신생혈관형성 생체표지자, 인테그린 αvβ3에 대한 예비표적화를 위한 아비딘 결합 펩타이드 유사체의 합성과 최적화 및 영상 연구 (Synthesis, Optimization and Imaging Study of Avidin-Conjugated Petidomimetic Antagonist to Pre-Target an Angiogenic Marker, Integrin αvβ3)

서지정보

· 발행기관 : 한국조직공학과 재생의학회
· 수록지 정보 : 조직공학과 재생의학 / 8권 / 4호 / 99 ~ 107페이지
· 저자명 : 신인수, 장범수, Chang H. Paik, 맹진수

초록

Determination of angiogenesis has been used for the verification of new tissue generation or tumor cell growth. In this study, we developed a pre-targeting method with non-invasive imaging technique, which can detect angiogenic stage of neovasculature in tumor xenografted mouse model. The angiogenesis was induced by transplanting M21 melanoma with continuous proliferation activity and the aid of biomaterial scaffold, Matrigel, as a tissue engineering drug preparations from basement membrane matrix. Angiogenic biomarker, integrin αvβ3 receptor molecule was selected as the target of this pre-targeting study and one of the RGD peptide mimics or integrin αvβ3 receptor antagonist (IA), 4-[2-(3,4,5,6-tetrahydro-pyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-amino-ethylsulfonyl-amino-β-alanine with specific binding ability to integrin αvβ3 was chosen as a potent bio-nano probe for imaging. IA was conjugated to avidin (Av) to increase its receptor-binding avidity and to optimize parameters to pre-target αvβ3-expressing tumor. Parameters including conjugation levels, amount of conjugates injected, and injection time intervals between Av-(IA)n and In-111-DOTA-biotin were investigated to optimize tumor-to-blood (T/B) and tumor-to-liver (T/L) ratios in nude mice with s.c. receptor-expressing M21 human melanoma. Mice were imaged 2 hours after In-111-DOTA-biotin injection with a gamma camera. Comparing the level (n) of Av-(IA)n (200 μg) injected, the case of n=10 to 15 produced higher T/B (8.11±4.23) and T/L (1.55±1.42) ratios than the case of n=5. This neovasculature pre-targeting approach using the avidin-biotin system resulted in high tumor-to-background (angiogenic-to-normal)ratios and warrants further studies for assessing the αvβ3 receptor expression in angiogenesis induced by the combined xenografts of implanted tumor and basement membrane matrix scaffold.

영어초록

Determination of angiogenesis has been used for the verification of new tissue generation or tumor cell growth. In this study, we developed a pre-targeting method with non-invasive imaging technique, which can detect angiogenic stage of neovasculature in tumor xenografted mouse model. The angiogenesis was induced by transplanting M21 melanoma with continuous proliferation activity and the aid of biomaterial scaffold, Matrigel, as a tissue engineering drug preparations from basement membrane matrix. Angiogenic biomarker, integrin αvβ3 receptor molecule was selected as the target of this pre-targeting study and one of the RGD peptide mimics or integrin αvβ3 receptor antagonist (IA), 4-[2-(3,4,5,6-tetrahydro-pyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-amino-ethylsulfonyl-amino-β-alanine with specific binding ability to integrin αvβ3 was chosen as a potent bio-nano probe for imaging. IA was conjugated to avidin (Av) to increase its receptor-binding avidity and to optimize parameters to pre-target αvβ3-expressing tumor. Parameters including conjugation levels, amount of conjugates injected, and injection time intervals between Av-(IA)n and In-111-DOTA-biotin were investigated to optimize tumor-to-blood (T/B) and tumor-to-liver (T/L) ratios in nude mice with s.c. receptor-expressing M21 human melanoma. Mice were imaged 2 hours after In-111-DOTA-biotin injection with a gamma camera. Comparing the level (n) of Av-(IA)n (200 μg) injected, the case of n=10 to 15 produced higher T/B (8.11±4.23) and T/L (1.55±1.42) ratios than the case of n=5. This neovasculature pre-targeting approach using the avidin-biotin system resulted in high tumor-to-background (angiogenic-to-normal)ratios and warrants further studies for assessing the αvβ3 receptor expression in angiogenesis induced by the combined xenografts of implanted tumor and basement membrane matrix scaffold.

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