A reactive oxygen species-generating, cancer stem cell-potent manganese(II) complex and its encapsulation into polymeric nanoparticles
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 NP5) enhances breast CSC uptake and greatly reduces overall toxicity. The nanoparticle formulation 1 NP5 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.