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Iron Oxide Nanoparticles as Autophagy Intervention Agents Suppress Hepatoma Growth by Enhancing Tumoricidal Autophagy.

ABSTRACT: The combined treatment with nanoparticles and autophagy inhibitors, such as chloroquine (CQ) and hydroxychloroquine (HCQ), is extensively explored for cancer therapy. However, the toxicity of autophagy inhibitors and their unselective for tumoricidal autophagy have seriously hindered the application of the combined treatment. In this study, a carboxy-functional iron oxide nanoparticle (Fe2O3@DMSA) is designed and identified to significantly exert an antitumor effect without adding CQ or HCQ. Further investigation indicates that the effective inhibition effect of Fe2O3@DMSA alone on hepatoma growth is triggered by inhibiting the fusion of autophagosomes and lysosomes to enhance tumoricidal autophagy, which is induced by intracellular iron-retention-induced sustained reactive oxygen species (ROS) production. Furthermore, in two hepatoma-bearing mouse models, Fe2O3@DMSA alone effectively suppresses the growth of tumors without obvious toxic side effects. These studies offer a promising strategy for cancer therapy.

SUBMITTER: Xie Y

PROVIDER: S-EPMC7435245 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Iron Oxide Nanoparticles as Autophagy Intervention Agents Suppress Hepatoma Growth by Enhancing Tumoricidal Autophagy.

Xie Yuexia Y Jiang Jiana J Tang Qianyun Q Zou Hanbing H Zhao Xue X Liu Hongmei H Ma Ding D Cai Chenlei C Zhou Yan Y Chen Xiaojing X Pu Jun J Liu Peifeng P

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200609 16

The combined treatment with nanoparticles and autophagy inhibitors, such as chloroquine (CQ) and hydroxychloroquine (HCQ), is extensively explored for cancer therapy. However, the toxicity of autophagy inhibitors and their unselective for tumoricidal autophagy have seriously hindered the application of the combined treatment. In this study, a carboxy-functional iron oxide nanoparticle (Fe<sub>2</sub>O<sub>3</sub>@DMSA) is designed and identified to significantly exert an antitumor effect without ...[more]

PMID: 32832347

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Project description:Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 Receptor domain-containing adaptor-inducing IFN-β (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent induced significant antitumor effects suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases support a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anti-cancer immune (nano)adjuvant properties to generate therapeutic benefit without requiring uptake by cancer cells. HuHER2 transgenic mice that developed palpable primary mammary tumors were assigned randomly into one of two groups (n = 3/group) to receive either PBS or BP (5 mg Fe/mouse). Mice were sacrificed 7 days after treatment and tumors, lungs, livers, spleens, lymph nodes, and bone marrows were collected. All nanoparticle-containing organs collected from BP treated mice were divided into two equal sections except for lungs (no detectable nanoparticle accumulation). One section was processed for RNA isolation from whole organ. The other tissue/organ section was further processed for magnetic sorting. These were digested to provide single cells as described before28,38 and nanoparticle associated cells were separated magnetically to obtain the nanoparticle-associated fraction (BP-NA). RNA was isolated from BP-NA cells from each organ and tumor and used for sequencing. For Nanostring analysis, HuHER2 transgenic tumor bearing mice were treated with PBS or BP (5 mg Fe) on the day of tumor detection (n = 12/group). Three mice from each group were sacrificed on day 1, 3, 7, or 31 and primary tumors collected for RNA isolation and gene expression analysis by Nanostring using the pan-immune cell marker panel.

Dataset Information

Iron Oxide Nanoparticles as Autophagy Intervention Agents Suppress Hepatoma Growth by Enhancing Tumoricidal Autophagy.

Publications

Iron Oxide Nanoparticles as Autophagy Intervention Agents Suppress Hepatoma Growth by Enhancing Tumoricidal Autophagy.

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