Linker Hydrophilicity Modulates the Anticancer Activity of RGD–Cryptophycin Conjugates. Issue 3 (8th December 2020)

• Record Type: Journal Article
• Authors: Anselmi, Michele; Borbély, Adina; Figueras, Eduard; Michalek, Carmela; Kemker, Isabell; Gentilucci, Luca; Sewald, Norbert
• Is Part Of: Chemistry. Volume 27:Issue 3(2021)
• Page Start: 1015
• Page End: 1022
• Publication Date: 2020-12-08
• Subjects: antitumor agents -- beta-glucuronidase -- drug delivery -- integrin -- small molecule drug conjugates; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202003471
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: 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. Abstract : Sweet specificity : A β‐glucuronidase‐responsive linker was chosen to minimize the hydrophobicity and connect the potent antimitotic agent cryptophycin‐55 glycinate to the αv β3 integrin ligand c (RGDfK). The presence of a hydrophilic carbohydrate linker significantly decreased the cytotoxicity of RGD–cryptophycin conjugates relative to the free drug. The conjugate efficiently releases the drug upon linker cleavage by β‐glucuronidase.