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

Autor:	Guo X; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding 071002, Hebei, P. R. China., Liang XJ; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding 071002, Hebei, P. R. China., Liu JL; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding 071002, Hebei, P. R. China., Li ZH; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding 071002, Hebei, P. R. China., You Z; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding 071002, Hebei, P. R. China., Zhao D; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding 071002, Hebei, P. R. China., Song Y; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding 071002, Hebei, P. R. China., Li L; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding 071002, Hebei, P. R. China., Song XQ; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, Hebei University, Baoding 071002, Hebei, P. R. China.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Dec 16. Date of Electronic Publication: 2024 Dec 16.
DOI:	10.1021/acs.jmedchem.4c02034
Abstrakt:	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 ( 5 NPs- 8 NPs) 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, 5 NPs 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.
Databáze:	MEDLINE
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