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

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

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 αvβ3 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.

ANTIMITOTIC agents; ANTINEOPLASTIC agents; GLUCURONIC acid; CELL membranes; INTEGRINS; SMALL molecules

Chemistry - A European Journal, 2021, Vol 27, Issue 3, p1015

0947-6539

Academic Journal

10.1002/chem.202003471