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須郷 由美; 大島 康宏; 佐々木 一郎; 石岡 典子
Peptide Science 2014, p.303 - 306, 2015/03
In the previous study, we have designed and synthesized Cu-DOTA-MARSGL as a novel positron emission tomography (PET) imaging probe for the human epidermal growth factor receptor 2 (HER2) overexpressing tumors. In order to evaluate the usefulness as a PET imaging probe, further
studies on the cellular binding and the stability in human or murine plasma were carried out in this work. In the cellular binding assay, it was observed that the radioactivity bound to the cells was dependent on the HER2 expression level. This result suggests the HER2 specificity of
Cu-DOTA-MARSGL. It was also confirmed that
Cu-DOTA-MARSGL had high stability in saline, while it had low stability in plasma. The degradation product was analyzed by LC/MS using a non-radioactive preparation. The main peak in the chromatogram after incubation in plasma was assigned to Cu-DOTA-MA, which was formed by an endogenous peptidase. To increase the resistance to the peptidase, a modification of the structure is in progress.
佐々木 一郎; 花岡 宏史*; 山田 圭一*; 渡辺 茂樹; 須郷 由美; 大島 康宏; 鈴木 博元; 石岡 典子
Peptide Science 2014, p.257 - 260, 2015/03
We have sought to establish drug discovery system using radioisotope (RI) labeled peptides which have high affinity to target proteins overexpressed in cancers. Of the target proteins, we chose the human epidermal growth factor receptor type 2 (HER2), a membrane protein overexpressed in various cancers to evaluate the drug discovery system. Three series of random hexapeptide libraries introduced a radioiodinated D-tyrosine (y(3-I)) to
-terminal were designed and binding assay with HER2-expressed cell lines were conducted in this study. First, we synthesized a series of random hexapeptide libraries with fixed amino acid sequence at 1 and 2 positions, y(3-
I)X
X
X
X
X
X
. Non-radioactive random peptide libraries, yXXXXXX, were prepared by Fmoc-SPPS with an automatic peptide synthesizer. Radioiodinated y(3-
I)XXXXXX were subsequently synthesized in 30-50% radiochemical yield. Binding assay using HER2-overexpressed cell line showed that high affinity (38-50% dose, n=6) was obtained with yIIXXXX, while other random peptide libraries were yielded low affinity (approximately 1% dose), which indicated that the system using RI labeled random peptide libraries have potential to discover peptide drug for cancer therapy. Preparation of other random hexapeptide libraries are being undertaken.