Delivery of an immunogenic cell death-inducing copper complex to cancer stem cells using polymeric nanoparticles

The major cause for cancer related deaths worldwide is tumour relapse and metastasis, both of which have been heavily linked to the existence of cancer stem cells (CSCs). CSCs are able to escape current treatment regimens, reform tumours, and promote their spread to secondary sites. Recently, our research group reported the first metal-based agent 1 (a copper(ii) compound ligated by a bidentate 4,7-diphenyl-1,10-phenanthroline and a tridentate Schiff base ligand) to potently kill CSCs via cytotoxic and immunogenic mechanisms. Here we show that encapsulation of 1 by polymeric nanoparticles at the appropriate feed (10%, 1 NP¹⁰) enhances CSC uptake and improves potency towards bulk cancer cells and CSCs (grown in monolayer and three-dimensional cultures). The nanoparticle formulation triggers a similar cellular response to the payload, which bodes well for further translation. Specifically, the nanoparticle formulation elevates intracellular reactive oxygen species levels, induces ER stress, and evokes damage-associated molecular patterns consistent with immunogenic cell death. To the best of our knowledge, this is the first study to demonstrate that polymeric nanoparticles can be used to effectively deliver immunogenic metal complexes into CSCs.