Journal
MOLECULAR PHARMACEUTICS
Volume 17, Issue 7, Pages 2734-2748Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.0c00419
Keywords
FGF2; auristatin Y; hydrophilic drug; PEGylation; conjugate; cancer
Funding
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw
- National Science Centre [2015/18/E/NZ3/00501]
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In spite of significant progress in the field of targeted anticancer therapy, the FDA has approved only five ADC-based drugs. Hence the search for new targeted anticancer agents is an unfulfilled necessity. Here, we present novel types of protein-drug conjugates (PDCs) that exhibit superior anticancer activities. Instead of a monoclonal antibody, we used fibroblast growth factor 2 (FGF2) as a targeting molecule. FGF2 is a natural ligand of fibroblast growth factor receptor 1 (FGFR1), a transmembrane receptor overproduced in various types of cancers. We synthesized site-specific and stoichiometric-controlled conjugates of FGF2 with a highly potent, hydrophilic derivative of auristatin called auristatin Y. To increase the hydrophilicity and hydrodynamic radius of conjugates, we employed PEG4 and PEG27 molecules as a spacer between the targeting molecule and the cytotoxic payload. All conjugates were selective to FGFR1-positive cell lines, effectively internalized via the FGFR1-dependent pathway, and exhibited a highly cytotoxic effect only on FGFR1-positive cancer cell lines.
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