Poster Presentation 10th Australian Peptide Conference 2013

An approach for formulation of self-assembled amphiphilic peptide containing- somatostatin sequence (#159)

Daisuke Takami 1 , Koushi Hidaka 1 , Anna Miyazaki 2 , Isoko Kuriyama 3 , Hiromi Yoshida 3 , Yoshiyuki Mizushina 3 , Yuko Tsuda 1
  1. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Hyogo, Japan
  2. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
  3. Faculty of Nutrition, Kobe Gakuin University, Kobe, Hyogo, Japan

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.