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Efficient uptake and retention of iron oxide-based nanoparticles in HeLa cells leads to an effective intracellular delivery of doxorubicin.

ABSTRACT: The purpose of this study was to construct and characterize iron oxide nanoparticles (IONPCO) for intracellular delivery of the anthracycline doxorubicin (DOX; IONPDOX) in order to induce tumor cell inactivation. More than 80% of the loaded drug was released from IONPDOX within 24?h (100% at 70?h). Efficient internalization of IONPDOX and IONPCO in HeLa cells occurred through pino- and endocytosis, with both IONP accumulating in a perinuclear pattern. IONPCO were biocompatible with maximum 27.9% ± 6.1% reduction in proliferation 96?h after treatment with up to 200?µg/mL IONPCO. Treatment with IONPDOX resulted in a concentration- and time-dependent decrease in cell proliferation (IC50?=?27.5?±?12.0??g/mL after 96?h) and a reduced clonogenic survival (surviving fraction, SF?=?0.56?±?0.14; versus IONPCO (SF?=?1.07?±?0.38)). Both IONP constructs were efficiently internalized and retained in the cells, and IONPDOX efficiently delivered DOX resulting in increased cell death vs IONPCO.

SUBMITTER: Popescu RC

PROVIDER: S-EPMC7324358 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Efficient uptake and retention of iron oxide-based nanoparticles in HeLa cells leads to an effective intracellular delivery of doxorubicin.

Popescu R C RC Savu D D Dorobantu I I Vasile B S BS Hosser H H Boldeiu A A Temelie M M Straticiuc M M Iancu D A DA Andronescu E E Wenz F F Giordano F A FA Herskind C C Veldwijk M R MR

Scientific reports 20200629 1

The purpose of this study was to construct and characterize iron oxide nanoparticles (IONPCO) for intracellular delivery of the anthracycline doxorubicin (DOX; IONPDOX) in order to induce tumor cell inactivation. More than 80% of the loaded drug was released from IONPDOX within 24 h (100% at 70 h). Efficient internalization of IONPDOX and IONPCO in HeLa cells occurred through pino- and endocytosis, with both IONP accumulating in a perinuclea ...[more]

PMID: 32601333

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Project description:In several cancers, the efflux and resistance against doxorubicin (DOX), an effective anticancer drug, are associated with cellular iron deficiency and overexpression of the mitochondrial exporter ABCB8. Conversely, decreased ABCB8 expression and disrupted iron homeostasis in the heart have been implicated in DOX-associated cardiotoxicity. While studies have demonstrated that altered iron status can modulate the susceptibility to DOX cardiotoxicity, the exact molecular mechanisms have not been clearly understood. Here, we hypothesized that iron stores influence cardiac ABCB8 expression and consequently cardiac retention and toxicity of DOX. First, we found that ABCB8 deficiency in cardiomyocytes decreased DOX efflux, increased DOX-induced toxicity, and decreased cell viability. Conversely, intracellular DOX retention and toxicity were ameliorated by ABCB8 overexpression. To determine if altered cardiac iron status modifies ABCB8 expression, we treated cardiomyocytes with high iron or iron chelators. Western blot and qPCR analyses revealed that ABCB8 levels were decreased in iron overload and increased in iron deficiency. Subsequently, DOX retention and toxicity were increased in cardiomyocytes with iron overload, whereas iron deficiency ameliorated these effects. Next, we validated our results using a mouse model of hereditary hemochromatosis (HH), a genetic iron overload disorder. HH mice exhibited decreased ABCB8 expression and increased DOX retention and toxicity. These changes were abolished by the treatment of HH mice with a low-iron diet. Finally, cardiac-specific overexpression of ABCB8 in HH mice prevented cardiac DOX accumulation and abrogated DOX-induced cardiotoxicity without altering iron overload in the heart. Together, our results demonstrate that ABCB8 mediates DOX efflux and that iron regulates DOX retention and toxicity by altering cardiac ABCB8 expression. Our study identifies a novel role of iron in DOX-induced cardiotoxicity and suggests potential therapeutic intervention for DOX and anthracycline-based cancer pharmacology.

Dataset Information

Efficient uptake and retention of iron oxide-based nanoparticles in HeLa cells leads to an effective intracellular delivery of doxorubicin.

Publications

Efficient uptake and retention of iron oxide-based nanoparticles in HeLa cells leads to an effective intracellular delivery of doxorubicin.

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