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The Relationship of Glycosylation and Isoelectric Point with Tumor Accumulation of Avidin

Department of Nuclear Medicine, Faculty of Medicine and Department of Radiopharmaceutical Chemistry, Faculty of Pharmaceutical Science, Kyoto University, Kyoto, Japan

Correspondence: For correspondence or reprints contact: Zhengsheng Yao, MD, Department of Nuclear Medicine, National Institutes of Health, Building 10, Rm. 1C-401, 10 Center Dr., MSC 1180, Bethesda, MD 20892-1180.

ABSTRACT

Radiolabeled avidin markedly accumulated in intraperitoneal tumors and was cleared rapidly from circulation when given intraperitoneally. This study investigated the mechanisms of the tumor localization of avidin. Methods: Avidin was deglycosylated through endoglycosydase-H digestion and/or neutralized by acetylation of its lysine amino acids with acetic acid N-hydroxysuccinimide ester. Avidin and modified avidins were analyzed using sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS/PAGE) and isoelectric focusing. A tumor model was established by intraperitoneal injection of human colon cancer cells, LS180, in nude mice. Avidin and modified avidins were labeled with ¹¹¹In using diethyleneamine pentaacetic acid-biotin and were administered intraperitoneally into the tumor-bearing mice. The biodistribution of radioactivity was examined 2 and 24 h postinjection. Results: Deglycosylated avidins revealed a major band of smaller molecules on SDS/PAGE. The isoelectric point of neutralized avidins was reduced to less than 5, whereas that of unneutralized avidins was more than 9.5. Biodistribution study demonstrated that liver uptake was decreased by deglycosylation and kidney accumulation was decreased by neutralization, respectively. The blood clearance was remarkably slowed by combined modification of deglycosylation and neutralization. The tumor uptake of radioactivity was reduced by either deglycosylation or neutralization and was further decreased with combined modification. Conclusion: Both high glycosylation and positive charge of avidin contributed to its accumulation in tumor. This study may facilitate development of a new vehicle for the delivery of therapeutic agents to intraperitoneal tumors.

Key Words: avidin modification • glycosylation • isoelectric point • tumor accumulation

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