Breaking the Intracellular Redox Balance with Diselenium Nanoparticles for Maximizing Chemotherapy Efficacy on Patient-Derived Xenograft Models

Abstract

Excessive oxidative stress in cancer cells can induce cancer cell death. Anticancer activity and drug resistance of chemotherapy are closely related to the redox state of tumor cells. Herein, five lipophilic Pt(IV) prodrugs were synthesized on the basis of the most widely used anticancer drug cisplatin, whose anticancer efficacy and drug resistance are closely related to the intracellular redox state. Subsequently, a series of cisplatin-sensitive and drug-resistant cell lines as well as three patient-derived primary ovarian cancer cells have been selected to screen those prodrugs. To verify if the disruption of redox balance can be combined with these Pt(IV) prodrugs, we then synthesized a polymer with a diselenium bond in the main chain for encapsulating the most effective prodrug to form nanoparticles (NP(Se)s). NP(Se)s can efficiently break the redox balance via simultaneously depleting GSH and augmenting ROS, thereby achieving a synergistic effect with cisplatin. In addition, genome-wide analysis via RNA-seq was employed to provide a comprehensive understanding of the changes in transcriptome and the alterations in redox-related pathways in cells treated with NP(Se)s and cisplatin. Thereafter, patient-derived xenograft models of hepatic carcinoma (PDX HCC ) and multidrugresistant lung cancer (PDX MDR ) were established to evaluate the therapeutic effect of NP(Se)s, and a significant antitumor effect was achieved on both models with NP(Se)s. Overall, this study provides a promising strategy to break the redox balance for maximizing the efficacy of platinum-based cancer therapy.

Targeting Hypoxic Tumors with Hybrid Nanobullets for Oxygen-Independent Synergistic Photothermal and Thermodynamic Therapy

“…3 h, i). Compared with the traditional PDT, a ROS-mediated therapeutic modality [ 47 ], the main advantage of TDT is that the cytotoxic alkyl radicals also can be generated under the hypoxic tumor microenvironment. To prove it, we also detected the in vitro ROS production during ZnPc-mediated PDT under both hypoxic and normoxic conditions.…”

A Versatile Theranostic Platform for Colorectal Cancer Peritoneal Metastases: Real‐Time Tumor‐Tracking and Photothermal‐Enhanced Chemotherapy

“…The combined and cascaded tailoring would obviously disturb the intratumoral GSH‐ROS balance to induce the apoptosis. [ 27 ] Based on these in vitro experiments, we also detected the TNF‐ α expression (reflecting ROS damage) of the tumors isolated from the orthotopic tumor‐bearing mice post different treatment by Western–Blots method. The results indicated that targeted SO 2 delivery plus a photothermal treatment would lead to the highest ROS injury to the tumor cells (Figure S25B , Supporting Information).…”

Convulsões Febris: Perspectivas Histórica E Futura À Luz Da Genética

“…Sabe-se que o equilíbrio de oxirredução celular desempena importante papel na regulação comportamental celular, tais quais se resumem em processos fisiopatológicos, como transcrição de genes, transdução de sinal, proliferação, diferenciação, apoptose e necrose são regidos pelo equilíbrio de redox (WEI et al, 2020).…”

“…No entanto, os mecanismos para todas essas estratégias quase dependem da depleção da glutationa (GSH) ou do aumento das espécies reativas de oxigênio (ROS), todavia, poucos sistemas conseguem atingir ambos os efeitos simultaneamente, o que limitaria a amplificação final do estresse oxidativo. Além disso, embora os nanocatalisadores tenham sido amplamente empregados para quebrar o equilíbrio redox, a maioria deles são materiais inorgânicos (WEI et al, 2020).…”