Ferroptosis/Apoptosis Induction by an Iridium Complex Encapsulated in PLGA Nanoparticles Enhances Efficacy and Reduces Toxicity in Breast Cancer

Conventional chemotherapy faces systemic toxicity and
suboptimal
efficacy, necessitating innovative strategies. Herein, three iridium(III)
complexes (PIQ, PPY, and BZQ) were synthesized, and PPY exhibited
remarkable cytotoxicity against breast cancer cells (IC50 = 2.08 μM) by coinducing apoptosis/ferroptosis. Mechanistically,
this dual effect is mediated via ROS overproduction, mitochondrial
dysfunction, PI3K/AKT/mTOR signaling pathway inhibition, and GPX4
suppression, which collectively augment lipid peroxidation. Encapsulating
PPY into biodegradable PLGA nanoparticles (PPY-NPs) enhanced tumor-specific
delivery, achieving 78% tumor growth inhibition in mice with attenuated
systemic toxicity. Pharmacokinetic studies revealed that PPY-NPs had
reduced AUC, comparable to MRT,
accelerated Cl, and increased Vd compared to free PPY, consistent with MPS-mediated clearance.
Collectively, this approach harnesses the multitarget activity of
iridium coupled with nanocarrier-enabled spatiotemporal control, overcoming
bioavailability limitations and amplifying tumor-specific oxidative
stress. By simultaneously activating apoptosis and ferroptosis, PPY-NPs
overcome the limitations of conventional agents’ single-pathway
therapeutic approaches, offering an expanded mechanistic therapeutic
paradigm.