A polymer nanoparticle with engineered affinity for a vascular endothelial growth factor (VEGF165)

Abstract

Protein affinity reagents are widely used in basic research, diagnostics and separations and for clinical applications, the most common of which are antibodies. However, they often suffer from high cost, and difficulties in their development, production and storage. Here we show that a synthetic polymer nanoparticle (NP) can be engineered to have many of the functions of a protein affinity reagent. Polymer NPs with nM affinity to a key vascular endothelial growth factor (VEGF) inhibit binding of the signalling protein to its receptor VEGFR-2, preventing receptor phosphorylation and downstream VEGF-dependent endothelial cell migration and invasion into the extracellular matrix. In addition, the NPs inhibit VEGF-mediated new blood vessel formation in Matrigel plugs in vivo. Importantly, the non-toxic NPs were not found to exhibit off-target activity. These results support the assertion that synthetic polymers offer a new paradigm in the search for abiotic protein affinity reagents by providing many of the functions of their protein counterparts.

Heparin‐Mimicking Sulfonated Polymer Nanoparticles via RAFT Polymerization‐Induced Self‐Assembly

“…Furthermore, their high surface area can be functionalized with a broad range of moieties, making them ideal candidates for protein binding . Although the synthesis of sulfonated/sulfated polymeric NPs has already been explored, only one report exists on synthetic heparin‐mimicking NPs as growth factor stabilizers . Koide et al.…”

Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers

“…2,5–10 These synthetic multivalent sugar-functionalized ligands are facile to prepare and have been illustrated to preserve the inhibitory and signal transduction properties of the natural polysaccharides. 2 The architecture of scaffolds used for glycoclustering are wide ranging from dendrimers, 11 polymers, 2,5–10 cyclodextrins, 12 calixarenes, 13 nanoparticles, 14 peptides, 15 to quantum dots. 16 Out of these multivalent motifs, linear glycopolymers were the first and have been the most widely studied in their interactions due to their ability to be easily manipulated and controlled; including saccharide composition and density, variation in linker (length, configuration, and flexibility), and polymer length.…”

Combinatorial screening of polymer nanoparticles for their ability to recognize epitopes of AAV‐neutralizing antibodies

“…The combinatorial design used in Shea group was more successful. The study entailed the screening of a polymer library in the development of polymer NPs capable of recognizing targets such as melittin and VEGF . The authors have used systematic variations in the ratio of functional monomers for the synthesis of polymer NPs, which were then screened for their affinity to the target molecules.…”

“…NPs in these experiments were synthesized by precipitation polymerization from a diluted solution. The monomers used for the synthesis of the NPs are similar to those used previously and include NIPAm, positively charged APM, negatively charged AAc, hydrophobic TBAm, and aromatic monomer PAm. BIS acted as the crosslinker (see Table ).…”

“…Following the same strategy, a small combinatorial library of polymeric NPs was prepared and screened against six peptide epitopes of the variable regions of the AAV‐neutralizing antibodies. The monomers used for the synthesis of the NPs are similar to these previously used in the work of Shea (Figure ) . Each of the NPs also contained a polymerizable fluorescein (Figure ), which was incorporated into the backbone of the polymeric matrices.…”