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    Cellular Internalization and Inhibition Capacity of New Anti-Glioma Peptide Conjugates: Physicochemical Characterization and Evaluation on Various Monolayer- and 3D-Spheroid-Based in Vitro Platforms

    Year: 2021

    Journal: J. Med. Chem., Volume 64, MAR 25, page 2982–3005

    Authors: Baranyai, Zsuzsa; Biri-Kovacs, Beata; Kratky, Martin; Szeder, Balint; Debreczeni, Marta L.; Budai, Johanna; Kovacs, Bence; Horvath, Lilla; Pari, Edit; Nemeth, Zsuzsanna; Cervenak, Laszlo; Zsila, Ferenc; Mehes, Elod; Kiss, Eva; Vinsova, Jarmila; Bosze, Szilvia

    Organizations: New National Excellence Program of The Ministry of Human Capacities [UNKP-17-3]; National Research, Development and Innovation Office [NVKP_16-1-2016-0036, TKP2020IKA-05]; ELTE Institutional Excellence Program - Hungarian Ministry of Human Capacities [NKFIH-1157-8/2019DT]; Czech Science Foundation [20-19638Y]; European Regional Development Fund [VEKOP-2.3.3-15-2017-00020]; EFSA-CDN [CZ.02.1.01/0.0/0.0/16_ 019/0000841]; Foundation for the Hungarian Peptide and Protein Research; Hungarian Chemical Society; Pazmany-Eotvos Foundation for Natural Sciences and Informatics; MedInProt Mentor Program; ELTE Thematic Excellence Programme; Hungarian Ministry for Innovation and Technology; ELTE Thematic Excellence Programme 2020; [VEKOP-2.3.216-2017-00014]

    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.
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