Abstract
α-N-Heterocyclic thiosemicarbazones such as triapine and COTI-2 are currently investigated as anticancer therapeutics in clinical trials. However, triapine was widely inactive against solid tumor types. A likely explanation is the short plasma half-life time and fast metabolism. One promising approach to overcome these drawbacks is the encapsulation of the drug into nanoparticles (passive drug-targeting). In a previous work we showed that it was not possible to stably encapsulate free triapine into liposomes. Hence, in this manuscript we present the successful preparation of liposomal formulations of the copper(ii) complexes of triapine and COTI-2. To this end, various drug-loading strategies were examined and the resulting liposomes were physico-chemically characterized. Especially for liposomal Cu–triapine, a decent encapsulation efficacy and a slow drug release behavior could be observed. In contrast, for COTI-2 and its copper(ii) complex no stable loading could be achieved. Subsequent in vitro studies in different cell lines with liposomal Cu–triapine showed the expected strongly reduced cytotoxicity and DNA damage induction. Also in vivo distinctly higher copper plasma levels and a continuous release could be observed for the liposomal formulation compared to free Cu–triapine. Taken together, the here presented nanoformulation of Cu–triapine is an important step further to increase the plasma half-life time and tumor targeting properties of anticancer thiosemicarbazones.
Highlights
Introduction αN-Heterocyclic thiosemicarbazones possess a distinctive N,N,S-donor ligand set, which characterizes them as strong metal chelators.[1]
Non-encapsulated drug was removed from the liposomal formulation by size exclusion chromatography (SEC) using the Sephadex G50 dextran matrix and phosphate-buffered saline (PBS) at pH 7.4
Any free COTI-2 could be observed on Scheme 1 Preparation of the liposomal formulations by addition of the drug at the beginning of the synthetic procedure
Summary
Introduction αN-Heterocyclic thiosemicarbazones possess a distinctive N,N,S-donor ligand set, which characterizes them as strong metal chelators.[1]. E-mail: christian.kowol@univie.ac.at bInstitute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8A, 1090 Vienna, Austria cResearch Cluster “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, 1090 Vienna, Austria † Electronic supplementary information (ESI) available. See DOI: 10.1039/ d1dt02763h ‡ These authors contributed to the main findings of this manuscript
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