Malkinson, John Paul; (2000) Lipoamino Acid- And Glycolipid-based Peptide Delivery System For Somatostatin Analogue TT-232 With Anti-tumour Activity. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Knowledge of abnormal signal transduction pathways, and of the roles played by various hormones and growth factors has suggested potential new targets for antitumour therapy. The anti-proliferative activity of the multi-functional hormone somatostatin and several of its analogues has long been known. However, their clinical use has been greatly restricted due to a lack of specificity for anti-tumour activity, and due to the additional problems of poor absorption, poor delivery and biological instability inherent to peptide drugs. One somatostatin analogue, the cyclic heptapeptide TT-232, has demonstrated specific and potent anti-proliferative activity. This peptide, and its bis-Acm protected linear precursor, was conjugated to a delivery system based upon lipoamino acids (a-amino acids with long alkyl side-chains). Lipoamino acid conjugation results in enhanced lipophilicity and an ability to partition into biological membranes, as well as improving resistance to degradation by proteolytic enzymes. Since these hpopeptides often suffer from impaired water solubility, the conjugate system was extended, additionally incorporating glycosyl moieties. A series of conjugates comprising both N~ and C-terminal Hpopeptides and glycopeptides was prepared, as well as conjugates incorporating both lipid and glycosyl components either adjacent to each other (glycolipid-modified peptides) or at opposite termini. The number and nature of the lipid (alkyl chain length) and glycosyl (monosaccharides, disaccharides) components was also varied in an effort to optimise permeability. C-terminal glycopeptides were prepared from resin-bound glycosyl azides via a modified Staudinger reaction. Each of the conjugates retained a degree of anti-proliferative activity, some demonstrating activity comparable to that of the parent peptide. Lipoamino acid conjugation alone did not result in enhanced permeability through Caco-2 cell monolayers, but the A-terminal glycolipid-modified conjugates demonstrated greatly improved permeation, possibly indicating the involvement of active transport processes. The cyclic conjugates had higher permeability coefficients than their linear precursors, most likely as a result of intramolecular hydrogen-bonding.

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