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.
摘要：
三阴性乳腺癌（TNBC）占所有乳腺癌（BC）的15-20％，并且已知具有高侵袭性，治疗选择较少，而且往往预后较差.然而,由于其生物异质性和多样化的临床和流行病学行为，TNBC缺乏肿瘤特异性靶向治疗。在目前的工作中，我们已经开发了一种TNBC特异性靶向纳米递送剂，包括cRGD标记的磁性脂质体（T-LMD）与油酸包被的氧化铁纳米颗粒（MN-OA）和多柔比星（Dox）共封装在脂质体双层和核心中，分别。发现T-LMD在MDA-MB-231(一种TNBC模型细胞系)中显示出铁细胞死亡的增强的摄取和诱导。此外,发现T-LMD诱导的铁凋亡伴随着免疫原性细胞死亡标志物HMGB1的释放，提示其免疫原性可增强TNBC中抗肿瘤免疫的激活。IONP在T-LMD的脂质体双层中的战略放置促进MDA-MB-231细胞的敏化以经历铁凋亡;主要通过铁/脂质代谢途径的激活,通过使用小分子铁凋亡抑制剂（铁抑制素-1）和铁螯合剂（去铁胺）进行验证。通过透射电子显微镜和明场成像观察到的细胞线粒体和细胞气球的形状/大小的铁凋亡特异性超微结构改变也证实了铁细胞死亡的激活。分别。因此，我们的铁凋亡纳米诱导剂（T-LMD）可以通过增强LPO和ROS的产生有效地杀死TNBC细胞，从而导致膜损伤并随后释放LDH和HMGB1，诱导线粒体改变和增强的DNA双链断裂。总之,我们的结果表明T-LMD对TNBC的治疗具有重要意义.
