Linker Hydrophilicity Modulates the Anticancer Activity of RGD-Cryptophycin Conjugates.

Michele Anselmi, Adina Borbély, Eduard Figueras, Carmela Michalek, Isabell Kemker, Luca Gentilucci, Norbert Sewald

Chemistry (Weinheim an der Bergstrasse, Germany) 2021 Jan 13

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Most anticancer agents are hydrophobic and can easily penetrate the tumor cell membrane by passive diffusion. This may impede the development of highly effective and tumor-selective treatment options. A hydrophilic β-glucuronidase-cleavable linker was used to connect the highly potent antimitotic agent cryptophycin-55 glycinate with the αv β3 integrin ligand c(RGDfK). Incorporation of the self-immolative linker containing glucuronic acid results in lower cytotoxicity than that of the free payload, suggesting that hydrophilic sugar linkers can preclude passive cellular uptake. In vitro drug-release studies and cytotoxicity assays demonstrated the potential of this small molecule-drug conjugate, providing guidance for the development of therapeutics containing hydrophobic anticancer drugs. © 2020 The Authors. Published by Wiley-VCH GmbH.

Citation

Michele Anselmi, Adina Borbély, Eduard Figueras, Carmela Michalek, Isabell Kemker, Luca Gentilucci, Norbert Sewald. Linker Hydrophilicity Modulates the Anticancer Activity of RGD-Cryptophycin Conjugates. Chemistry (Weinheim an der Bergstrasse, Germany). 2021 Jan 13;27(3):1015-1022