Tailored mechano-responsive micelles mimic the iron starvation response and impair pH homeostasis for triggered cancer therapy

IF 11.5 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Hongyu Leng , Yao Li , Han Wang , Panyu Du , Ning Zhao , Zheng Wang , Xin Li , Huikai Li , Yanjun Zhao
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Abstract

Carbonic anhydrase IX (CAIX) and cysteine desulfurase (NFS1) are a synthetic lethal pair for cancer treatment. The suppression of NFS1 upregulates the iron starvation response and enriches intracellular Fe2+, leading to increased lipid peroxidation. However, the potency of the NFS1 inhibitor is compromised by the hypoxic microenvironment. To address this issue, we report a mechano-responsive ferrocene-bearing micelle that mimics the CAIX/NFS1 axis via ultrasound-activated iron release and the co-delivery of SLC-0111, a CAIX inhibitor. Upon ultrasound stimulation, the micelles disassemble in acidic lysosomes, releasing ferrous ions and SLC-0111, triggering intracellular acidification, reactive oxygen species accumulation, and lipid peroxidation. Moreover, the liberation of Fe2+ is facilitated by the presence of hydrogen peroxide and further enhanced by mechanical force. SLC-0111 leads to intracellular acidification and synergizes with Fe2+ to boost the Fenton reaction. This cascade disrupted redox homeostasis and induced multiple cell death pathways, including ferroptosis, apoptosis, pyroptosis, and necroptosis, in a tumor-selective manner. The in vivo efficacy studies in a 4T1 breast cancer model confirmed potent tumor suppression with minimal systemic toxicity. This work introduces a mechanical force-controlled strategy as a substitute for CAIX/NFS1 synthetic lethality therapy without the interference of oxygen level, holding promise for advancing tumor-specific therapy.

Abstract Image

Abstract Image

量身定制的机械反应胶束模拟铁饥饿反应和损害pH稳态触发癌症治疗
碳酸酐酶IX (CAIX)和半胱氨酸脱硫酶(NFS1)是治疗癌症的合成致死酶对。NFS1的抑制上调了铁饥饿反应,丰富了细胞内的Fe2+,导致脂质过氧化增加。然而,NFS1抑制剂的效力受到缺氧微环境的影响。为了解决这个问题,我们报道了一种机械响应的含二茂铁胶束,它通过超声激活铁释放和CAIX抑制剂SLC-0111的共同递送来模拟CAIX/NFS1轴。超声刺激下,酸性溶酶体中的胶束解体,释放亚铁离子和SLC-0111,引发细胞内酸化、活性氧积累和脂质过氧化。此外,过氧化氢的存在促进了Fe2+的释放,机械力进一步促进了Fe2+的释放。SLC-0111导致细胞内酸化,并与Fe2+协同促进Fenton反应。这种级联破坏了氧化还原稳态,并以肿瘤选择性的方式诱导多种细胞死亡途径,包括铁死亡、凋亡、焦亡和坏死死亡。4 T1乳腺癌模型的体内疗效研究证实了有效的肿瘤抑制作用和最小的全身毒性。这项工作介绍了一种机械力控制策略,作为不受氧水平干扰的CAIX/NFS1合成致死性治疗的替代品,有望推进肿瘤特异性治疗。
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来源期刊
Journal of Controlled Release
Journal of Controlled Release 医学-化学综合
CiteScore
18.50
自引率
5.60%
发文量
700
审稿时长
39 days
期刊介绍: The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System. Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries. Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.
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