A novel chemical approach to drug delivery: lipidic amino acid conjugates

J Drug Target. 1994;2(3):217-39. doi: 10.3109/10611869408996805.

Abstract

A novel infinity-amino acid based oligopeptide system has been designed, which combines structural features of lipids with those of amino acids and peptides. Because of their bifunctional nature, the fatty amino acids and peptides have the capacity to be chemically conjugated to drugs and peptides with a wide variety of functional groups. The linkage between drug and lipidic unit may either be biologically stable (ie. a new drug is formed) or exhibit biological or chemical instability (ie. the conjugate is a pro-drug). In either case, the resulting conjugates would be expected to possess a high degree of membrane-like character, which may be sufficient to facilitate their passage across membranes. The long alkyl side chains may also have the additional effect of protecting a labile parent drug from enzymatic attack. The lipidic system has been conjugated to a wide variety of different compounds, including (i) alkaloids (ii) beta-lactam antibiotics, (iii) anticancer compounds (iv) CNS drugs and (v) peptides. The biological examination of the conjugates showed that an increase in lipophilicity caused an increase in the in vitro cellular and in vivo oral uptake, as well as passage through the blood-brain-barrier, suggesting that conjugation to lipidic amino acids and peptides is a useful approach to improve the absorption of poorly-absorbed drugs. Lipidic conjugates of peptides (TRH, LHRH) resulted in higher enzymatic stability of the conjugates, proving that the long alkyl side chains also have the additional effect of protecting a labile parent drug or peptide in a biological environment. A novel Lipid-Core-Peptide (LCP) system has also been synthesised by incorporating lipidic amino acids to a lysine based polyamino acid system to enhance lipophilicity and membrane binding effects and the metabolic stability of the compound. The LCP system as a combined adjuvant-carrier-vaccine greatly increased the immunogenicity of synthetic peptides.

Publication types

  • Review

MeSH terms

  • Absorption
  • Administration, Oral
  • Amino Acid Sequence
  • Amino Acids / chemistry*
  • Amino Acids / metabolism
  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Chlorambucil / administration & dosage
  • Drug Delivery Systems*
  • Humans
  • Lipid Metabolism
  • Lipids / chemistry*
  • Molecular Sequence Data
  • Morphine / administration & dosage
  • Peptides / chemistry*
  • Peptides / metabolism
  • Structure-Activity Relationship
  • gamma-Aminobutyric Acid / administration & dosage
  • gamma-Aminobutyric Acid / pharmacokinetics

Substances

  • Amino Acids
  • Anti-Bacterial Agents
  • Lipids
  • Peptides
  • Chlorambucil
  • gamma-Aminobutyric Acid
  • Morphine