Liposome‐Polymer Nanoparticles Loaded with Copper Diethyldithiocarbamate and 6‐Bromo‐Indirubin‐3′‐Oxime Enable the Treatment of Refractive Melanoma

Abstract Despite significant advances in cancer immunotherapy, many patients fail to respond to current treatments, outlining the need to develop novel therapeutic modalities. Therapeutic resistance in cancer cells is mediated by significant genomic instability due to their oncogenic transformation and evolutionary pressures inside the tumor microenvironment (TME). However, these cellular and molecular adaptations can result in a significant increase in the baseline endoplasmic reticulum (ER) stress in TME‐resident cells. This can be taken advantage of as a therapeutic strategy by using the metal chelate copper diethyldithiocarbamate (CuET), a potent inhibitor of the p97‐UFD1‐NPL4 protein complex to induce cytotoxicity and exacerbate ER stress in cancer cells. Here, CuET is combined with the anti‐inflammatory drug 6‐bromo‐indirubin‐3′‐oxime (BIO), a potent GSK3 inhibitor, to modulate the aberrant inflammatory response inside the TME. However, both CuET and BIO are highly hydrophobic and exhibit poor bioavailability, requiring the development of an appropriate carrier. Herein, it is demonstrated that CuET and BIO can be efficiently loaded into liposomes that are stabilized by poly(vinylpyrrolidone). The liposome‐loaded drug combination resulted in a significant decrease of 47% and 76% in the tumor burden of syngeneic B16F10 and YUMM1.7 mouse models, respectively, without any major acute toxicity.