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論文

Medical application of radiohalogenated peptides; Synthesis and ${it in vitro}$ evaluation of F(${it p}$-$$^{131}$$I)KCCYSL for targeting HER2

佐々木 一郎; 渡辺 茂樹; 大島 康宏; 須郷 由美; 山田 圭一*; 花岡 宏史*; 石岡 典子

Peptide Science 2015, p.243 - 246, 2016/03

Radioisotope labeled peptides with high affinity to receptors overexpressing on the surface of tumor cells are promising for applications in nuclear medicine such as diagnostic radiography and radiotherapy. Radiohalogens such as $$^{131}$$I and $$^{211}$$At are useful for clinical imaging and therapeutic applications, and it can be introduced at the ${it para}$ position of phenylalanine residue via electrophilic destannylation. KCCYSL (Lys$$^{1}$$-Cys$$^{2}$$-Cys$$^{3}$$-Tyr$$^{4}$$-Ser$$^{5}$$-Leu$$^{6}$$) is a hexapeptide containing disulfide bond. Previous study revealed that KCCYSL has potential as tumor imaging and therapeutic agent targeting tumor cells overexpressing the human epidermal growth factor receptor type 2 (HER2). In this study, we report synthesis and ${it in vitro}$ evaluation of radiohalogenated KCCYSL derivatives. Precursor peptides, Boc-F(${it p}$-SnBu$$_{3}$$)K(Boc)C(Trt)C(Trt)Y($$^{t}$$Bu)S($$^{t}$$Bu)L-OH and Boc-F(${it p}$-SnBu$$_{3}$$)GS($$^{t}$$Bu)GK(Boc)C(Trt)C(Trt)Y($$^{t}$$Bu)S($$^{t}$$Bu)L-OH, were synthesized by the Fmoc solid phase peptide synthesis. Then, precursor peptides were radioiodinated via electrophilic destannylation, and they were deprotected to obtain F(${it p}$-$$^{131}$$I)KCCYSL and F(${it p}$-$$^{131}$$I)GSGKCCYSL in radiochemical yield 15% and 17%, respectively. ${it In vitro}$ assays of the radioiodinated peptides for HER2 and stability in serum are being undertaken.

論文

Exploring of peptides with affinity to HER2 from random peptide libraries using radioisotope; Random hexapeptide libraries with fixed amino acid sequence at 1 and 2 positions

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-$$^{131}$$I)) to $$N$$-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-$$^{131}$$I)X$$^{1}$$X$$^{2}$$X$$^{3}$$X$$^{4}$$X$$^{5}$$X$$^{6}$$. Non-radioactive random peptide libraries, yXXXXXX, were prepared by Fmoc-SPPS with an automatic peptide synthesizer. Radioiodinated y(3-$$^{131}$$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.

論文

ポリデプシペプチド,2; 3つのアミノ酸moietyと1つのオキシ酸moietyから構成されるAla-X-Glu(OEt)-Lac sequence(アミノ酸moiety,X=Gly,Ala,Leu)とAla-Ala-Glu(OEt)-Y sequence(オキシ酸moiety,Y=Hea,Lac,Hmp)のポリマー素材のin vivo 分解

浅野 雅春; 吉田 勝; 嘉悦 勲; 片貝 良一*; 今井 強一*; 真下 透*; 湯浅 久子*; 山中 英寿*

生体材料, 4(2), p.65 - 75, 1986/00

3つのアミノ酸moietyと1つのオキシ酸moietyから成るAla-X-Ala-Glu(OEt)-Lac(X=Gly,Ala,Leu)とAla-Ala-Glu(OEt)-Y(Y=Hea,Lac,Hmp)のsuquential polydepsipeptideを合成した。加圧-加熱溶融処理した円柱状担体(1.6mm径、3.5mm長さ)のpoly(Ala-X-Glu(OEt)-Lac)をラットの背中皮下部に埋入した時のin vivo分離速度はアミノ酸moiety(X-moiety)の側鎖基(H基がGly,CH$$_{3}$$基がAla,CH$$_{2}$$CH(CH$$_{3}$$)$$_{2}$$基がLeu)が大きくなるほど、すなわちGly$$>$$Ala$$>$$Leuの順に抑制された。同じような傾向は、Poly(Ala-Ala-Glu(OEt)-Y)のin vivo分解にも観察された。このタイプのオキシ酸(Y-mo;ety)の側鎖基はH基がHea,CH$$_{3}$$基がLac,CH$$_{2}$$CH(CH$$_{3}$$)$$_{2}$$基がHmpに相当する。一方、この研究に用いたpolydepsipeptideのin vivo分解はラットの埋入箇所によって著しく影響を受けることが分かった。さらに、エステラーゼ酵素、プロテアーゼ酵素を用いてpolydepsipeptideの酵素分解メカニズムを検討した。

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