Despite the success of TNF-inhibitors and other new biological drugs for the treatment of autoimmune and other chronic inflammatory diseases, there are still many patients that are only poorly controlled. Vasoactive intestinal peptide (VIP) is an immunomodulatory peptide that induces regulatory T-cells and anti-inflammatory cytokine responses and has shown efficacy in numerous rodent models of autoimmune diseases with predominant TH1-type immune responses. Use of VIP in humans is severely hindered by its short in vivo half-life, and the therapeutic window is limited by the vasodilatory properties of this peptide that can cause an unsafe drop in blood pressure upon injection. Formulating VIP into a nanocarrier can improve both properties as the binding to the nanocarrier sequesters it from degrading enzymes and excretion by the kidney. The binding of VIP to a nanocarrier also decreases the concentration of free VIP in serum, thereby decreasing the blood pressure drop and increasing the therapeutic window. In this application two different nanocarriers will be compared in their ability to formulate VIP for the treatment of chronic inflammatory diseases. The nanocarriers are a Protected Graft Copolymer (PGC), in which a poly-lysine backbone is grafted with polyethylene glycol (PEG) side chains. The load-molecule will bind to specific residues between the PEG-side chains. The other nanocarrier consists of a sterically stabilized micelle (SSM). These different nanocarrier-VIP formulations will be compared in terms of efficacy in collagen induced arthritis, a mouse model of rheumatoid arthritis. Additionally, the pharmacokinetics of the different nanocarrier-VIP formulations will be determined. Toxicity will be tested using non-invasive blood pressure monitors that measure peripheral arterial pressure in the tail with an inflatable tail cuff, in addition to monitoring general parameters of health (behavior, appearance, diarrhea etc).
Vasoactive intestinal peptide (VIP) is a hormone in the human body that can be used for the treatment of autoimmune diseases in animal models. Rapid degradation and side effects at high dose have so far limited VIP use in humans. In this project VIP will be formulated into forms that will deal with these problems that will allow its universal use in many human diseases.
| Reichstetter, Sandra; Castillo, Gerardo M; Rubinstein, Israel et al. (2013) Protected graft copolymer excipient leads to a higher acute maximum tolerated dose and extends residence time of vasoactive intestinal Peptide significantly better than sterically stabilized micelles. Pharm Res 30:670-82 |
