Ferroptotic antitumor therapy has been compromised by various intracellular antioxidants, particularly glutathione and thioredoxin. Both are cofactors of glutathione peroxide 4 (GPX4) that act against oxidative stress via catalyzing the reduction of lipid peroxides. It was postulated that tailored polymer micelles could enhance ferroptotic antitumor efficacy via diminishing glutathione and thioredoxin under hypoxia. The aim was to engineer hypoxia-responsive micelles for selective enhancement of ferroptotic cell death in solid tumor. The polymer contains hydrophilic poly(ethylene glycol) (PEG) that is linked by azobenzene linker with nitroimidazole-conjugated polypeptide. The tailored polymer could self-assemble into nanoscale micelles to encapsulate RAS-selective lethal small molecule 3, a covalent GPX4 inhibitor. Under hypoxia, the azobenzene moiety enabled PEG shedding and enhanced micelles uptake in 4T1 cells. Likewise, the nitroimidazole moiety was reduced by the overexpressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient depletion of NADPH. This impaired both the glutathione and thioredoxin redox cycle, leading to diminished intracellular glutathione and thioredoxin. The selective potency of ferroptotic micelles in depleting NADPH, glutathione and thioredoxin was further verified in vivo in the 4T1 tumor xenograft mice model. This work highlights the role of hypoxia-responsive polymers in enhancing the potency of ferroptotic inducers against solid tumors without additional side effects to healthy organs.
Mesoporous silica nanocarriers (MSNs) are appealing in terms of their large cavity surface area and high loading capacity, but they have been suffering from premature cargo release. Herein, we report a gated smart MSN that is sensitive to low oxygen concentration (i.e., hypoxia) via taking advantage of the superior electron-accepting ability of the azobenzene moiety. The azobenzene polymer was employed as the responsive gate-keeper that was deposited on the MSN surface, followed by coating with amphiphilic Pluronic F68 for steric stabilization. The obtained nanocarriers were less than 200 nm. The in vitro polymer degradation was spectrophotometrically witnessed via the employment of a reducing agent, namely, sodium dithionite, with a strong electron-donating ability. The hypoxia-responsive cargo release from the gated MSN was quantitatively demonstrated in breast cancer cells (MCF-7) using the fluorescence resonance energy transfer (FRET) technique where coumarin 6 and rhodamine B was selected as the FRET donor and acceptor, respectively. The FRET ratio was used as the index and decreased linearly over time under hypoxia, whereas it almost remained steady under normoxia. In addition, a model photosensitizer, namely, chlorin e6, was also loaded in the gated MSN whose toxicity under hypoxia was verified. This study developed a hypoxia-responsive MSN with the azobenzene polymer as the removable gate-keeper, which would expand the application of MSNs in pharmaceutical and biomedical areas since the low oxygen concentration is a unique trigger in many pathological conditions.
The combination of apoptosis and ferroptosis is highly appealing in addressing the tumor heterogeneity‐induced therapy resistance. Reactive oxygen species (ROS)‐based cancer nanomedicine can assemble multiple cell death modalities in a single platform, but the potency of ferroptosis induction is limited. Here, a novel mechano‐responsive polymeric micellar system for selective ferroptosis boosting and ROS therapy sensitization is reported. The mechanophore, ferrocene (Fc) is the key to such design, and the ultrasound can speed up the dissociation of Fc and the release of Fe2+ and hydroxyl radical in the presence of elevated H2O2 in the tumor microenvironment. The Fc‐conjugated amphiphilic copolymers self‐assemble into nanoscale micelles wherein a model sonosensitizer, protoporphyrin IX is physically encapsulated. Upon triggering, the mechano‐responsive micelles produce both singlet oxygen and hydroxyl radical for apoptotic cell death in a model murine breast cancer cell line (4T1). The ROS also depletes intracellular glutathione and thioredoxin, which together with the heightened Fe2+ level boosts lipid peroxidation and hence ferroptotic cell death. The interactive apoptosis and ferroptosis induction and sensitization is further demonstrated in a 4T1 tumor‐bearing mice model with negligible adverse effects. The current work provides a novel approach to simultaneously sensitize apoptosis and ferroptosis for efficient on‐demand cancer therapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.