| Autor: |
Wang X; Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States., Zhang R; Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States., Lindaman BD; Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States., Leeper CN; Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States., Schrum AG; Departments of Molecular Microbiology & Immunology, Surgery, and Biomedical, Biological & Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States., Ulery BD; Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States. |
| Abstrakt: |
Vasoactive intestinal peptide (VIP) is a neuropeptide capable of downregulating innate immune responses in antigen presenting cells (APCs) by suppressing their pro-inflammatory cytokine secretion and cell surface marker expression. Though VIP's bioactivity could possibly be leveraged as a treatment for transplant tolerance, drug delivery innovation is required to overcome its intrinsically limited cellular delivery capacity. One option is to employ peptide amphiphiles (PAs) which are lipidated peptides capable of self-assembling into micelles in water that can enhance cellular association. With this approach in mind, a series of triblock VIP amphiphiles (VIPAs) has been synthesized to explore the influence of block arrangement and hydrophobicity on micelle biocompatibility and bioactivity. VIPA formulation has been found to influence the shape, size, and surface charge of VIPA micelles (VIPAMs) as well as their cytotoxicity and immunomodulatory effects. Specifically, the enclosed work provides strong evidence that cylindrical VIPAMs with aspect ratios of 1.5-150 and moderate positive surface charge are able to potentiate the bioactivity of VIP limiting TNF-α secretion and MHC II and CD86 surface expression on APCs. With these criteria, we have identified PalmK-(EK) 4 -VIP as our lead formulation, which showed comparable or enhanced anti-inflammatory effects relative to the unmodified VIP at all dosages evaluated. Additionally, the relationships between peptide block location and lipid block size provide further information on the chemical structure-function relationships of PA micelles for the delivery of VIP as well as potentially for other peptides more broadly. |
