The Korean Journal of Nuclear Medicine (대한핵의학회지)

The Korean Society of Nuclear Medicine (대한핵의학회)
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Biodistribution of $^{99m}Tc$-Lactosylated Serum Albumin in Mice with Diethylnitrosamine or Thiacetamide Induced Liver Injury

Diethylnitrosamine 및 Thioacetamide 유발 간손상 생쥐에서의 $^{99m}Tc$-Lactosylated Serum Albumin의 체내 분포상

  • Whang, Jae-Seok (Department of Nuclear Medicine, Kyungpook National University Medical School) ;
  • Ahn, Byeong-Cheol (Department of Nuclear Medicine, Kyungpook National University Medical School) ;
  • Sung, Young-Ok (Department of Nuclear Medicine, Kyungpook National University Medical School) ;
  • Seo, Ji-Hyoung (Department of Nuclear Medicine, Kyungpook National University Medical School) ;
  • Bae, Jin-Ho (Department of Nuclear Medicine, Kyungpook National University Medical School) ;
  • Jeong, Shin-Young (Department of Nuclear Medicine, Kyungpook National University Medical School) ;
  • Yoo, Jung-Soo (Department of Nuclear Medicine, Kyungpook National University Medical School) ;
  • Jeong, Jae-Min (Department of Nuclear Medicine, Seoul National University College of Medicine) ;
  • Lee, Jae-Tae (Department of Nuclear Medicine, Kyungpook National University Medical School) ;
  • Lee, Kyu-Bo (Department of Nuclear Medicine, Kyungpook National University Medical School)
  • 황재석 (경북대학교 의과대학 핵의학교실) ;
  • 안병철 (경북대학교 의과대학 핵의학교실) ;
  • 성영옥 (경북대학교 의과대학 핵의학교실) ;
  • 서지형 (경북대학교 의과대학 핵의학교실) ;
  • 배진호 (경북대학교 의과대학 핵의학교실) ;
  • 정신영 (경북대학교 의과대학 핵의학교실) ;
  • 유정수 (경북대학교 의과대학 핵의학교실) ;
  • 정재민 (서울대학교 의과대학 핵의학교실) ;
  • 이재태 (경북대학교 의과대학 핵의학교실) ;
  • 이규보 (경북대학교 의과대학 핵의학교실)
  • Published : 2005.06.30
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Abstract

Purpose: Tc-99m labeled diethylenetriaminepentaacctic acid (DTPA)-coupled galactosylated human serum albumin (GSA) is a currently used imaging agent for asialoglycoprotein receptor (ASGPR) of the liver, but, it has several shortcomings. Recently a new ASGPR imaging agent, $^{99m}Tc$-lactosylated human serum albumin (LSA), with simple labeling procedure, high labeling efficiency, high stability was developed. In order to assess the feasibility of the $^{99m}Tc$-LSA as a ASGPR imaging radiopharmaceuticals, we performed biodistribution study of the tracer in liver injured mice model and the results were compared with histolgic data. Materals and Methods: To induce hepatic damage in ICR mice, diethylnitrosamine (DEN) ($60mg/kg/week{\times}5time$, low dose or $180mg/kg/week{\times}2times$, high dose) and thioacetamide (TAA) ($50mg/kg{\times}1time$) were administrated intraperitoneally. Degree of liver damage was evaluated by tissue hematoxilin-eosin stain, and expression of asialoglycoprotein receptor (ASGPR) was assessed by immunohistochemistry using ASGPR antibody. $^{99m}Tc$-LSA was intravenously administrated via tail vein in DEN or TAA treated mice, and biodistribution study of the tracer was also performed. Results: DEN treated mice showed ballooning of hepatocyte and inflammatory cell infiltration in low dose group and severe hapatocyte necrosis in high dose group, and low dose group showed higher ASGPR staining than control mice in immunohistochemical staining. TAA treated mice showed severe hepatic necrosis. $^{99m}Tc$-LSA Biodistribution study showed that mice with hepatic necrosis induced by high dose DEN or TAA revealed higher blood activity and lower liver activity than control mice, due to slow clearance of the tracer by the liver. The degree of liver uptake was inversely correlated with the degree of histologic liver damage. But low dose DEN treated mice with mild hepatic injury showed normal blood clearance and hepatic activity, partly due to overexpression of ASGPR in mice with mild degree hepatic injury. Conclusion: Liver uptake of $^{99m}Tc$-LSA was inversely correlated with degree of histologic hepatic injury in DEN and TAA treated mice. These results support that $^{99m}Tc$-LSA can be used to evaluate the liver status in liver disease patients.

목적: 비침습적으로 간의 상태를 예측하기 위하여 여러 검사법들이 시도되고 있으나 각각의 제한점이 있다. 간 신티그라피는 방사성교질과 방사능 표지 iminodiacetic acid (IDA) 화합물이 가장 널리 사용되고 있으나, 실제 간세포의 상태를 나타내는데는 부족한 점이 있다. 최근에는 간세포 표면에 발현되는 asialoglycoprotein (ASGP) 수용체 (ASGP receptor: ASGPR)에 특이적으로 결합 할 수 있는 제제인 galactosylated serum albumin (GSA)이 간 신티그라피에 유용한 방사성의약품으로 성장하고 있으나 제한점을 가지고 있다. 본 연구는 현재 상용화된 GSA보다 유용한 ASGPR 영상용 방사성의약품인 lactosylated serum albumin (LSA)이 간세포의 ASGPR 발현 정도의 평가에 이용될 수 있는지와 조직학적 간손상정도 비침습적 평가 하는데 이용될 수 있는 방사성의약품인지를 알아보고자 시행하였다. 대상 및 방법: $^{99m}Tc$-LSA의 간기능 평가 성능을 알아보기 위하여 diethylnitrosamine (DEN)과 thioacetamide (TAA) 투여로 간손상을 일으킨 생쥐에서 생체내 분포변화를 알아보았으며, DEN 투여로 간손상을 일으킨 흰쥐에서 영상을 통하여 간 및 혈액내 방사능 분포 변화 양상을 알아보았다. 방사성의약품의 체내 분포 변화 및 간 및 혈액내 분포 변화가 간손상 여부를 잘 반영하는 지를 알아보기 위하여 간조직 검사를 시행하여 비교하였다. 결과: 체중 kg당 DEN 60 mg이 주당 1회 5번 투여된 생쥐는 광학현미경상 간손상 정도가 미약하였으며, 면역조직화학검사상 ASGPR의 발현이 높았으며, $^{99m}Tc$-LSA의 체내 분포는 정상생쥐와 유의한 차이가 없었다. 체중 kg당 DEN 180 mg이 주당 1회 2번 투여된 생쥐는 조직검사상 간조직의 괴사가 광범위하였으며, 면역조직화학검사상 ASGPR의 발현이 감소되어 있었고, $^{99m}Tc$-LSA의 체내 분포는 정상생쥐에 비해 간섭취가 감소되어 있었으며, 혈액에서의 제거나 늦었다. TAA를 투여하여 간조직의 괴사가 발생한 생쥐에서도 $^{99m}Tc$-LSA의 체내 분포는 정상생쥐에 비해 간섭취가 감소되어 있었으며, 혈액에서의 제거가 늦었다. 결론: 새로이 개발된 $^{99m}Tc$-LSA는 정상 간조직에 섭취정도가 높으며, ASGPR 발현정도에 비례하여 간섭취를 나타내며, 간손상 정도에 따라 섭취가 감소하여, 간손상 정도를 비침습적으로 잘 반영해 주는 것으로 나타나 향후 간기능 평가용 방사성의약품으로 임상에 손쉽게 쓰일 수 있을 것으로 기대된다.

Keywords

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