PEGylated Tissue Repair Peptide TP508 Derivatives as Second Generation Drugs for Radiomitigation and Other Systemic Applications
Mcvicar, Scott Davenport
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TP508 is a therapeutic peptide that represents a specific receptor-binding domain of human thrombin with many potential clinical applications. However, it shares several weaknesses common to peptides when administered systemically, such as a short circulating half-life and rapid proteolytic degradation. One FDA-approved method for modifying therapeutic peptides and small proteins to improve these characteristics is through covalent attachment to polyethylene glycol moieties, a process known as PEGylation. Because TP508 is currently being evaluated as a nuclear countermeasure drug for radiomitigation, this project was initiated to evaluate several different PEGylated TP508 derivatives in an attempt to increase TP508 efficacy or decrease the therapeutic dose required for efficacy. We demonstrate that the circulating half-life of TP508 derivatives increase in a size-dependent manner with the length of polyethylene glycol attached to TP508. The PEGylated TP508 derivatives were evaluated for biological activity to determine if increased half-life correlated with increased activity using a combination of in vitro and in vivo methods. In vitro activity of TP508 derivatives was demonstrated in human dermal microvascular endothelial cells (HDMEC) where TP508 and its derivatives accelerated repair of radiation induced DNA double strand breaks. To test in vivo activity, murine models for mitigation of ionizing radiation using outbred male CD-1 mice were used. These studies demonstrated that injection of only two of the TP508 derivatives enhanced aortic explant angiogenesis when the explants were cultured on extracellular matrix ex vivo. Moreover, equimolar doses of TP508 and two of the TP508 derivatives injected intraperitoneally into male CD-1 mice 24h after receiving 8Gy ionizing radiation showed enhanced closure of full-thickness dorsal excisions, with the PEGylated TP508 derivatives restoring the wound healing rate to that of unirradiated mice. These results have identified two TP508 derivatives that may be promising second-generation drugs for radiomitigation and tissue repair applications where the peptide must be administered systemically.