BHQ-Cyanine-Based “Off–On” Long-Circulating Assembly as a Ferroptosis Amplifier for Cancer Treatment: A Lipid-Peroxidation Burst Device

Abstract

Ferroptosis is an iron-dependent cell death caused by accumulation of lipid peroxidation (LPO), which is a new strategy for cancer treatment. Th current ferroptosis therapy nanodevices have low efficiency and side effects generally. Hence, we developed a Black Hole Quencher (BHQ)-based fluorescence “off–on” nanophotosensitizer complex assembly (CSO-BHQ-IR780-Hex/MIONPs/Sor). CSO-connected BHQ-IR780-Hex and -loaded magnetic iron oxide nanoparticles (MIONPs) and sorafenib (Sor) formed a very concise functionalized delivery system. CSO-BHQ-IR780-Hex disassembled by GSH attack and released IR780-Hex, MIONPs, and sorafenib. IR780-Hex anchored to the mitochondrial membrane, which would contribute to amplifying the efficiency of the photosensitizer. When NIR irradiation was given to CSO-BHQ-IR780-Hex/MIONPs/Sor-treated cells, iron supply increased, the xCT/GSH/GPX-4 system was triggered, and a lot of LPO burst. A malondialdehyde test showed that LPO in complex assembly-treated cells was explosive and increased about 18-fold compared to the control. The accumulation process of particles was monitored by an IR780-Hex photosensitizer, which showed an excellent tumor target ability by magnetic of nanodevice in vivo. Interestingly, the half-life of sorafenib in a nanodevice was increased about 26-fold compared to the control group. Importantly, the complex assembly effectively inhibits tumor growth in the breast tumor mouse model. This work would provide ideas in designing nanomedicines for the ferroptosis treatment of cancer.

Co-Administration of iRGD with Sorafenib-Loaded Iron-Based Metal-Organic Framework as a Targeted Ferroptosis Agent for Liver Cancer Therapy

“…HepG2 cells were seeded into 96-well plates and incubated until attachment. Then the medium was replaced with fresh culture medium containing 200 μM DFOM (an ironchelating agent), 28 ferrostatin-1 (Fer-1, an inhibitor of ferroptosis; 1 μM), 28 and DMEM and incubated for 1 h. Next, the cell culture medium was replaced with DMEM, MIL-101(Fe), sorafenib, MIL-101(Fe)@sor, or MIL-101(Fe)@sor/iRGD) for 24 h at an equivalent dosage of 10 μM sorafenib and 30 μmol/L iRGD. Finally, cell viability was quantitatively analyzed using MTT assays.…”

Nanomedicine of tyrosine kinase inhibitors

“…Chitosan oligosaccharide was conjugated with IR780 cyanine fluorescent label and Black Hole Quencher for visualization of fluorescence triggered by NIR irradiation. This complex then self-assembled, encapsulating sorafenib and superparamagnetic iron oxide NPs that were intended for induction of ferroptosis characterized by a high rate of lipid peroxidation 144 . This elaborate structure was capable of causing explosive lipid peroxidation upon irradiation with NIR (> 18-fold compared to non-irradiated structure) and exhibited > 26-fold increase in half-life of sorafenib.…”

Regulated lytic cell death in breast cancer

“…Nanoparticles have the characteristics of a high load capacity, strong permeability and retention effects, specific targeting and controlled release, and they can be imaged. Recently, many modifications of iron‐based nanoparticles, including iron oxide nanoparticles, FePt nanoparticles, iron‐based metal–organic frameworks and others have been widely used to initiate ferroptosis by triggering the Fenton reaction (L. Chen et al, 2019; Sang et al, 2019a, 2019b; Shen et al, 2018; Yue et al, 2018). Based on the enhancement of the Fenton reaction, the design strategies of these nanoparticles include increasing the types of substrate, including iron and H 2 O 2 and changing the reaction conditions (such as the pH and GSH level) to overcome the limitation of insufficient endogenous H 2 O 2 and acidity in the tumour area to induce ferroptosis for cancer treatment (L. Chen et al, 2019; Huo et al, 2019; T. Liu et al, 2018; Shen et al, 2018; S. Wang et al, 2019; Xiong et al, 2019).…”