Fenton-Reaction-Acceleratable Magnetic Nanoparticles for Ferroptosis Therapy of Orthotopic Brain Tumors

Abstract

Cancer is one of the leading causes of morbidity and mortality in the world, but more cancer therapies are needed to complement existing regimens due to problems of existing cancer therapies. Herein, we term ferroptosis therapy (FT) as a form of cancer therapy and hypothesize that the FT efficacy can be significantly improved via accelerating the Fenton reaction by simultaneously increasing the local concentrations of all reactants (Fe 2+ , Fe 3+ , and H 2 O 2 ) in cancer cells. Thus, Fenton-reaction-acceleratable magnetic nanoparticles, i.e., cisplatin (CDDP)-loaded Fe 3 O 4 /Gd 2 O 3 hybrid nanoparticles with conjugation of lactoferrin (LF) and RGD dimer (RGD2) (FeGd-HN@Pt@LF/RGD2), were exploited in this study for FT of orthotopic brain tumors. FeGd-HN@Pt@LF/RGD2 nanoparticles were able to cross the blood−brain barrier because of its small size (6.6 nm) and LF-receptor-mediated transcytosis. FeGd-HN@Pt@LF/RGD2 can be internalized into cancer cells by integrin α v β 3 -mediated endocytosis and then release Fe 2+ , Fe 3+ , and CDDP upon endosomal uptake and degradation. Fe 2+ and Fe 3+ can directly participate in the Fenton reaction, whereas the CDDP can indirectly produce H 2 O 2 to further accelerate the Fenton reaction. The acceleration of Fenton reaction generates reactive oxygen species to induce cancer cell death. FeGd-HN@Pt@LF/RGD2 successfully delivered reactants involved in the Fenton reaction to the tumor site and led to significant inhibition of tumor growth. Finally, the intrinsic magnetic resonance imaging (MRI) capability of the nanoparticles was used to assess and monitor tumor response to FT (self-MRI monitoring).

Camouflaging Nanoparticles with Brain Metastatic Tumor Cell Membranes: A New Strategy to Traverse Blood–Brain Barrier for Imaging and Therapy of Brain Tumors

“…The TEER of 150–300 Ω cm 2 was achieved, indicating the tight junction of the BBB model can be considered to be similar to that of the in vivo BBB. [ 16,27 ] PCL‐ICG, B16‐PCL‐ICG, 4T1‐PCL‐ICG, and COS7‐PCL‐ICG were added into the apical chamber, respectively. After 8 h incubation, the ICG concentration in the apical side (AP) and basolateral side (BL) were measured by a fluorescence spectrometer.…”

Recent Progress in Ferroptosis Inducers for Cancer Therapy

“…F) Volume variation of the orthotopic brain tumors with different treatment (mean ± S.E., n = 5). B–F) Reproduced with permission . Copyright 2018, American Chemical Society.…”

“…In addition to researches focusing on the enhancement of iron release efficiency, a recent work by Shen et al tried to boost ROS production by increasing concentrations of all reactants (Fe 3+ , Fe 2+ , and H 2 O 2 ) simultaneously . In this study, cisplatin‐loaded Fe 3 O 4 /Gd 2 O 3 nanoparticles were conjugated with lactoferrin (LF, facilitates nanoparticles cross blood brain barrier) and RGD peptide dimer (RGD2, targeting ligand for integrin α V β 3 on brain tumor) to form the multifunctional nanocomposites, FeGd‐HN@Pt@LF/RGD2 (Figure B), of which the ferroptosis therapeutic efficacy was significantly improved by accelerating ROS generation in brain tumor (Figure C).…”

Intelligent Nanocomposites with Intrinsic Blood–Brain‐Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma

“…Magnetic resonance imaging (MRI) is widely used for the diagnosis of GBM in clinical practice because of its admirable soft tissue contrast, high spatial resolution, deep tissue penetration, and negligible irradiation damage. Many nanocarriers have been prepared to carry contrast agents across the BBB for the MRI of brain tumors . Nevertheless, most such loaded contrast agents are Fe‐ or Gd‐based, which feature “always‐on” enhancement of MR signals in tumor regions and adjacent normal tissues and are therefore unfavorable for the specific MRI of glioblastoma.…”