Molecular Design of Bioconjugated Cell Adhesion Peptide with a Water-Soluble Polymeric Modifier for Enhancement of Antimetastatic Effect

Yoko      Yamamoto; Yasuo      Tsutsumi; Tadanori      Mayumi

Abstract

The adhesive interaction of tumor cells with various components of the extracellular matrix (ECM), such as laminin and fibronectin appears to play a crucial role in tumor metastasis. It has been reported that adhesive peptides, such as Tyr-Ile-Gly-Ser-Arg (YIGSR) in laminin and Arg-Gly-Asp (RGD), inhibited adhesion and invasion of various tumor cells to ECM in vitro, and exhibited inhibitory effects on pulmonary metastasis of B16-BL6 melanoma cells in mice. However, large doses of these peptides were required for significant anti-metastatic effects in vivo, probably due to their rapid degradation by various peptidases and their rapid excretion from the blood into the urine. To overcome these problems, the development of an appropriate drug delivery system (DDS) is required to improve in vivo stability and prolong plasma half-lives. Several strategies such as peptide-cyclization and D-amino acid substation have been reported to improve stability in blood by inhibiting enzymatic degradation. However, e ven these approaches have proven insufficient to overcome rapid renal clearance from the circulation. On the other hand, bioconjugation with water-soluble polymeric modifiers could markedly prolong the plasma half-lives by not only increasing peptidase resistance but also impeding renal excretion. In addition, it is possible to strictly control the in vivo pharmacokinetics of a peptide by introducing functional molecules with targeting or slow release capacities to the polymeric modifier. In this review we demonstrate with reference to our recent studies that bioconjugation of adhesive peptides with the appropriate polymeric modifier can enhance antimetastatic activity and may facilitate therapeutic use.

Keywords: Polymeric modifier, Pulmonary metastasis, pegylation, Bioactive proteins, bioconjugation, proteins

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