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

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL Journal of Medicinal Chemistry Pub Date : 2024-12-16 DOI:10.1021/acs.jmedchem.4c02034
Xu Guo, Xue-Jiao Liang, Jia-Le Liu, Zhi-Hui Li, Zhihao You, Dandan Zhao, Yali Song, Longfei Li, Xue-Qing Song
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Abstract

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.

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新出现的铂类凋亡/铁突变协同疗法备受关注,但由于全身毒性较大,还远未应用于临床。本文通过将非诺贝特酸(FA)与顺铂或奥沙利铂衍生的铂(IV)中间体以二硫键连接,构建了一系列具有脂质调节作用的新型无载体精确自组装铂(IV)纳米颗粒,命名为FSPNPs(5NPs-8NPs)。FSPNPs 可在高谷胱甘肽/抗坏血酸和酸性环境的刺激下产生 "爆炸式 "级联释放过程。细胞活性显示,FSPNPs 在肿瘤细胞中积累较多,能抑制细胞增殖。尤其是 5NPs 比顺铂具有更高的细胞选择性。FSPNPs 下调谷胱甘肽/谷胱甘肽过氧化物酶 4,增加活性氧/脂质过氧化/丙二醛,诱导 DNA 损伤/S 期停滞,并调节 p53/Bcl-2/Bax,引发细胞凋亡/铁凋亡混合途径。释放出的 FA 及其衍生物与过氧化物酶体增殖激活受体α对接,激活胆固醇代谢,破坏膜的完整性。FSPNPs 还表现出良好的生物相容性和卓越的抗肿瘤活性,且无明显的组织损伤。
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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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