One-Step Synthesis of Nanoliposomal Copper Diethyldithiocarbamate and Its Assessment for Cancer Therapy

Abstract

The metal complex copper diethyldithiocarbamate (CuET) induces cancer cell death by inhibiting protein degradation and induces proteotoxic stress, making CuET a promising cancer therapeutic. However, no clinical formulation of CuET exists to date as the drug is insoluble in water and exhibits poor bioavailability. To develop a scalable formulation, nanoliposomal (LP) CuET was synthesized using ethanol injection as a facile one-step method that is suitable for large-scale manufacturing. The nanoparticles are monodispersed, colloidally stable, and approximately 100 nm in diameter with an encapsulation efficiency of over 80%. LP-CuET demonstrates excellent stability in plasma, minimal size change, and little drug release after six-month storage at various temperatures. Additionally, melanoma cell lines exhibit significant sensitivity to LP-CuET and cellular uptake occurs predominantly through endocytosis in YUMM 1.7 cancer cells. Intracellular drug delivery is mediated by vesicle acidification with more nanoparticles being internalized by melanoma cells compared with RAW 264.7 macrophages. Additionally, the nanoparticles preferentially accumulate in YUMM 1.7 tumors where they induce cancer cell death in vivo. The development and characterization of a stable and scalable CuET formulation illustrated in this study fulfils the requirements needed for a potent clinical grade formulation.

Sonoprinting nanoparticles on cellular spheroids via surface acoustic waves for enhanced nanotherapeutics delivery

“…58 Nanoliposomes are used to carry CuET, as the drug is not soluble in aqueous media, such as body fluids. 59 Since the nanoliposomal CuET formulation might prevent the penetration of CuET into the deep layers of tumors, and potentially limit its efficacy, we used our SAW platform to overcome the physical and cellular barriers of LP-CuET delivery. Both cell spheroids were exposed to 5, 10, and 20 μM LP-CuET with a mean size of 110.7 ± 1.0 nm (Fig.…”

Advances in the Application of Nanomaterials to the Treatment of Melanoma

“…LP-CuET was biocompatible and stable in plasma for several hours without any signs of hemolysis. Using nanoliposomal formulations in cancer cells has enhanced the cytotoxicity of LP-CuET, making CuET a potential adjuvant for currently approved therapies [ 65 ].…”

Sonoprinting Nanoparticles on Cellular Spheroids via Surface Acoustic Waves for Enhanced Nanotherapeutics Delivery

“…44 Nanoliposomes are used to carry CuET, as the drug is not soluble in aqueous media, such as body uids. 45 Since the nanoliposomal CuET formulation might prevent the penetration of CuET into deep layers of tumors and potentially limit its e cacy, we used our SAW platform to overcome the physical and cellular barriers of LP-CuET delivery. Both cell spheroids were exposed to 5, 10, and 20 LP-CuET with the mean size of 110.7 1.0 nm (Figure S1) for 10 minutes in the presence or absence of SAW.…”

“…CuET encapsulation was performed using the ethanol injection method, as previously described. 45 Brie y, phospholipids, cholesterol, and CuET were dissolved in 100% ethanol and heated to 50℃. The solution was then rapidly injected into ultrapure water to yield liposomal CuET.…”