+-DOX complex into the cytosol. The pH-triggered release of Fe2+ ions and DOX is anticipated to act synergistically to escalate the oxidative stress, where the H2O2 produced during DOX metabolism sustains the Fe2+-catalysed lipid peroxidation and by extension the ferroptotic toxicity of Fe2+ ions to tumour cells.

“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,” explained Yu. “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 tumour cells to prevent DNA replication, leading to complementary ferroptosis/apoptosis effect against a broad spectrum of tumour indications,” Luo elaborated.

In the future, Yu and Luo hope to further simplify the synthesis procedures of the ACC-based nanoplatform and thoroughly investigate their efficacy and safety in a clinically relevant context. “The coordination complex is rapidly dissociated into free Fe2+ and doxorubicin under acidic conditions. However, both species must interact with intracellular components to take effect, necessitating further refinement of the drug delivery process,” said Yu. “This system may open up new avenues for treatment against tumours that are resistant to conventional therapies.” [APBN]