Ultrasound-Induced Reactive Oxygen Species Mediated Therapy and Imaging Using a Fenton Reaction Activable Polymersome.
Li Wei-Peng,Su Chia-Hao,Chang Yi-Ching,Lin Yu-Jiung,Yeh Chen-Sheng
Ultrasound techniques have been extensively employed for diagnostic purposes. Because of its features of low cost, easy access, and noninvasive real-time imaging, toward clinical practice it is highly anticipated to simply use diagnostic ultrasound to concurrently perform imaging and therapy. We report a H2O2-filled polymersome to display echogenic reflectivity and reactive oxygen species-mediated cancer therapy simply triggered by the microultrasound diagnostic system accompanied by MR imaging. Instead of filling common perfluorocarbons, the encapsulation of H2O2 in H2O2/Fe3O4-PLGA polymersome provides O2 as the echogenic source and (•)OH as the therapeutic element. On exposure to ultrasound, the polymersome can be easily disrupted to yield (•)OH through the Fenton reaction by reaction of H2O2 and Fe3O4. We showed that malignant tumors can be completely removed in a nonthermal process.
Fenton-Reaction-Acceleratable Magnetic Nanoparticles for Ferroptosis Therapy of Orthotopic Brain Tumors.
Shen Zheyu,Liu Ting,Li Yan,Lau Joseph,Yang Zhen,Fan Wenpei,Zhou Zijian,Shi Changrong,Ke Chaomin,Bregadze Vladimir I,Mandal Swadhin K,Liu Yijing,Li Zihou,Xue Ting,Zhu Guizhi,Munasinghe Jeeva,Niu Gang,Wu Aiguo,Chen Xiaoyuan
Cancer is one of the leading causes of morbidity and mortality in the world, but more cancer therapies are needed to complement existing regimens due to problems of existing cancer therapies. Herein, we term ferroptosis therapy (FT) as a form of cancer therapy and hypothesize that the FT efficacy can be significantly improved via accelerating the Fenton reaction by simultaneously increasing the local concentrations of all reactants (Fe, Fe, and HO) in cancer cells. Thus, Fenton-reaction-acceleratable magnetic nanoparticles, i.e., cisplatin (CDDP)-loaded FeO/GdO hybrid nanoparticles with conjugation of lactoferrin (LF) and RGD dimer (RGD2) (FeGd-HN@Pt@LF/RGD2), were exploited in this study for FT of orthotopic brain tumors. FeGd-HN@Pt@LF/RGD2 nanoparticles were able to cross the blood-brain barrier because of its small size (6.6 nm) and LF-receptor-mediated transcytosis. FeGd-HN@Pt@LF/RGD2 can be internalized into cancer cells by integrin αβ-mediated endocytosis and then release Fe, Fe, and CDDP upon endosomal uptake and degradation. Fe and Fe can directly participate in the Fenton reaction, whereas the CDDP can indirectly produce HO to further accelerate the Fenton reaction. The acceleration of Fenton reaction generates reactive oxygen species to induce cancer cell death. FeGd-HN@Pt@LF/RGD2 successfully delivered reactants involved in the Fenton reaction to the tumor site and led to significant inhibition of tumor growth. Finally, the intrinsic magnetic resonance imaging (MRI) capability of the nanoparticles was used to assess and monitor tumor response to FT (self-MRI monitoring).
Ferrous-Supply-Regeneration Nanoengineering for Cancer-Cell-Specific Ferroptosis in Combination with Imaging-Guided Photodynamic Therapy.
Liu Tao,Liu Wenlong,Zhang Mingkang,Yu Wuyang,Gao Fan,Li Chuxin,Wang Shi-Bo,Feng Jun,Zhang Xian-Zheng
Non-apoptotic ferroptosis is of clinical importance because it offers a solution to the inevitable biocarriers of traditional apoptotic therapeutic means. Inspired by industrial electro-Fenton technology featured with electrochemical iron cycling, we construct ferrous-supply-regeneration nanoengineering to intervene tumorous iron metabolism for enhanced ferroptosis. Fe ion and naturally derived tannic acid (TA) spontaneously form a network-like corona onto sorafenib (SRF) nanocores. The formed SRF@FeTA nanoparticles can respond to a lysosomal acid environment with corona dissociation, permitting SRF release to inhibit GPX4 enzyme for ferroptosis initiation. TA is arranged to chemically reduce the liberated and the ferroptosis-generated Fe to Fe, offering iron redox cycling to, thus, effectively produce lipid peroxide required in ferroptosis. Sustained Fe supply leads to long-term cytotoxicity, which is identified to be specific to HO-overloaded cancer cells but minimal in normal cells. SRF@FeTA-mediated cell death proves to follow the ferroptosis pathway and strongly inhibits tumor proliferation. Moreover, SRF@FeTA provides a powerful platform capable of versatile integration between apoptosis and non-apoptosis means. Typically, photosensitizer-adsorbed SRF@FeTA demonstrates rapid tumor imaging owing to the acid-responsive fluorescence recovery. Together with ferroptosis, imaging-guided photodynamic therapy induces complete tumor elimination. This study offers ideas about how to advance anticancer ferroptosis through rational material design.
Switching Apoptosis to Ferroptosis: Metal-Organic Network for High-Efficiency Anticancer Therapy.
Zheng Di-Wei,Lei Qi,Zhu Jing-Yi,Fan Jin-Xuan,Li Chu-Xin,Li Cao,Xu Zushun,Cheng Si-Xue,Zhang Xian-Zheng
Discovering advanced materials for regulating cell death is of great importance in the development of anticancer therapy. Herein, by harnessing the recently discovered oxidative stress regulation ability of p53 and the Fenton reaction inducing capability of metal-organic network (MON), MON encapsulated with p53 plasmid (MON-p53) was designed to eradicate cancer cells via ferroptosis/apoptosis hybrid pathway. After confirming the detailed mechanism of MON-p53 in evoking ferroptosis, we further discovered that MON-p53 mediated a "bystander effect" to further sensitize cancer cells toward the MON-p53 induced ferroptosis. A 75-day anticancer experiment indicated that MON-p53 treatment not only suppressed the tumor growth but also prolonged the life-span of tumor bearing mice. Owing to its ability to promote intracellular oxidative stress, MON-p53 decreased the blood metastasis, lung metastasis, and liver metastasis. As a consequence, discovering methods to induce cell ferroptosis would provide a new insight in designing anticancer materials.
Development of a novel FePt-based multifunctional ferroptosis agent for high-efficiency anticancer therapy.
Yue Ludan,Dai Zhichao,Chen Xue,Liu Chunmiao,Hu Zunfu,Song Bo,Zheng Xiuwen
Ferroptosis as an emerging mechanism has become a research hotspot for killing cancer cells. In this work, a novel ferroptosis agent, FePt-PTTA-Eu3+-FA (FPEF), was rationally designed by harnessing the luminescent lanthanide complexes PTTA-Eu3+ and folic acid (FA) in FePt nanoparticles. FePt-Based nanomaterials have potential applications in magnetic resonance imaging/computed tomography (MRI/CT) in clinical diagnosis and have excellent capacity to induce cancer cell death. Mechanistic studies of FPEP showed that the FePt induced cancer cell death was affirmed as the ferroptosis mechanism. To the best of our knowledge, it will be the first report that proves the existence of the ferroptosis process in FePt NPs. The in vitro tests of FPEF demonstrated that the as-prepared NPs exhibit a satisfactory anticancer effect towards FA-positive tumor cells including 4T1, MCF-7 and HeLa cells. The in vivo studies using tumor-bearing balb/c mice revealed that the FPEF NPs could significantly inhibit tumor progression. Such all-in-one therapeutic strategies have great potential in early diagnosis, prognosis and treatment of cancer.
Enhanced Cisplatin Chemotherapy by Iron Oxide Nanocarrier-Mediated Generation of Highly Toxic Reactive Oxygen Species.
Ma Ping'an,Xiao Haihua,Yu Chang,Liu Jianhua,Cheng Ziyong,Song Haiqin,Zhang Xinyang,Li Chunxia,Wang Jinqiang,Gu Zhen,Lin Jun
Reactive oxygen species (ROS) plays a key role in therapeutic effects as well as side effects of platinum drugs. Cisplatin mediates activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), which triggers oxygen (O) to superoxide radical (O) and its downstream HO. Through the Fenton's reaction, HO could be catalyzed by Fe/Fe to the toxic hydroxyl radicals (OH), which cause oxidative damages to lipids, proteins, and DNA. By taking the full advantage of Fenton's chemistry, we herein demonstrated tumor site-specific conversion of ROS generation induced by released cisplatin and Fe/Fe from iron-oxide nanocarriers with cisplatin(IV) prodrugs for enhanced anticancer activity but minimized systemic toxicity.
Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth.
Kim Sung Eun,Zhang Li,Ma Kai,Riegman Michelle,Chen Feng,Ingold Irina,Conrad Marcus,Turker Melik Ziya,Gao Minghui,Jiang Xuejun,Monette Sebastien,Pauliah Mohan,Gonen Mithat,Zanzonico Pat,Quinn Thomas,Wiesner Ulrich,Bradbury Michelle S,Overholtzer Michael
The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.
Five-Membered Ring Peroxide Selectively Initiates Ferroptosis in Cancer Cells.
Abrams Rachel P,Carroll William L,Woerpel K A
ACS chemical biology
A 1,2-dioxolane (FINO2) was identified as a lead compound from a screen of organic peroxides. FINO2 does not induce apoptosis, but instead initiates ferroptosis, an iron-dependent, oxidative cell death pathway. Few compounds are known to induce primarily ferroptosis. In contrast to the perceived instability of peroxides, FINO2 was found to be thermally stable to at least 150 °C. FINO2 was more potent in cancer cells than nonmalignant cells of the same type. One of the enantiomers was found to be more responsible for the observed activity.
Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model.
Zhang Yan,Tan Hui,Daniels Jacob D,Zandkarimi Fereshteh,Liu Hengrui,Brown Lewis M,Uchida Koji,O'Connor Owen A,Stockwell Brent R
Cell chemical biology
Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system x. Among the existing system x inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system x and inducer of ferroptosis potentially suitable for in vivo applications. We investigated the pharmacokinetic and pharmacodynamic features of IKE in a diffuse large B cell lymphoma (DLBCL) xenograft model and demonstrated that IKE exerted an antitumor effect by inhibiting system x, leading to glutathione depletion, lipid peroxidation, and the induction of ferroptosis biomarkers both in vitro and in vivo. Using untargeted lipidomics and qPCR, we identified distinct features of lipid metabolism in IKE-induced ferroptosis. In addition, biodegradable polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles were employed to aid in IKE delivery and exhibited reduced toxicity compared with free IKE in a DLBCL xenograft model.
Application of Nanoparticles and Nanomaterials in Thermal Ablation Therapy of Cancer.
Ashikbayeva Zhannat,Tosi Daniele,Balmassov Damir,Schena Emiliano,Saccomandi Paola,Inglezakis Vassilis
Nanomaterials (Basel, Switzerland)
Cancer is one of the major health issues with increasing incidence worldwide. In spite of the existing conventional cancer treatment techniques, the cases of cancer diagnosis and death rates are rising year by year. Thus, new approaches are required to advance the traditional ways of cancer therapy. Currently, nanomedicine, employing nanoparticles and nanocomposites, offers great promise and new opportunities to increase the efficacy of cancer treatment in combination with thermal therapy. Nanomaterials can generate and specifically enhance the heating capacity at the tumor region due to optical and magnetic properties. The mentioned unique properties of nanomaterials allow inducing the heat and destroying the cancerous cells. This paper provides an overview of the utilization of nanoparticles and nanomaterials such as magnetic iron oxide nanoparticles, nanorods, nanoshells, nanocomposites, carbon nanotubes, and other nanoparticles in the thermal ablation of tumors, demonstrating their advantages over the conventional heating methods.