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Intracellular redox modulation offers a viable approach to effectively remove cancer stem cells (CSCs), a subpopulation of tumour cells thought to be responsible for cancer recurrence and metastasis. Here we report the breast CSC potency of reactive oxygen species (ROS)-generating manganese(ii)- and copper(ii)-4,7-diphenyl-1,10-phenanthroline complexes bearing diclofenac, a nonsteriodial anti-inflammatory drug (NSAID), 1 and 3 . Notably, the manganese(ii) complex, 1 , exhibits 9-fold, 31-fold, and 40-fold greater potency towards breast CSCs than 3 , salinomycin (an established breast CSC-potent agent), and cisplatin (a clinically approved anticancer drug) respectively. Encouragingly, 1 displays 61-fold higher potency toward breast CSCs than normal skin fibroblast cells. Clinically relevant epithelial spheroid studies show that 1 is able to selectively inhibit breast CSC-enriched HMLER-shEcad mammosphere formation and viability (one order of magnitude) over non-tumorigenic breast MCF10A spheroids. Mechanistic studies show that 1 prompts breast CSC death by generating intracellular ROS and inhibiting cyclooxygenase-2 (COX-2) activity. The manganese(ii) complex, 1 , induces a greater degree of intracellular ROS in CSCs than the corresponding copper(ii) complex, 3 , highlighting the ROS-generating superiority of manganese(ii)- over copper(ii)-phenanthroline complexes. Encapsulation of 1 by biodegradable methoxy poly(ethylene glycol)- b -poly(d,l-lactic- co -glycolic) acid (PEG-PLGA) copolymers at the appropriate feed (5%, 1 NP 5  ) enhances breast CSC uptake and greatly reduces overall toxicity. The nanoparticle formulation 1 NP 5  indiscriminately kills breast CSCs and bulk breast cancer cells, and evokes a similar cellular response to the payload, 1 . To the best of our knowledge, this is the first study to investigate the anti-CSC properties of managense complexes and to demonstrate that polymeric nanoparticles can be used to effectively deliver managense complexes into CSCs.

A reactive oxygen species-generating, cancer stem cell-potent manganese(ii) complex and its encapsulation into polymeric nanoparticles