Abstract
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.
Highlights
Cancer stem cells (CSCs) are a small sub-population of tumours with the capacity to differentiate, self-renew, and form secondary tumours.[1,2] cancer stem cells (CSCs) can evade current chemotherapeutic and radiotherapeutic approaches as these treatments tend to target fast growing cancer cells, and CSCs, due to their quiescent stem cell-like nature, divide relatively slowly.[3,4,5] As CSCs only make up a small fraction of any given tumour and reside in hard to reach niches, they are o en missed by surgical interventions as well.[6]
An anti-CSC agent that is effective in clinical settings has not been reported, this is despite the identi cation of targetable CSC features such as constituents of the CSC microenvironment, overexpressed plasmatic membrane proteins, and overactive cell signalling pathways.[9,10,11]
The capacity of chemical agents to trigger immunogenic cell death (ICD) of cancer cells is directly linked to their ability to localise in the endoplasmic reticulum (ER) and elevated reactive oxygen species (ROS) levels, which o en leads to ER stress and apoptosis.[16,17]
Summary
Exogenous agents can impart a cancer cell-targeting immune response by evoking an atypical mode of cell death called immunogenic cell death (ICD), whereby non-viable cancer cells prompt immune cells within the tumour microenvironment to nd, envelop, process, and destroy them by revealing speci c protein signals.[15]. Tissue type and only a handful contain a metal.[18,19] Very recently, our research group reported a copper(II)-containing compound 1, made up of a bidentate 4,7-diphenyl-1,10-phenanthroline ligand and a tridentate Schiff base ligand, that was able to induce ICD of CSCs (see Fig. 1 for chemical structure of 1).[20] The copper(II) complex 1 was the rst inorganic compound to kill CSCs (of any tissue type) in an immunogenic manner This discover was a positive step toward the development of clinically applicable metal-based immuno-chemotherapeutics, as the removal of CSCs by immunogenic agents in tandem with traditional bulk cancer cell-active treatments, could prove to be an effective way of removing heterogeneous tumour populations in their entirety. Polymeric nanoparticles have been previously used to deliver cytotoxic agents into CSCs, this is as far as we are aware, the rst study to demonstrate that polymeric nanoparticles can be used to effectively deliver an immunogenic metal complex into CSCs
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