Engineering Coil-Coiled Domains for the Design of Modular Theranostic Agents: Galectin-3 as a Targeting Moiety

To generate drug-targeting agents with a modular and efficient design for disease treatments, including cancer, we used protein coil-coiled dimerization motifs to eliminate the need for chemical conjugation techniques, generating a versatile theranostic system: a targeting moiety genetically fused to an E₃ coil and a fusion protein of maltose-binding protein and a monomeric streptavidin that includes a K₃ coil. The system can be directed to other targets by changing the targeting moiety. The second component enables simultaneous binding to two different ligands (maltosylated or biotinylated). We tested the system using a truncated human Galectin-3 as the targeting moiety, which binds to β-galactoside-containing oligosaccharides overexpressed on the plasma membranes of tumor cells, and biotinylated doxorubicin as the cargo molecule. In vitro experiments using cell lines that express or do not express Galectin-3 ligands andin vivo mouse xenografts demonstrated the system's capability, specificity, and flexibility.