PEPTIDE TARGETING AND DELIVERY ACROSS THE BLOOD-BRAIN-BARRIER UTILIZING SYNTHETIC TRIGLYCERIDE ESTERS - DESIGN, SYNTHESIS, AND BIOACTIVITY

As an approach to the development of therapeutically useful peptide ph armaceuticals that can penetrate the blood-brain barrier, we have desi gned and demonstrated the application of a carrier-targeting system. W e have developed a prodrug design strategy that is designed to utilize membrane-bound enzymes whereby release of a bioactive peptide from a highly lipophilic triglyceride peptide-carrier is achieved in situ, th us attaining high localized concentrations of the bioactive peptide. F ollowing localization of such a system, normal peptidase and lipase ac tion is utilized to release the active peptide (deltorphin II) intact and in high concentration. At present, the exact mechanisms are unclea r, but the observed results in which analgesia is observed following p eripheral administration suggest that the active peptide is able to cr oss the blood-brain barrier and sustain prolonged periods of analgesia as determined by antinociception tests by release of the bioactive pe ptide. In vitro tests of binding and bioactivity by the peptide conjug ate show essentially no potency in either target or control analogues, but potent antinociceptive effects are observed following peripheral administration.