Piperlongumine loaded PLGA nanoparticles inhibit cancer stem-like cells through modulation of STAT3 in mammosphere model of triple negative breast cancer

TNBC exhibits higher rate of chemoresistance, metastasis, and relapse among all subtypes of breast cancer. This malignant statein TNBC is due to self-renewing sub-population of cells called cancer stem cells (CSCs). They are major caveats in TNBC treatment and need to be obliterated. In this regard, we explored piperlongumine (PL) that has remarkable anti-cancerous property but poor pharmacokinetics limits its application. So, to enhance its biological activity we developed PLGA based nanoformulation for PL (PL-NPs) and examined anti-CSCs effects of PL and PL-NPs in mammospheres. Results indicated that PL-NPs have higher cellular uptake than PL in mammospheres. Further, we demonstrated that PL-NPs remarkably inhibit various characteristics of CSCs like expression of ALDH, self-renewability, chemoresistance, and EMT in mammopsheres. We next investigated the possible mechanism underlying these multi-modal effects, and found that inhibition of STAT3 might be the driving force. In order to confirm this, we used colivelin a potent synthetic peptide activator of STAT3 in combination with treatments and found that anti-CSCs effects of PL and PL-NPs were reversed. Taken together, our data indicates that PL-NPs show enhanced inhibition of CSCs through downregulation of STAT3 and provides insight into development of PL based nanomedicine for targeting CSCs in TNBC.