Most therapeutic agents used for treating brain malignancies face hindered transport through the blood-brain barrier (BBB) and poor tissue penetration. To overcome these problems, we developed peptide conjugates of conventional and experimental anticancer agents. SynB3 cell-penetrating peptide derivatives were applied that can cross the BBB. Tuftsin derivatives were used to target the neuropilin-1 transport system for selectivity and better tumor penetration. Moreover, SynB3-tuftsin tandem compounds were synthesized to combine the beneficial properties of these peptides. Most of the conjugates showed high and selective efficacy against glioblastoma cells. SynB3 and tandem derivatives demonstrated superior cellular internalization. The penetration profile of the conjugates was determined on a lipid monolayer and Transwell co-culture system with noncontact HUVEC-U87 monolayers as simple ex vivo and in vitro BBB models. Importantly, in 3D spheroids, daunomycin-peptide conjugates possessed a better tumor penetration ability than daunomycin. These conjugates are promising tools for the delivery systems with tunable features.

3rd Department of Medicine Research Laboratory Semmelweis University Kútvölgyi út 4 H 1125 Budapest Hungary

Centre for Ecological Research Institute of Ecology and Botany Alkotmány u 2 4 H 2163 Vácrátót Hungary

Department of Biological Physics Institute of Physics Eötvös Loránd University Pázmány Péter Sétány 1 A H 1117 Budapest Hungary

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy in Hradec Králové Charles University Akademika Heyrovského 1203 500 05 Hradec Králové Czech Republic

Eötvös Loránd Research Network Research Group of Peptide Chemistry Eötvös Loránd University Pázmány Péter Sétány 1 A H 1117 Budapest Hungary

Institute of Chemistry Eötvös Loránd University Pázmány Péter Sétány 1 A H 1117 Budapest Hungary

Institute of Enzymology Research Centre for Natural Sciences Magyar Tudósok Körútja 2 H 1117 Budapest Hungary

Institute of Materials and Environmental Chemistry Research Centre for Natural Sciences Magyar Tudósok Körútja 2 H 1117 Budapest Hungary

Laboratory of Interfaces and Nanostructures Institute of Chemistry Eötvös Loránd University Pázmány Péter Sétány 1 A H 1117 Budapest Hungary

References provided by Crossref.org

New Salicylanilide Derivatives and Their Peptide Conjugates as Anticancer Compounds: Synthesis, Characterization, and In Vitro Effect on Glioblastoma