活性氧响应型抗肿瘤前药研究进展

活性氧(ROS)在机体信号转导和代谢中起着至关重要的作用,而ROS水平的升高与多种病变(癌症和炎症等)息息相关,基于肿瘤组织高水平ROS开发的肿瘤特异杀伤性前药策略,在增强药效和药物选择性方面提供了一种新颖的方法.本综述介绍了目前用于构建抗肿瘤前药的ROS敏感键:芳基硼酸/酯、烷基硫/硒醚、硫缩酮、过氧草酸酯、氨基丙烯酸酯、噻唑烷酮和α-酮酰胺等,并且详叙了基于这些敏感键设计的前药在抗肿瘤方向上的应用,同时探讨了现有ROS响应型前药系统的研究进展和局限性,并对未来的研究方向进行了展望.     

Hydrogen Sulfide Donors Activated by Reactive Oxygen Species

Hydrogen sulfide (H₂S) exhibits promising protective effects in many (patho)physiological processes, as evidenced by recent reports using synthetic H₂S donors in different biological models. Herein, we report the design and evaluation of compounds denoted PeroxyTCM, which are the first class of reactive oxygen species (ROS)‐triggered H₂S donors. These donors are engineered to release carbonyl sulfide (COS) upon activation, which is quickly hydrolyzed to H₂S by the ubiquitous enzyme carbonic anhydrase (CA). The donors are stable in aqueous solution and do not release H₂S until triggered by ROS, such as hydrogen peroxide (H₂O₂), superoxide (O₂^?), and peroxynitrite (ONOO^?). We demonstrate ROS‐triggered H₂S donation in live cells and also demonstrate that PeroxyTCM‐1 provides protection against H₂O₂‐induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H₂S‐related therapies.     

A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential

Persulfides (RSSH) have been hypothesized as critical components in sulfur‐mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H₂S). Hindering the study of persulfides is a lack of persulfide‐donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS‐responsive (ROS=reactive oxygen species), self‐immolative persulfide donor. The donor, termed BDP‐NAC, showed selectivity towards H₂O₂ over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N‐acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H₂O₂ revealed that BDP‐NAC mitigated the effects of a highly oxidative environment in a dose‐dependent manner over relevant controls and to a greater degree than common H₂S donors sodium sulfide (Na₂S) and GYY4137. BDP‐NAC also rescued cells more effectively than a non‐persulfide‐releasing control compound in concert with common H₂S donors and thiols.     

Fluorescence Evaluation of Scavenging Efficiency of Antioxidants Against Reactive Oxygen Species (ROS) in Cigarette Smoke

Cigarette smoke can cause cellular oxidative stress that contributes to various adverse health effects associated with smoke exposure, partially due to reactive oxygen species (ROS) present in cigarette smoke. Reduction of abundant ROS in the cigarette mainstream smoke (MSS) is of importance for human health. In this work, a simple, rapid, and reliable fluorescence evaluation of scavenging efficiency of antioxidants as potential filter additives against ROS in cigarette smoke is reported. This method was based on the combination of model glass reactor and a fluorescence assay of ROS in cigarette smoke using dihydrorhodamine 6 G (DHR-6 G). The antioxidant was added into a glass reactor attached to cigarette filter, which simplified the preparation of combined filter containing additives. The ROS scavenging efficiency of antioxidants was then determined using spectrofluorimetry by the change in fluorescence intensity of whole smoke-bubbled solutions before and after addition of antioxidants into the glass reactor. The proposed method was successfully applied to the determination of ROS scavenging efficiency of several potential additives, such as tert-butylhydroquinone (TBHQ), vitamin C, β-carotene, grape seed extract, and Ginkgo biloba extract. Moreover, the relationship between MSS ROS scavenging efficiency and antioxidant activities (DPPH radicals scavenging efficiency and Fe²⁺ reducing power) of these compounds was also investigated.     

微流控芯片毛细管电泳法检测细胞内活性氧与细胞凋亡关系

建立了微流控芯片毛细管电泳激光诱导荧光同时测定细胞内活性氧和凋亡信号的方法。先用AlexaFluor488 annexin V细胞凋亡试剂盒标记细胞凋亡的外翻磷脂酰丝氨酸,再用双氢罗丹明123(DHR123)标记细胞内活性氧,用PBS将细胞调整为终密度1.2×106cells/mL的细胞悬液。细胞群经反复冻融法破碎后,以20 mmol/L硼砂(pH 9.2)作电泳缓冲溶液,分离电压1.2 kV,进样时间60 s,1 min内可完成活性氧和细胞凋亡信号的同时测定。方法简单、快速,细胞内活性氧和DHR123的反应产物(Rh123)在0.5～3μmol/L浓度范围内线性关系良好,相关系数(r)为0.998,检出限(S/N=3)为0.058μmol/L,可用于细胞内活性氧的定量分析。测得HepG2肝癌细胞活性氧含量为0.16μmol/L,被阿霉素诱导凋亡后,细胞内活性氧含量升高至1.77μmol/L。     

Anticancer Aminoferrocene Derivatives Inducing Production of Mitochondrial Reactive Oxygen Species

Elevated levels of reactive oxygen species (ROS) and deficient mitochondria are two weak points of cancer cells. Their simultaneous targeting is a valid therapeutic strategy to design highly potent anticancer drugs. The remaining challenge is to limit the drug effects to cancer cells without affecting normal ones. We have previously developed three aminoferrocene (AF)-based derivatives, which are activated in the presence of elevated levels of ROS present in cancer cells with formation of electron-rich compounds able to generate ROS and reduce mitochondrial membrane potential (MMP). All of them exhibit important drawbacks including either low efficacy or high unspecific toxicity that prevents their application in vivo up to date. Herein we describe unusual AF-derivatives lacking these drawbacks. These compounds act via an alternative mechanism: they are chemically stable in the presence of ROS, generate mitochondrial ROS in cancer cells, but not normal cells and exhibit anticancer effect in vivo.     

活性氧捕获材料的研究进展

生命从呼吸中获得氧气, 氧气再进一步在线粒体中将糖类等氧化得到能量, 提供给生命过程使用. 然而在氧化过程中, 会生成高度活泼的活性氧. 当体内控制失衡的时候, 它的浓度会大大增加, 发生氧化应激, 对机体产生不可逆的破坏, 引起衰老、肿瘤、心血管以及神经性疾病等. 抵抗活性氧的核心物质是抗氧化物, 它的存在使氧化应激受到控制, 从而保护机体免遭伤害. 本文对国内外近年来在活性氧自由基捕获方面的研究进行系统的综述, 通过梳理, 提出研究的金字塔型三级结构. 设计抗氧化物大分子与无机纳米粒子复合的纳米杂化自由基捕获器可以一方面解决无机纳米粒子的毒性问题, 另一方面还可以赋予纳米粒子额外的功能. 期待这篇综述文章能为改性纳米粒子捕捉活性氧提供一些有益思路, 为功能高分子材料与杂化纳米技术在生物医学领域的探索提供借鉴.     

酶振荡"探针"研究生物活性氧的新进展

评述了研究生物活性氧的意义和方法，简要概述了时空振荡反应中酶振荡的某些研究进展，提出了以酶振荡“探针”研究生物活性氧的新方法。     

PLGA Nanoparticles Decorated with Anti-HER2 Affibody for Targeted Delivery and Photoinduced Cell Death

The effect of enhanced permeability and retention is often not sufficient for highly effective cancer therapy with nanoparticles, and the development of active targeted drug delivery systems based on nanoparticles is probably the main direction of modern cancer medicine. To meet the challenge, we developed polymer PLGA nanoparticles loaded with fluorescent photosensitive xanthene dye, Rose Bengal, and decorated with HER2-recognizing artificial scaffold protein, affibody Z_HER2:342. The obtained 170 nm PLGA nanoparticles possess both fluorescent and photosensitive properties. Namely, under irradiation with the green light of 540 nm nanoparticles, they produced reactive oxygen species leading to cancer cell death. The chemical conjugation of PLGA with anti-HER2 affibody resulted in the selective binding of nanoparticles only to HER2-overexpressing cancer cells. HER2 is a receptor tyrosine kinase that belongs to the EGFR/ERbB family and is overexpressed in 30% of breast cancers, thus serving as a clinically relevant oncomarker. However, the standard targeting molecules such as full-size antibodies possess serious drawbacks, such as high immunogenicity and the need for mammalian cell production. We believe that the developed affibody-decorated targeted photosensitive PLGA nanoparticles will provide new solutions for ongoing problems in cancer diagnostics and treatment, as well in cancer theranostics.     

Development of a Sensitive Bioluminogenic Probe for Imaging Highly Reactive Oxygen Species in Living Rats

A sensitive bioluminogenic probe for highly reactive oxygen species (hROS), SO₃H‐APL, was developed based on the concept of dual control of bioluminescence emission by means of bioluminescent enzyme‐induced electron transfer (BioLeT) and modulation of cell‐membrane permeability. This probe enables non‐invasive visualization of physiologically relevant amounts of hROS generated deep inside the body of living rats for the first time. It is expected to serve as a practical analytical tool for investigating a wide range of biological functions of hROS in vivo. The design concept should be applicable to other in vivo bioluminogenic probes.     

Aggregation-Induced Generation of Reactive Oxygen Species: Mechanism and Photosensitizer Construction

Luminogens with aggregation-induced emission (AIEgens) have been widely applied in the field of photodynamic therapy. Among them, aggregation-induced emission photosensitizers (AIE–PSs) are demonstrated with high capability in fluorescence and photoacoustic bimodal imaging, as well as in fluorescence imaging-guided photodynamic therapy. They not only improve diagnosis accuracy but also provide an efficient theranostic platform to accelerate preclinical translation as well. In this short review, we divide AIE–PSs into three categories. Through the analysis of such classification and construction methods, it will be helpful for scientists to further develop various types of AIE–PSs with superior performance.     

Reactive Oxygen Species‐Responsive Protein Modification and Its Intracellular Delivery for Targeted Cancer Therapy

Herein we report a convenient chemical approach to reversibly modulate protein (RNase A) function and develop a protein that is responsive to reactive oxygen species (ROS) for targeted cancer therapy. The conjugation of RNase A with 4‐nitrophenyl 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl) benzyl carbonate (NBC) blocks protein lysine and temporarily deactivates the protein. However, the treatment of RNase A–NBC with hydrogen peroxide (one major intracellular ROS) efficiently cleaves the NBC conjugation and restores the RNase A activity. Thus, RNase A–NBC can be reactivated inside tumor cells by high levels of intracellular ROS, thereby restoring the cytotoxicity of RNase A for cancer therapy. Due to higher ROS levels inside tumor cells compared to healthy cells, and the resulting different levels of RNase A–NBC reactivation, RNase A–NBC shows a significant specific cytotoxicity against tumor cells.     

Orthogonal Activation of RNA‐Cleaving DNAzymes in Live Cells by Reactive Oxygen Species

RNA‐cleaving DNAzymes are useful tools for intracellular metal‐ion sensing and gene regulation. Incorporating stimuli‐responsive modifications into these DNAzymes enables their activities to be spatiotemporally and chemically controlled for more precise applications. Despite the successful development of many caged DNAzymes for light‐induced activation, DNAzymes that can be intracellularly activated by chemical inputs of biological importance, such as reactive oxygen species (ROS), are still scarce. ROS like hydrogen peroxide (H₂O₂) and hypochlorite (HClO) are critical mediators of oxidative stress‐related cell signaling and dysregulation including activation of immune system as well as progression of diseases and aging. Herein, we report ROS‐activable DNAzymes by introducing phenylboronate and phosphorothioate modifications to the Zn²⁺‐dependent 8–17 DNAzyme. These ROS‐activable DNAzymes were orthogonally activated by H₂O₂ and HClO inside live human and mouse cells.     

Reactive Oxygen Species (ROS) Responsive Polymers for Biomedical Applications

Reactive oxygen species (ROS) play important roles in cell signaling pathways, while increased production of ROS may disrupt cellular homeostasis, giving rise to oxidative stress and a series of diseases. Utilizing these cell‐generated species as triggers for selective tuning polymer structures and properties represents a promising methodology for disease diagnosis and treatment. Recently, significant progress has been made in fabricating biomaterials including nanoparticles and macroscopic networks to interact with this dynamic physiological condition. These ROS‐responsive platforms have shown potential in a range of biomedical applications, such as cancer targeted drug delivery systems, cell therapy platforms for inflammation related disease, and so on.

     

Reactive Oxygen Species Play an Important Role in the Bactericidal Activity of Quinolone Antibiotics

Recent studies posit that reactive oxygen species (ROS) contribute to the cell lethality of bactericidal antibiotics. However, this conjecture has been challenged and remains controversial. To resolve this controversy, we adopted a strategy that involves DNA polymerase IV (PolIV). The nucleotide pool of the cell gets oxidized by ROS and PolIV incorporates the damaged nucleotides (especially 8oxodGTP) into the genome, which results in death of the bacteria. By using a combination of structural and biochemical tools coupled with growth assays, it was shown that selective perturbation of the 8oxodGTP incorporation activity of PolIV results in considerable enhancement of the survival of bacteria in the presence of the norfloxacin antibiotic. Our studies therefore indicate that ROS induced in bacteria by the presence of antibiotics in the environment contribute significantly to cell lethality.     

Detection of Reactive Oxygen and Nitrogen Species by Upconversion Nanoparticle-Based Near-Infrared Nanoprobes: Recent Progress and Perspectives

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are essential oxidative metabolites of organisms, which are closely related to physiological, pathological and pharmacological processes. The accurate detection of ROS/RNS is important for the understanding of biological processes, monitoring of pharmacological effects, and predicting the course of disease. The recently developed NIR nanoprobes based on upconversion nanoparticles (UCNPs) hold great prospects in sensitive and deep-tissue detection of ROS/RNS, and considerable progress has been achieved so far. In this review, we systematically summarize the up-to-date advances of UCNPs-based near-infrared (NIR) probes for ROS/RNS sensing, and the potential challenges and perspectives for further research are also highlighted. We envision that such a research field will have a bright future for modern biomedical applications.