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

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 ?-glucuronidase-cleavable linker was used to connect the highly potent antimitotic agent cryptophycin-55 glycinate with the ?v?3 integrin ligand c(RGDfK). Incorporation of the self-immolative linker containing glucuronic acid results in decreased cytotoxicity compared to 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.

SUBMITTER: Anselmi M

PROVIDER: S-EPMC7839693 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Anselmi Michele M Borbély Adina A Figueras Eduard E Michalek Carmela C Kemker Isabell I Gentilucci Luca L Sewald Norbert N

Chemistry (Weinheim an der Bergstrasse, Germany) 20201208 3

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 t ...[more]

PMID: 32955139

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