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 is insensitive to many chemotherapeutic agents. Ferroptosis is a form of programmed cell death with a Fenton reaction mechanism. It converts endogenous hydrogen peroxide into highly toxic hydroxyl radicals, which inhibit hepatocellular carcinoma progression. Methods The morphology, elemental composition, and tumour microenvironment responses of various organic/inorganic nanoplatforms were characterised by different analytical methods. Their in vivo and in vitro tumour-targeting efficacy and imaging capability were analysed by magnetic resonance imaging. Confocal microscopy, flow cytometry, and western blotting were used to investigate the therapeutic efficacy and mechanisms of complementary ferroptosis/apoptosis mediated by the nanoplatforms. Results The nanoplatform consisted of a silica shell doped with iron and disulphide bonds and an etched core loaded with doxorubicin that generates hydrogen peroxide in situ and enhances ferroptosis. It relied upon transferrin for targeted drug delivery and could be activated by the tumour microenvironment. Glutathione-responsive biodegradability could operate synergistically with the therapeutic interaction between doxorubicin and iron and induce tumour cell death through complementary ferroptosis and apoptosis. The nanoplatform also has a superparamagnetic framework that could serve to guide and monitor treatment under T2-weighted magnetic resonance imaging. Conclusion This rationally designed nanoplatform is expected to integrate cancer diagnosis, treatment, and monitoring and provide a novel clinical antitumour therapeutic strategy. Graphical Abstract

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

“…Qiao-Mei Zhou et al developed iron-doped nanoparticles containing doxorubicin. Doxorubicin and iron act synergistically on the induction of tumor cell death via ferroptosis and apoptosis [ 121 ]. Furthermore, this platform with a superparamagnetic framework could be used to monitor treatment under T2-weighted magnetic resonance imaging as well [ 121 ].…”

“…Doxorubicin and iron act synergistically on the induction of tumor cell death via ferroptosis and apoptosis [ 121 ]. Furthermore, this platform with a superparamagnetic framework could be used to monitor treatment under T2-weighted magnetic resonance imaging as well [ 121 ]. Therefore, the authors concluded that such a nanoplatform could integrate cancer diagnosis, treatment and the monitoring of HCC.…”

Ferroptosis: From Basic Research to Clinical Therapeutics in Hepatocellular Carcinoma

“…114 Nanoplatforms incorporating ferroptosis inducers, chemotherapy drugs, or other therapies such as sonodynamic therapy can effectively inhibit HCC progression. Zhou et al 115 designed a multifunctional nanoplatform with the potential to integrate cancer diagnosis, treatment, and monitoring. It provided a novel clinical antitumor therapeutic strategy to induce ferroptosis via the consumption of GSH, disrupt redox balance by the Fenton reaction and doxorubicin-supplied hydrogen peroxide, synergistic cytotoxicity of doxorubicin inhibition of recurrence and metastasis of HCC, and reversing drug resistance in translational therapy.…”

Iron-Based Hollow Nanoplatforms for Cancer Imaging and Theranostics

“…In recent years, it has been found that metal ions-doped organosilicon NPs show rapid responsiveness towards TME and can serve as biodegradable nanocarriers [ 116 , 117 ]. Zhou et al [ 118 ] prepared an Fe-doped hollow mesoporous organosilicon (HMON) transferrin (Tf)-modified and DOX-loaded nanoplatform (denoted as DOX@Fe-HMON-Tf) for MRI-guided enhanced ferroptosis/chemical combination therapy of cancer. In this design, the anti-tumor efficacy was achieved through sequential TME-activatable reactions.…”