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위암의 암성복수 마우스모델을 이용한 방사면역치료에서 64Cu-DOTA-Cetuximab의 복강내주사 또는 정맥내주사 투여 후의 생물학적 분포 비교
- Alternative Title
- Sung-Ho Jin
- Author(s)
- Jin,Sung Ho
- Alternative Author(s)
- Sung-Ho Jin
- Advisor
- 한상욱
- Department
- 일반대학원 의학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2014-02
- Language
- eng
- Keyword
- Stomach neoplasm; epidermal growth factor receptor; ascites; intraperitoneal; radioimmunotherapy; radioimmunoconjugates; cetuximab; 64Cu-DOTA-cetuximab; positron emission tomography; biodistribution
- Alternative Abstract
- Intraperitoneal (i.p.) radioimmunotherapy (RIT) may be a promising treatment strategy for intraperitoneally-confined malignant diseases including malignant ascites (MA) in gastric cancer. We conducted a comparative biodistribution study of 64Cu-DOTA-cetuximab in subcutaneous (SQ) tumor and MA mouse models. A mouse xenograft model of bilateral SQ tumors that express epidermal growth factor receptor (EGFR) was established by SQ injections of NUGC-4 and MKN-45 gastric cancer cells into either shoulder of female BALB/c nude mice. The MA model was produced by i.p. injection of NUGC-4 cells. Cetuximab was conjugated to a bifunctional chelator (p-SCN-Bn-DOTA) and labeled with Copper-64 (T1/2 = 12.7 hours). Radiolabeled cetuximab was then administered intravenous (i.v.) or i.p. injection. Positron emission tomography (PET) imaging and biodistribution studies were conducted at the indicated time points. In the bilateral SQ tumor model, the peak uptake of radiolabeled cetuximab in the NUGC-4 and MKN-45 tumors was detected at 24 h post-injection of 64Cu-DOTA-cetuximab by PET imaging and biodistribution analysis. NUGC-4 tumor uptake of radiolabeled cetuximab was significantly higher than MKN-45 tumor uptake at all time points. The EGFR expression levels of the two cell lines were similar according to in vitro experiments. However, based on flow cytometry analyses at different incubation times with primary antibody (cetuximab) ranging from 3 min to 3 h, the EGFR expression levels were increased over time, and the increasing slope was higher in NUGC-4 cells than in MKN-45 cells. In the i.v.-induced MA model mice, the biodistribution of radiolabeled cetuximab in the blood pool and liver was high at 1 h and 3 h after i.v. injection and decreased over time. In the i.p.-induced MA model mice, the percent injected dose per gram (% ID/g) of ascites was very high and more than 8% at 1, 3, 24, and 48 h post injection; however, the % ID/g in all normal organs was equal to or less than 6% at all time points. In addition, all peak uptakes of normal organs and i.p.-induced NUGC-4 tumors appeared at 24 h after injection. In addition, the uptake ratios of tumor, peritoneum, and ascites to normal organs after i.p. injection were greater than after i.v. injection, particularly at the early time points. Finally, autoradiography studies using excised peritoneum and mesentery indicated several hot spots corresponding to peritoneal seeding. The results suggest that using the i.p. route for RIT in malignant ascites models shows advantages over the i.v. route with regard to tumor targeting and half-life prolongation of radioimmunoconjugates in the peritoneal cavity.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Medicine > 3. Theses(Master)
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