Pulmonary Delivery of Theranostic Nanoclusters for Lung Cancer Ferroptosis with Enhanced Chemodynamic/Radiation Synergistic Therapy

Abstract

Inefficient tumor accumulation and penetration remain as the main challenges to therapy efficacy of lung cancer. Local delivery of smart nanoclusters can increase drug penetration and provide superior antitumor effects than systemic routes. Here, we report self-assembled pH-sensitive superparamagnetic iron oxide nanoclusters (SPIONCs) that enhance in situ ferroptosis and apoptosis with radiotherapy and chemodynamic therapy. After pulmonary delivery in orthotopic lung cancer, SPIONCs disintegrate into smaller nanoparticles and release more iron ions in an acidic microenvironment. Under single-dose X-ray irradiation, endogenous superoxide dismutase converts superoxide radicals produced by mitochondria to hydrogen peroxide, which in turn generates hydroxyl radicals by the Fenton reaction from iron ions accumulated inside the tumor. Finally, irradiation and iron ions enhance tumor lipid peroxidation and induce cell apoptosis and ferroptosis. Thus, rationally designed pulmonary delivered nanoclusters provide a promising strategy for noninvasive imaging of lung cancer and synergistic therapy.

Ionizing Radiation-Induced Ferroptosis Based on Nanomaterials

“…Ultimately, ferroptosis ensued because IR and NPs exacerbated generation of hydroxyl radicals and tumor lipid peroxidation. 53 Additionally, this analysis demonstrated that SPIONCs have no effect on the level of blood biochemical and normal kidney and liver function and has the potential for clinical translation. 53 In addition, certain studies have employed nanomaterials as radionuclide carriers to supply sufficient tumor-targeted delivery and improve effect of radionuclide therapy.…”

“… 53 Additionally, this analysis demonstrated that SPIONCs have no effect on the level of blood biochemical and normal kidney and liver function and has the potential for clinical translation. 53 In addition, certain studies have employed nanomaterials as radionuclide carriers to supply sufficient tumor-targeted delivery and improve effect of radionuclide therapy. Chen et al utilized the therapeutic radionuclide iodine-131( 131 I) to label HSA-CAT nanoreactors (NRs), and dramatically attenuate tumor hypoxia, hence boosting the therapeutic efficacy of radionuclide 131 I.…”

Targeting ferroptosis as a vulnerability in pulmonary diseases

“…Prussian blue/calcium peroxide nanocomposites promote iron mineralization in lung cancers, which greatly facilitates early diagnosis of lung carcinoma and activates ferroptosis to inhibit tumor growth [ 117 ]. Most recently, a self-assembled pH-sensitive superparamagnetic iron oxide nanoclusters (SPIONCs) is reported to enhance in situ ferroptosis and apoptosis of lung tumors with radiotherapy and chemodynamic therapy via releasing iron in the tumor microenvironment (TME) [ 118 ].…”

Metabolic Adaptation-Mediated Cancer Survival and Progression in Oxidative Stress

“…For example, the doxorubicin, bleomycin, or platinum coordination complexe causes mitochondrial DNA damage or prevent DNA synthesis by inducing cellular oxidative distress [ 47 , 48 ]. Furthermore, genetically unstable clones generated upon irradiation also displayed higher intracellular ROS levels, potentially due to reduced mitochondrial activity and respiration [ 49 , 50 ]. In addition, cancer cells under hypoxia are associated with an increase in ROS, likely because of the deficiency in O 2 that prevents electron transfer across the mitochondrial complexes, thereby increasing the possibility of electron leakage to generate ROS [ 27 , 51 , 52 ].…”