Platinum (Pt)-based chemotherapy is the main treatment for ovarian cancer (OC); however, most patients develop Pt resistance (Pt-R). This work shows that Pt-R OC cells increase intracellular cholesterol through uptake via the HDL receptor, scavenger receptor type B-1 (SR-B1). SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death and inhibition of tumor growth. Reduced cholesterol accumulation in cancer cells induces lipid oxidative stress through the reduction of glutathione peroxidase 4 (GPx4) leading to ferroptosis. In turn, GPx4 depletion induces decreased cholesterol uptake through SR-B1 and re-sensitizes OC cells to Pt. Mechanistically, GPx4 knockdown causes lower expression of the histone acetyltransferase EP300, leading to reduced deposition of histone H3 lysine 27 acetylation (H3K27Ac) on the sterol regulatory element binding transcription factor 2 (SREBF2) promoter and suppressing expression of this key transcription factor involved in the regulation of cholesterol metabolism. SREBF2 downregulation leads to decreased SR-B1 expression and diminished cholesterol uptake. Thus, chemoresistance and cancer cell survival under high ROS burden obligates high GPx4 and SR-B1 expression through SREBF2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.

Transition metal complexes are a promising class of redox mediators for targeting redox flow batteries due to the tunability of their electrochemical potentials. However, reliable time-efficient tools for the prediction of their reduction potentials are needed. In this work, we establish a suitable density functional theory protocol for their prediction using an initial experimental data set of aqueous iron complexes with bidentate ligands. The approach is then cross-validated using different complexes found in the redox-flow literature. We find that the solvation model affects the prediction accuracy more than the functional or basis set. The smallest errors are obtained using the COSMO-RS solvation model (mean average error (MAE)=0.24 V). With implicit solvation models, a general deviation from experimental results is observed. For a set of similar ligands, they can be corrected using simple linear regression (MAE=0.051 V for the initial set of iron complexes).

The hydrophilic poly(2,2,6,6-tetramethylpiperdinyloxy-4-yl-methacrylamide) (PTMAm) was utilized as redox target material in an aqueous organic redox targeting flow battery (RTFB). This polymer is processed into granules, which contain a conductive agent and an alginate binder. By this, a hydrophilic, yet water-insoluble redox target can be obtained. The target was combined with the redox mediator molecule N,N,N-trimethyl-2-oxo-2-[(2,2,6,6-tetramethylpiperidin-4-yloxyl)amino]ethan-1-ammonium chloride (TEMPOAmide), that has been reported earlier as flow battery active material. This target/mediator combination has been characterized electrochemically and flow battery testing has been done. Furthermore, in-operando characterization of the redox target via electrolyte state-of-charge (SOC) monitoring has been performed for the first time. The approach provides estimates for the redox target\'s SOC changes during cycling. In addition, a figure of merit - the \"redox targetivity\" - is proposed, which provides insights into the efficiency of the targeting reaction and supports the future optimization of materials, cell designs, and operational parameters for RTFBs.

We describe the nonaqueous redox-matched flow battery (RMFB), where charge is stored on redox-active moieties covalently tethered to non-circulating, insoluble polymer beads and charge is transferred between the electrodes and the beads via soluble mediators with redox potentials matched to the active moieties on the beads. The RMFB reported herein uses ferrocene and viologen derivatives bound to crosslinked polystyrene beads. Charge storage in the beads leads to a high (approximately 1.0-1.7 M) effective concentration of active material in the reservoirs while preventing crossover of that material. The relatively low concentration of soluble mediators (15 mM) eliminates the need for high-solubility molecules to create high energy density batteries. Nernstian redox exchange between the beads and redox-matched mediators was fast relative to the cycle time of the RMFB. This approach is generalizable to many different redox-active moieties via attachment to the versatile Merrifield resin.

Glioblastoma is one of the most aggressive brain tumors, characterized by a pronounced redox imbalance, expressed in a high oxidative capacity of cancer cells due to their elevated glycolytic and mitochondrial oxidative metabolism. The assessment and modulation of the redox state of glioblastoma are crucial factors that can provide highly specific targeting and treatment. Our study describes a pharmacological strategy for targeting glioblastoma using a redox-active combination drug. The experiments were conducted in vivo on glioblastoma mice (intracranial model) and in vitro on cell lines (cancer and normal) treated with the redox cycling pair menadione/ascorbate (M/A). The following parameters were analyzed in vivo using MRI or ex vivo on tissue and blood specimens: tumor growth, survival, cerebral perfusion, cellular density, tissue redox state, expression of tumor-associated NADH oxidase (tNOX) and transforming growth factor-beta 1 (TGF-β1). Dose-dependent effects of M/A on cell viability, mitochondrial functionality, and redox homeostasis were evaluated in vitro. M/A treatment suppressed tumor growth and significantly increased survival without adverse side effects. This was accompanied by increased oxidative stress, decreased reducing capacity, and decreased cellular density in the tumor only, as well as increased cerebral perfusion and down-regulation of tNOX and TGF-β1. M/A induced selective cytotoxicity and overproduction of mitochondrial superoxide in isolated glioblastoma cells, but not in normal microglial cells. This was accompanied by a significant decrease in the over-reduced state of cancer cells and impairment of their \"pro-oncogenic\" functionality, assessed by dose-dependent decreases in: NADH, NAD+, succinate, glutathione, cellular reducing capacity, mitochondrial potential, steady-state ATP, and tNOX expression. The safety of M/A on normal cells was compromised by treatment with cerivastatin, a non-specific prenyltransferase inhibitor. In conclusion, M/A differentiates glioblastoma cells and tissues from normal cells and tissues by redox targeting, causing severe oxidative stress only in the tumor. The mechanism is complex and most likely involves prenylation of menadione in normal cells, but not in cancer cells, modulation of the immune response, a decrease in drug resistance, and a potential role in sensitizing glioblastoma to conventional chemotherapy.

The volumetric capacities and the lifetime of organic redox flow batteries (RFBs) are strongly dependent on the concentrations of the redox-active molecules in the electrolyte. Single-molecule redox targeting represents an efficient approach toward realizing viable organic RFBs with low to moderate electrolyte concentrations. For the first time, an all-organic Nernstian potential-driven redox targeting system is investigated that directly combines a single-electrode material from organic radical batteries (ORBs) with a single redox couple of an aqueous, organic RFB, which are based on the same redox moiety. Namely, poly(TEMPO-methacrylate) (PTMA) is utilized as the redox target (\"solid booster\") and N,N,N-2,2,6,6-heptamethylpiperidinyloxy-4-ammonium chloride (TMATEMPO) is applied as the sole redox mediator to demonstrate the redox targeting mechanisms between the storage materials of both battery types. The formal potentials of both molecules are investigated, and the targeting mechanism is verified by cyclic voltammetry and state-of-charge measurements. Finally, battery cycling experiments demonstrate that 78-90% of the theoretical capacity of the ORB electrode material can be addressed when this material is present as the redox target in the electrolyte tank of an operating, aqueous organic RFB.

Solid boosters are an emerging concept for improving the performance and especially the energy storage density of the redox flow batteries, but thermodynamical and practical considerations of these systems are missing, scarce or scattered in the literature. In this paper we will formulate how these systems work from the point of view of thermodynamics. We describe possible pathways for charge transfer, estimate the overpotentials required for these reactions in realistic conditions, and illustrate the range of energy storage densities achievable considering different redox electrolyte concentrations, solid volume fractions and solid charge storage densities. Approximately 80% of charge storage capacity of the solid can be accessed if redox electrolyte and redox solid have matching redox potentials. 100 times higher active areas are required from the solid boosters in the tank to reach overpotentials of <10 mV.

A large amount of low-grade heat (<100 °C) is produced in electrical devices and mostly wasted. This type of heat without effective dissipation also causes compromised device performance, reliability, and lifespan. To tackle these issues, a redox targeting (RT)-based flow cell with judiciously designed thermoelectrically active redox materials is demonstrated for the first time for efficient heat-to-electricity conversion through a thermally regenerative electrochemical cycle (TREC). Compared with the conventional TREC systems, the RT-based flow cell not only reveals considerably enhanced thermoelectric efficiency, but the flow of redox fluids also provides a cooling function to the system. In this work, solid material Ni0.2 Co0.8 (OH)2 and redox mediator [Fe(CN)6 ]4-/3- , both of which have negative temperature coefficient and share identical redox potential, are paired via RT-reactions to boost the capacity and meanwhile thermoelectric efficiency of a [Fe(CN)6 ]4-/3- /Zn0/2+ -based flow cell. Upon operating over the TREC cycle, the RT-based flow cell converts heat to electricity at an unprecedented absolute thermoelectric efficiency of 3.61% in the temperature range of 25-55 °C.

Aqueous organic redox flow batteries (AORFBs) have received considerable attention for large-scale energy storage. Quinone derivatives, such as 9,10-anthraquinone-2,7-disulphonic acid (2,7-AQDS), have been explored intensively owing to potentially low cost and swift reaction kinetics. However, the low solubility in pH-neutral electrolytes restricts their application to corrosive acidic or caustic systems. Herein, the single molecule redox-targeting reactions of 2,7-AQDS anolyte are presented to circumvent its solubility limit in pH-neutral electrolytes. Polyimide was employed as a low-cost high-capacity solid material to boost the capacity of 2,7-AQDS electrolyte to 97 Ah L-1 . Through in situ FTIR spectroscopy, a hydrogen-bonding mediated reaction mechanism was disclosed. In conjunction with NaI as catholyte and nickel hexacyanoferrate as the catholyte capacity booster, a single-molecule redox-targeting reaction-based full cell with energy density up to 39 Wh L-1 was demonstrated.

Mitochondria play multifaceted roles in malignant tumor progression. Beyond their bioenergetic role, mitochondria are essential for providing malignant cells a higher plasticity to face the harsh environmental conditions. Cell-autonomous metabolic deregulation of cancer cells, or metabolic adaptation to microenvironmental cues (lack of nutrients, stromal supply, hypoxia, etc.), represent the triggering event of mitochondria overexploitation to orchestrate nutrient sensing and upload, signaling, and redox circuits. As readout of their higher function, mitochondria produce high amounts of reactive oxygen species (ROS) that are functional for multiple signaling networks underlying tumor proliferation, survival, and metastatic process. To compensate for the higher rate of mitochondrial ROS production, cancer cells have evolved adaptive mechanisms to increase their antioxidant systems and to address ROS activating pathways useful for the tumor cell adaptation to environmental changes. As these properties are critical for cancer progression, mitochondrial ROS have recently become an attractive target for anti-cancer therapies. We discuss how understanding of mitochondrial function in the tumor-specific generation of ROS will impact on the development of novel redox-based targeted therapeutic strategies.