Liposomal vasoactive intestinal peptide.

Liposomes have been investigated as drug carriers since first discovered in the 1960s. However, the first-generation, so-called classic liposomes found relatively limited therapeutic utility. Nonetheless, the advent in the 1980s of the second-generation sterically stabilized liposomes (SSL) that evade uptake by the host's reticuloendothelial system greatly enhanced their utility as drug carriers because of their prolonged circulation half-life and passive targeting to injured and cancerous tissues. Over the past decade, our work focused on exploiting the bioactivity of vasoactive intestinal peptide (VIP), a ubiquitous 28-amino acid, amphipathic and pleiotropic mammalian neuropeptide, as a drug. To this end, the peptide expresses distinct and unique innate bioactivity that could be harnessed to treat several human diseases that represent unmet medical needs, such as pulmonary hypertension, stroke, Alzheimer's disease, sepsis, female sexual arousal dysfunction, acute lung injury, and arthritis. Unfortunately, the bioactive effects of VIP last only a few minutes due to its rapid degradation and inactivation by enzymes, catalytic antibodies, and spontaneous hydrolysis in biological fluids. Hence, our goal was to develop and test stable, long-acting formulations of VIP using both classic and SSL as platform technologies. We found that spontaneous association of VIP with phospholipid bilayers leads to a transition in the conformation of the peptide from random coil in an aqueous environment to alpha-helix, the preferred conformation for ligand-receptor interactions, in the presence of lipids. This process, in turn, protects VIP from degradation and inactivation and amplifies its bioactivity in vivo. Importantly, we discovered that the film rehydration and extrusion technique is the most suitable to passively load VIP onto SSL at room temperature and yields the most consistent results. Collectively, these attributes indicate that VIP on SSL represents a suitable formulation that could be tested in human disease.