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 2+ , Fe 3+ , and H 2 O 2 ) in cancer cells. Thus, Fenton-reaction-acceleratable magnetic nanoparticles, i.e., cisplatin (CDDP)-loaded Fe 3 O 4 /Gd 2 O 3 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 α v β 3 -mediated endocytosis and then release Fe 2+ , Fe 3+ , and CDDP upon endosomal uptake and degradation. Fe 2+ and Fe 3+ can directly participate in the Fenton reaction, whereas the CDDP can indirectly produce H 2 O 2 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).
The long sought-after, intrinsically short-lived molecule ethylenedione (OCCO) was observed and investigated by anion photoelectron spectroscopy. The adiabatic electron affinity of its quasi-bound (3)Σ(g)(-) state is 1.936(8) eV. The vibrational progression with a 417(15) cm(-1) frequency observed within the triplet band corresponds to a trans-bending mode. Several dissociative singlet states are also observed, corresponding to two components of the (1)Δg state and the (1)Σ(g)(+) state. The experimental results are in agreement with theoretical predictions and constitute the first spectroscopic observation and characterization of this elusive compound.
There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.
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