Dual Targeting of Endoplasmic Reticulum by Redox-Deubiquitination Regulation for Cancer Therapy

Abstract

Background Recently, nanocatalyst-induced endoplasmic reticulum (ER) stress for cancer therapy has been attracting considerable attention. However, cancer cells are often able to overcome ER stress-induced death by activating the unfolded protein response (UPR), making nanocatalytic monotherapy a poor defense against cancer progression. Purpose In this study, to improve the nanocatalytic treatment efficacy, a phase change material (PCM) was used to encapsulate the upstream ER stress initiator, iron oxide nanoparticles (Fe 3 O 4 NPs), and the downstream UPR modulator, PR-619. Subsequently, the tumor-homing peptide tLyP-1 was coupled to it to form tLyP-1/PR-619/Fe 3 O 4 @PCM (tPF@PCM) theranostic platform. Materials and Methods tPF@PCM was synthesized using nanoprecipitation and resolidification methods followed by the EDC/NHS cross-linking method. The targeting capacity of tPF@PCM was evaluated in vitro and in vivo using flow cytometry and magnetic resonance imaging, respectively. The therapeutic efficacy of tPF@PCM was investigated in a renal cell carcinoma mouse model. Moreover, we explored the synergistic anti-tumor mechanism by examining the intracellular reactive oxygen species (ROS), aggregated proteins, ER stress response levels, and type of cell death. Results tPF@PCM had excellent tumor-targeting properties and exhibited satisfactory photothermal-enhanced tumor inhibition efficacy both in vitro and in vivo. Specifically, the phase transition temperature (45 °C) maintained using 808 nm laser irradiation significantly increased the release and catalytic activity of the peroxidase mimic Fe 3 O 4 NPs. This strongly catalyzed the generation of hydroxyl radicals (•OH) via the Fenton reaction in the acidic tumor microenvironment. The redox imbalance subsequently resulted in an increase in the level of damaged proteins in the ER and initiated ER stress. Moreover, the pan-deubiquitinase inhibitor PR-619 blocked the “adaptive” UPR-mediated degradation of these damaged proteins, exacerbating the ER burden. Consequently, irremediable ER stress activated the “terminal” UPR, leading to apoptosis in cancer cells. Conclusion This ER stress-exacerbating strategy effectively suppresses tumorigenesis, offering novel directions for advances in the treatment of conventional therapy-resistant cancers.

Engineering Chemotherapeutic-Augmented Calcium Phosphate Nanoparticles for Treatment of Intraperitoneal Disseminated Ovarian Cancer

“…Some previous studies have shown that the excessive ROS induced the damage of the cell membrane . In addition, the ER is vulnerable to ROS attack. , The western blot revealed that the expression of ER stress markers, including BiP (ER chaperones, a binding immunoglobulin protein) and phosphorylated-eIF2α (eukaryotic initiation factor 2α), was significantly increased in SKOV3 cells after the incubation with DOX or RGD-CaPO/DOX for 48 h. In addition, it should be noted that another ER stress marker, CHOP, a transcription factor closely associated with apoptosis, was obviously increased after incubation with DOX or RGD-CaPO/DOX, which suggested that ER stress induced by DOX could further promote cell apoptosis (Figure B). However, the ER stress could promote calcium disorders in tumor cells since ER was well recognized as the intracellular Ca 2+ store .…”

Nanomedicine for renal cell carcinoma: imaging, treatment and beyond

“…Also, Biao Cai and his colleagues developed an efficient approach, by regulating redox homeostasis concurrently with the activity of deubiquitinases (DUBs), to convert the pro-survival unfolded protein response (UPR) into the pro-apoptotic one (Fig. 5 ) [ 113 ]. A nanocatalytic system, tLyP-1/PR-619/Fe 3 O 4 @PCM (tPF@PCM) co-loaded with Fe 3 O 4 nanoparticles and the pan-DUB inhibitor PR-619, was synthesized by taking advantage of a melting point-controlled thermal responsive phase-change material (PCM).…”

“…C Schematic of the treatment regimen for 786-O tumor-bearing mice. Figure adapted from Biao Cai et al [ 113 ] …”

Phase-change materials-based platforms for biomedicine

“…These hydrophobic TRIDENT PCMs encapsulated with a broad-spectrum antibiotic (imipenem, IMP) and IR780 and subsequently coated with lecithin and DSPE-PEG 2000 not only resulted in the NIR-assisted melting of the nanotransporter but also damaged the membrane facilitating the permeation, as well as interfering in the cell wall biosynthesis and enable bacterial death (Figure 2C) (Qing et al, 2019). In this regard, several PCMs-based on LA and SA, as well as oleic acid, were fabricated for nanotheranostics with the ability of hyperthermia-triggered spatiotemporally tunable drug release (Cai et al, 2021;Lai et al, 2022).…”