Nano-inducer of ferroptosis for targeted chemotherapy of human triple negative breast carcinoma

Neena G Shetake; Sourav Kumar Das; Amit Kumar; Badri N Pandey

doi:10.1016/j.bioadv.2024.213868

Nano-inducer of ferroptosis for targeted chemotherapy of human triple negative breast carcinoma

Biomater Adv. 2024 Apr 20:161:213868. doi: 10.1016/j.bioadv.2024.213868. Online ahead of print.

Authors

Neena G Shetake¹, Sourav Kumar Das², Amit Kumar², Badri N Pandey²

Affiliations

¹ Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400094, India. Electronic address: neenavj@barc.gov.in.
² Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400094, India.

PMID: 38677038
DOI: 10.1016/j.bioadv.2024.213868

Abstract

Triple negative breast carcinoma (TNBC) accounts for 15-20 % of all incident breast cancers (BC) and is known to be highly invasive, has fewer treatment options, and tends to have a worse prognosis. However, due to its biological heterogeneity and diverse clinical and epidemiological behaviors, TNBC lacks a tumor-specific targeted therapy. In the present work we have developed a TNBC-specific targeted nano-delivery agent comprising of a cRGD labeled magneto-liposome (T-LMD) co-encapsulated with oleic acid coated iron oxide nanoparticles (MN-OA) and doxorubicin (Dox) in the liposome bilayer and core, respectively. T-LMD was found to show enhanced uptake and induction of ferroptotic cell death in MDA-MB-231, a TNBC model cell line. Additionally, T-LMD induced ferroptosis was found to be accompanied by release of HMGB1, an immunogenic cell death marker, suggesting its immunogenicity for augmenting the activation of anti-tumor immunity in TNBC. The strategic placement of IONPs in the liposome bilayer of T-LMD facilitates the sensitization of MDA-MB-231 cells to undergo ferroptosis; predominantly via the activation of the iron/lipid metabolism pathway, as validated by use of small molecule ferroptosis inhibitor (ferrostatin-1) and iron chelator (deferoxamine). Activation of ferroptotic cell death was also corroborated by ferroptosis specific-ultrastructural alterations in the shape/size of cellular mitochondria and cell ballooning as observed by transmission electron microscopy and bright field imaging, respectively. Thus, our ferroptosis nano-inducer (T-LMD) can efficiently kill TNBC cells via enhanced LPO and ROS generation leading to membrane damage and consequent release of LDH and HMGB1, induce mitochondrial alterations and enhanced DNA double strand breaks. Altogether, our results suggest significant implications of T-LMD for treatment of TNBC.

Keywords: DNA damage response; Endocytosis; Ferroptosis; Lipid peroxidation; Magneto-liposomes; Mitochondrial fusion; Reactive oxygen species.