Growth Factor Tethering to Protein Nanoparticles via Coiled-Coil Formation for Targeted Drug Delivery

Abstract

Protein-based nanoparticles are attractive carriers for drug delivery because they are biodegradable and can be genetically designed. Moreover, modification of protein-based nanoparticles with cell-specific ligands allows for active targeting abilities. Previously, we developed protein nanoparticles comprising genetically engineered elastin-like polypeptides (ELPs) with fused polyaspartic acid tails (ELP-D). Epidermal growth factor (EGF) was displayed on the surface of the ELP-D nanoparticles via genetic design to allow for active cell-targeting abilities. Herein, we focused on the coiled-coil structural motif as a means for noncovalent tethering of growth factor to ELP-D. Specifically, two peptides known to form a heterodimer via a coiled-coil structural motif were fused to ELP-D and single-chain vascular endothelial growth factor (scVEGF121), to facilitate noncovalent tethering upon formation of the heterodimer coiled-coil structure. Drug-loaded growth factor-tethered ELP-Ds were found to be effective against cancer cells by provoking cell apoptosis. These results demonstrate that tethering growth factor to protein nanoparticles through coiled-coil formation yields a promising biomaterial candidate for targeted drug delivery.

Epidermal Growth Factor Tethered to β-Tricalcium Phosphate Bone Scaffolds via a High-Affinity Binding Peptide Enhances Survival of Human Mesenchymal Stem Cells/Multipotent Stromal Cells in an Immune-Competent Parafascial Implantation Assay in Mice

“…Due to its relatively straightforward design and the ubiquitous expression of EGFR on many cell types, the EGF tethering system has a wide array of potential applications in regenerative medicine. Growth factor tethering (and specifically EGF tethering) has been used in a variety of contexts, including improving survival of other cell types such as vascular smooth muscle cells [31] or targeted therapeutic growth factor delivery [32, 33]. In the context of MSC clinical utility, although this study analyzed the effects of tEGF on a construct designed primarily for bone regeneration, the applications of EGF tethering may also extend outside of tricalcium phosphate scaffolds and bone repair in general.…”

Genetically Engineered Elastin-based Biomaterials for Biomedical Applications

“…Furthermore, the combination of coiled-coil heterodimers that are able to form nanoparticles with targeted drug delivery enhances tumor suppression and increases apoptotic cell death. This study demonstrates that customized drug-delivery systems that target different cell types and receptors can be constructed using ELRs and may be a good candidate for cancer therapy applications [58].…”

Biomaterials Made from Coiled-Coil Peptides

“…These systems also offer the potential for multi-valent drug binding, which improves the loading efficiency by minimizing the entropic penalty for binding. Assuming one chain in a heterodimeric coiled-coil system contains a single binding site, its sequence may be doubled to introduce a second binding site (Assal et al 2015). Recently, Klok and co-workers investigated a heterodimeric coiled-coil carrier comprising two peptides (K 3 and E 3 ), which self-assemble at pH 7.0, but dissociate at pH 5.0 (endosomal pH), thereby releasing their cargo (Apostolovic et al 2010(Apostolovic et al , 2011.…”