Precise Carrier-Free Pt(IV)-Nanobombs for Apoptosis/Ferroptosis Synergistic Tumor Therapy: A New Effective Method to Obtain Good Chemotherapy and Low Toxicity

The
emerged apoptosis/ferroptosis synergistic platinum-based
therapy
has attracted a lot of attention but is far from clinic use due to
high systemic toxicity. Herein, a series of novel precise carrier-free
self-assembled platinum(IV) nanoparticles with lipid regulation effect
named FSPNPs (5NPs–8NPs) were constructed
via connecting fenofibrate acid (FA) to cisplatin or oxaliplatin-derived
platinum(IV)-intermediates with disulfide bonds. FSPNPs can be stimulated
by high-glutathione/ascorbic acid and acidity environment to produce
an “explosion-like” cascade release process. Cell-activity
showed precision of FSPNPs, which accumulated more in tumor cells
and inhibited cell proliferation. Especially, 5NPs have
higher cell selectivity than cisplatin. FSPNPs downregulated glutathione/glutathione
peroxidase 4, increased reactive oxygen species/lipid peroxidation/malondialdehyde,
induced DNA damage/S-phase arrest, and regulated p53/Bcl-2/Bax to
trigger the apoptosis/ferroptosis hybrid pathway. The released FA
and derivates were docked into the peroxisome proliferator-activated
receptor α with activating cholesterol metabolism to destroy
membrane integrity. FSPNPs also showed good biocompatibility and superior
antitumor activity with no observable tissue damage.