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 β‐glucuronidase‐cleavable linker was used to connect the highly potent antimitotic agent cryptophycin‐55 glycinate with the α vβ3 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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Chemistry – A European Journal - 27(2021), 3, Seite 1015-1022 |
| Beteiligte Personen: |
Anselmi, Michele [VerfasserIn] |
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| BKL: |
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| Anmerkungen: |
© 2021 Wiley‐VCH GmbH |
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| Umfang: |
8 |
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| doi: |
10.1002/chem.202003471 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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WLY003490351 |
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| 520 | |a 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 α vβ3 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. | ||
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| 700 | 1 | |a Sewald, Norbert |4 aut | |
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