Self-amplification of Oxidative Stress With Tumour Microenvironment-activatable Iron-doped Nanoplatform for Targeting Hepatocellular Carcinoma Synergistic Cascade Therapy and Diagnosis

Abstract

Background: Hepatocellular carcinoma (HCC) is insensitivity to chemotherapy drugs and conventional chemotherapy has long been regarded as ineffective against HCC. Ferroptosis is a form of programmed cell death with a definite Fenton reaction mechanism that converts endogenous hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (·OH), expected to inhibit HCC in cooperation with chemotherapy.Methods: The organic/inorganic nanoplatform were characterized by various methods to analyze the morphology, element composition and tumour microenvironment response-ability. Determine the tumour-targeting efficiency and imaging capabilities of nanoplatform through magnetic resonance imaging (MRI) in vivo and in vitro. Confocal microscopy, flow cytometry and western blotting were used to study the therapeutic efficacy and mechanism of complementary ferroptosis/apoptosis treatment of nanoplatform. Results: This nanoplatform consists of a silica shell doped with iron and disulfide bonds, and the etched core loaded DOX that generate H2O2 in situ to enhance the ferroptosis effect. The ultrasensitive nanoplatform relied on transferrin for precise delivery and could be activated by the tumour microenvironment (TME) in which the glutathione (GSH)-responsive biodegradability could synergize with the therapeutic interaction between DOX and iron and induce tumour cells death through complementary ferroptosis and apoptosis mechanisms. Simultaneously, the nanoplatform had a superparamagnetic framework that can be used for treatment guidance and monitoring under the guidance of T2-weighted MRI.Conclusion: The rationally designed nanoplatform is expected to realize the integration of diagnosis, treatment and monitoring, and provides a new strategy for anti-tumour effects.

HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer

“…Doxorubicin (DOX) is a cytotoxic anthracycline antibiotic, widely used for treating a variety of cancers, which is considered as the foundation of chemotherapy for breast cancer (40). Accumulating studies have shown that doxorubicin promoted cancer cell death through inhibiting DNA replication and generating H 2 O 2 , which is the Fenton reaction substrate leading to increased ROS production (41, 42). Thus, doxorubicin might kill cancer cells by indirectly inducing ferroptosis.…”