The noncovalent self-assembly of molecules into nanostructures is used as target selective drug carriers, or contrast agents in MRI. For example, amphiphilic molecules, comprised of hydrophobic and hydrophilic blocks, self-assemble to form micelles that solubilize hydrophobic drugs under aqueous environments, thus improving their bioavailability. On other hand, somatostatin-14 (SS-14) related peptide, octreotide (cyclic 8-amino acid peptide) is successfully applied for preparation of nanoparticles targeting SS-14 receptors (SSTRs) overexpressed on cancer cells. Added to octreotide, a lot of efforts have been made to develop SS-14 analogue with clinically useable anti-tumor activity. Keri et al. reported that TT-232 [H-D-Phe-c(Cys-Tyr-D-Trp-Lys-Cys)-Thr-NH2], exhibited a potent antiproliferative activity without antisecretory action through SSTRs [1]. Based on its sequence, we synthesized H-Tyr-D-Trp-NH-1-(Ada; Adamantane) (YO-14) and reported YO-14 had potent antiproliferative activity on human colon carcinoma (HCT116) cells. A structure-activity relationship analysis revealed that the hydrophobicity of YO-14 could be responsible for its antiproliferative activity.
In this presentation, we described design of amphiphilic peptides and their self-assembly formulation. Amphiphilic peptides consist of a charged amino acid sequence (Tyr-D-Trp-Lys or TT-232 itself) covalently attach to hydrophobic alkyl chain (Stearic acid or palmitic acid) through a variety of linkers. YO-135, in which a stearic acid bound to the Tyr-D-Trp-Lys, through the linker, (AdOO; 8-amino-3,6-dioxaoctanoic acid)2-Gly, showed both antiproliferative activity on HCT116 cells and DNA polymerase inhibitory activity at 100 microM. YO-136, in which Tyr-D-Trp-Lys sequence was substituted with TT-232 , showed more potent antiproliferative activity than YO-135. Furthermore, in the aqueous YO-135, the critical micelle concentration (cmc), 1.1 x 10-4 M, was obtained, suggesting that YO-135 could self-assemble to form micelles. Physicochemical properties and anti-cancer activity of the self-assemblies will be discussed.