Protein-protein interactions control diverse biological processes and nexus of signal transduction. Antibodies and their fragments are commonly used as an inhibitor of the protein-protein interaction. However, their high cost, long timelines for development and difficulties in production are often a problem. Synthetic polymer hydrogel nanoparticle (NP) capable of capturing and/or releasing target biomacromolecules is of interest as a plastic antibody. Recently, poly-N-isopropylacrylamide (pNIPAm) based NPs have been prepared with the capacity to bind and neutralize the hemolytic toxin melittin. These NPs were found to neutralize the toxicity of melittin in vivo. In the present study, we developed a synthetic NP that captures vascular endothelial growth factor (VEGF) in the bloodstream and tumor for anticancer therapy.NP was prepared by a modified precipitation polymerization from solutions of monomers containing 1.7 mol% of 3,4,6 trisulfated N-acetylglucosamineacrylamide (3,4,6S GlcNAc), 56.3 mol% of NIPAm, 40 mol% of N-tert-butylacrylamide (TBAm, a hydrophobic monomer), and 2 mol% of N,N'methylenebisacrylamide (Bis, a crosslnker). A quartz crystal microbalance (QCM) sensor functionalized with VEGF165 was used to screen the NP library for protein binding. NP affinity for VEGF165was very sensitive to the relative amounts of functional monomers. An optimized NP inhibited the VEGF-dependent phosphorylation (Tyr951) of VEGF receptor and cell growthin vitro. NPs suppressed tumor growth and reduced tumor vasculature density by the intravenous injection of it into the tumor-bearing mice. These results indicate that NPs captured and neutralized VEGF in the bloodstream or tumor. Combination therapy with doxorubicin resulted in increased doxorubicin concentration in the tumor and dramatic inhibition of tumor growth. Although NPs include a heparin-mimic monomer (3,4,6S GlcNAc), NPs treatment did not show off target anti-coagulant activity. This biologically inspired nanoparticle may very well point the way to a novel and cost-effective cancer therapeutic agent.

Development of a plastic antibody that captures vascular endothelial growth factor (VEGF) for anticancer therapy

2019 Fall National Meeting

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