Synthesis of Dextran-(5-FU)-Galactosamine Conjugate through a Tripeptide Spacer Group and Its in Vitro Properties

聚葡萄糖－（５－ＦＵ）－半乳糖胺含三氨基酸鏈間距之偶合藥物的合成及其生物體外性質

古振安(Jan-An Guu) ； 莊祚敏(Tzuoh-Miin Juang) ； 薛敬和(Ging-Ho Hsiue) ； 邱信程(Hsin-Cheng Chiu)

《Journal of the Chinese Institute of Chemical Engineers》 31卷4期 (2000/07) Pp. 351-359

https://doi.org/10.6967/JCICE.200007.0351

摘要

本研究是將抗癌藥物5-fluorouracil（5-FU）和半乳糖胺（galactosamine）經由三氨基酸間距接上聚葡萄糖（dextran），合成出水溶性高分子前驅藥。首先dextran以４－nitrophenyl chloroformate活化，Gly-Leu-G1y-5-FU和galactosamine再以胺基與活化之dextran偶合。Gly-Leu-G1Y-5-FU之裝備，先以溶液態反應依序合成Gly-Leu-G1y間距，然後在氰化二乙基磷酸（diethylphosphoric cyanide）件用下接上5FU。將此高分子前驅藥置於木瓜蛋白?（papain）溶液中，釋放出5FU，顯示5FU結合三氨基酸間距「Gly-Leu-G1y」可被目標細胞中溶?體（lysosomes）的cathepsin B切斷而釋出。此外，由觀察得知，帶有galactosamine的dextran-5FU高分子藥物對於Hep-3B cell的細胞毒性高於無galactosamine者，顯示此標的性基團會針對細胞膜上接受器進行結合，導引其經由接受器－傳遞之胞飲作用，加強細胞對此高分子藥物的攝取。

並列摘要

In this study, conjugation of 5-fluorouracil (5-FU) and galactosamine with dextran a Glycyl-L-Leucyl-Glycine (Gly-Leu-Gly) tripeptidyl spacer was performed first by activation of dextran with p-nitrophenyl chloroformate, fowllowed by aminolysis of Glycyl-L-Leucyl-Gly cyl-5flurouracil (Gly-Leu-G1y-5-FU) and galactosamine with activated dextrans. Preparation of Gly-Leu-Gly-5-FU was carried out by sequential reactions of peptide synthesis in solution phases and coupling with 5-FU in the presence of diethylphosphoric cyanide. The release of 5-FU form the conjugates upon the exposure of polymeric prodrugs to papain implied that the attachment of 5-FU with the tripeptidyl spacer, Gly-Leu-Gly, was capable of being liberated by cathepsin B in lysosomes of targeted cells. The observation that the cytoxicity in vitro from the incubation of dextran-5-FU conjugate containing galactosamine residues with Hep-3B cells is higher than that in the void of galactosamine indicated the occurrence of specific binding of the targeting moieties with its receptors on cell membrane, leading to an enhanced cellular uptake of the conjugate via receptor-mediated endocytosis.

並列關鍵字

Dextran ； Polymeric Prodrug ； Galactosamine ； Targeting ； 5-Fluorouracil