Peptide targeting and delivery across the blood-brain barrier utilizing synthetic triglyceride esters: Design, synthesis, and bioactivity

Dinesh Patel, Brian D. McKinley, Thomas P. Davis, Frank Porreca, Henry I. Yamamura, Victor J. Hruby

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

As an approach to the development of therapeutically useful peptide pharmaceuticals that can penetrate the blood-brain barrier, we have designed and demonstrated the application of a carrier-targeting system. We 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, thus attaining high localized concentrations of the bioactive peptide. Following localization of such a system, normal peptidase and lipase action is utilized to release the active peptide (deltorphin II) intact and in high concentration. At present, the exact mechanisms are unclear, but the observed results in which analgesia is observed following peripheral administration suggest that the active peptide is able to cross the blood brain barrier and sustain prolonged periods of analgesia as determined by antinociception tests by release of the bioactive peptide. In vitro tests of binding and bioactivity by the peptide conjugate show essentially no potency in either target or control analogues, but potent antinociceptive effects are observed following peripheral administration.

Original languageEnglish (US)
Pages (from-to)434-441
Number of pages8
JournalBioconjugate Chemistry
Volume8
Issue number3
DOIs
StatePublished - May 1 1997

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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