Abstract
Preclinical in vitro studies of drug candidates for anticancer therapy are generally conducted on well-established 2D cell models. Unfortunately, these models are unable to mimic the properties of in vivo tumors. However, in vitro 3D models (spheroids) have been proven to be superior in reflecting the tumor microenvironment. Diethyldithiocarbamate (DDC−) is the active metabolite of Disulfiram, an approved drug for alcoholism and repurposed for cancer treatment. DDC− binds copper in a molar ratio of 2:1 resulting in a water-insoluble Cu(DDC)2 complex exhibiting anticancer activities. Delivery of the Cu(DDC)2 complex using nanoparticulate carriers provides decisive advantages for a parental application. In this study, an injectable liposomal Cu(DDC)2 formulation was developed and the toxicity was compared with a 2D neuroblastoma and a 3D neuroblastoma cell model. Our results indicate that Cu(DDC)2 liposomes complied with the size requirements of nanoparticles for intravenous injection and demonstrated high drug to lipid ratios as well as colloidal stability upon storage. Furthermore, an efficient cytotoxic effect on neuroblastoma 2D cell cultures and a very promising and even more pronounced effect on 3D cell cultures in terms of neuroblastoma monoculture and neuroblastoma co-culture with primary cell lines was proven, highly encouraging the use of Cu(DDC)2 liposomes for anticancer therapy.
Highlights
Accepted: 12 June 2021The development of drug candidates for anticancer therapy needs proper preclinical in vitro and in vivo studies to prevent clinical trial failure
Liposomal agglomeration occurring after the preparation process of Cu(DDC)2 liposomes was noticed via dynamic light scattering (DLS) and Cryo-TEM
This was mainly due to the presence of extraliposomal precipitated Cu(DDC)2 which agglomerates with liposomes due to the lipophilicity of the
Summary
Accepted: 12 June 2021The development of drug candidates for anticancer therapy needs proper preclinical in vitro and in vivo studies to prevent clinical trial failure. The drug candidate should be able to reach the target tissue and eliminate cancer cells without significantly affecting non-malignant cells [1]. 2D cell monoculture models are most frequently used. These models are established, generate reproducible results, and are performable at low costs. They can be applied as a primary testing model using cancer cells, as well as nonmalignant cells to assess efficiency, toxicity, and selectiveness of anticancer drugs. Cells can interact with the ECM and among each other, affecting cell proliferation, differentiation, gene and protein expression, and resistance to anticancer drugs [3]. Cells can interact with the ECM and among each other, affecting cell proliferation, differentiation, gene and protein expression, and resistance to anticancer drugs [3]. 3D cultures can be categorized as scaffold-free or scaffold-based culture systems, where scaffolds can be produced with natural or synthetic
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