Delivery of therapeutic peptides from thermoplastic polyurethane films

Abstract

Thermoplastic polyurethanes (TPUs) are widely used in biomedical applications due to their excellent mechanical properties and biocompatibility. Their roles as matrices to incorporate therapeutics have been investigated in different areas. With the advance of peptides as therapeutics, there is critical need for investigating delivery of peptides using drug delivery systems. However, there is little work on understanding the release of peptides from TPUs. The aim of this study is to understand how therapeutic peptides might be incorporated and released from TPUs. Initially, we compared the effect of supercritical carbon dioxide treatment and solvent casting on the loading and release of model drugs from polyurethane films. We found that scCO2 treatment may cause a shift of hard segment to the surface of film, but this treatment did not significantly affect physical properties of TPUs. This rearrangement of hard segment caused by scCO2 may affect drug release. We then examined the loading and release of 3 model drugs using scCO2 and compared with solvent casting. ScCO2 was able to load all these 3 model drugs consistently and homogeneously into the films, and the release of these 3 drugs was qualitatively similar by scCO2 or solvent casting. However, the amount of drug accumulated in the films by scCO2 was much less than the total amount of drug in the reaction vessel. This could be a practical limitation for therapeutics such as peptides that are expensive to synthesise. In addition, we found the composition of hard and soft segments may contribute greatly to the efflux of drugs. On the basis of these results, we next investigated the in vitro efflux of peptides from polyurethane films by solvent casting. Interestingly, we found there was a correlation between cumulative release and molecular weight of the peptides. Because one of the causes of implant failure is localised inflammation, we were specifically interested in the delivery of C5aR antagonists from TPU films. First, we found that cyclic peptides may be more stable under harsh casting conditions (elevated temperatures, organic solvents) compared to the linear peptides. Mild conditions are required to retain the bioactivity of peptides. Interestingly, similar to the efflux results of model drugs, the release profiles of peptides were also dependent on the composition of hard and soft segments of TPUs. We also found serum proteins in the medium could facilitate the release of peptides. In addition, in vitro bioactivity of the released peptides was examined by measuring intercellular Ca2+ concentration mobilization in a cell model of C5a receptor signaling. The results demonstrate that released peptides retained their bioactivity. To better control the efflux of peptides, we examined blending of different TPUs. We found that the initial rate and extent of drug released from Tecoflex 80A was significant suppressed by increasing the amount of ElastEon 5325 in the blend. These results offer a simple approach for controlling drug release from TPUs. Further studies were conducted to understand how the peptide delivery systems we developed could improve the in vivo pharmacokinetics and pharmacodynamics of PMX53, an anti-inflammatory cyclic peptide that targets the C5a receptor. While the peptide shows rapid clearance from the blood (half-life < 30 min), the blended TPU films were able to prolong the plasma level of PMX53 for up to 9 days. In addition, PMX53 released from this system was able to impair in vivo melanoma B16-F10 tumor growth, a previously reported effect of anti-inflammatories. In conclusion, the TPU-based peptide delivery systems we developed show great potential for future clinical drug delivery applications. Moreover, the novel approach presented here may improve the pharmacological utility of some peptides as therapeutics.