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Graft Through Polymerization of Peptides: Applications in Peptide Therapeutics and In Vivo Tissue Targeting


A strategy for the synthesis of peptides displayed as high density brush polymers is detailed. With this strategy, numerous high density brush polymers displaying peptides were prepared and studied for their ability to protect the peptides from proteolysis. Furthermore, strategies to enable cellular internalization of peptide high density brush polymers were investigated. Finally, peptides were incorporated into polymeric nanomaterials and used for tumor and ischemic tissue targeting.

Peptide high density brush polymers were prepared using graft through ring opening metathesis polymerization (ROMP) to investigate which amino acids could be incorporated into the peptide and polymerized successfully using a ruthenium-based initiator. It was found that only cysteine was unable to be polymerized, whereas lysine and methionine showed difficulty. Strategies to incorporate these problematic amino acids include maintaining protecting groups on the side chains, and incorporating a longer linker between the peptide and the polymerizable moiety.

With this strategy in hand, a variety of high density brush polymers bearing peptides that are enzyme substrates were prepared. These peptides were investigated for their ability to be proteolytically degraded by thrombin, trypsin and pepsin. It was found that in general, peptides displayed as high density brush polymers were protected from proteolysis compared to their monomeric counterparts. When the recognition sequence was spaced closer to the norbornene backbone, the peptide was more protected from proteolysis. Furthermore, peptides were more protected from proteolysis when polymerized to higher molecular weights. With these data, it was believed that polymerizing peptides into high density brushes could protect peptides from proteolysis, a major problem in peptide therapeutics.

A second problem in peptide therapeutics is the inability to internalize into cells. Using high density brushed polymers displaying cationic peptides, the polymeric material is able to internalize into cells in a concentration and degree of polymerization dependent process. Furthermore, a therapeutic peptide was displayed as a high density brush polymer and internalized into cells, and maintained its bioactivity of inducing mitochondrial dependent apoptosis.

Matrix metalloproteinases (MMPs) are enzymes that are upregulated in many diseased states such as hind limb ischemia and cancer. A peptide polymer amphiphile that displayed an MMP substrate as the hydrophilic block, and was labeled with a near infrared dye was prepared. Peptide polymer amphiphiles are able to self-assemble into micellar nanoparticles. It was previously shown that when the nanomaterial is incubated with MMPs, the enzyme cleaves off the peptide, resulting in a change in polymer amphiphilicity inducing an aggregation event. Near infrared labeled polymeric materials were intravenously administered to animal models of cancer and peripheral artery disease, two diseases where MMPs are upregulated, and the particles were able to accumulate into the diseased tissue, albeit not significantly over the non-responsive control. It was found, however, that when incorporating a zwitterionic dye to the polymeric material, there was a significant decrease in off target accumulation.

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