Evaluation of Radiolabeled Type IV Collagen Fragments as Potential Tumor Imaging Agents
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- 作者：W. Barry Edwards ; Carolyn J. Anderson ; Gregg B. Fields ; and Michael J. Welch
- 刊名：Bioconjugate Chemistry
- 出版年：2001
- 出版时间：November 2001
- 年：2001
- 卷：12
- 期：6
- 页码：1057 - 1065
- 全文大小：98K
- 年卷期：v.12,no.6(November 2001)
- ISSN：1520-4812
文摘
The objective of this study was to examine radiopharmaceuticals that target the 
3
1 integrin todetermine if these agents target tumors for diagnostic imaging and/or targeted radiotherapy of cancer.Prior studies had shown that residues 531-542 from the 1 chain of type IV collagen bind a varietyof tumor cell 31 integrins. A peptide mimic of this sequence containing all D-amino acids (designatedD-Hep-III) was synthesized by solid-phase methods. The tetraazamacrocyclic chelator, TETA, wasconjugated to the peptide while it was resin-bound. TETA-D-Hep-III and D-Hep-III were radiolabeledwith 64Cu and 125I, respectively, in high specific activity and radiochemical purity. Heterologouscompetitive binding assays between D-Hep-III and either 125I-D-Hep-III or 64Cu-TETA-D-Hep-IIIindicated low micromolar affinity of D-Hep-III. The biodistribution of each radiolabeled analogue ofD-Hep-III was carried out in rats and tumor-bearing mice. Both analogues were rapidly cleared fromthe blood in normal rats, with the kidneys receiving the highest accumulation of each. SKOV3 humanovarian tumor cells, known to strongly express 31, were xenografted in SCID mice. Localization of125I-D-Hep III and 64Cu-TETA-D-Hep III in the xenografts were low (<2% ID/g), and in the case of125I-D-Hep III, not inhibited by a competitive dose of D-Hep III. The low tumor accumulation is likelynot due to receptor down-regulation, but rather due to the weak affinity of the radioligands for the31 integrin.
31 integrin todetermine if these agents target tumors for diagnostic imaging and/or targeted radiotherapy of cancer.Prior studies had shown that residues 531-542 from the 1 chain of type IV collagen bind a varietyof tumor cell 31 integrins. A peptide mimic of this sequence containing all D-amino acids (designatedD-Hep-III) was synthesized by solid-phase methods. The tetraazamacrocyclic chelator, TETA, wasconjugated to the peptide while it was resin-bound. TETA-D-Hep-III and D-Hep-III were radiolabeledwith 64Cu and 125I, respectively, in high specific activity and radiochemical purity. Heterologouscompetitive binding assays between D-Hep-III and either 125I-D-Hep-III or 64Cu-TETA-D-Hep-IIIindicated low micromolar affinity of D-Hep-III. The biodistribution of each radiolabeled analogue ofD-Hep-III was carried out in rats and tumor-bearing mice. Both analogues were rapidly cleared fromthe blood in normal rats, with the kidneys receiving the highest accumulation of each. SKOV3 humanovarian tumor cells, known to strongly express 31, were xenografted in SCID mice. Localization of125I-D-Hep III and 64Cu-TETA-D-Hep III in the xenografts were low (<2% ID/g), and in the case of125I-D-Hep III, not inhibited by a competitive dose of D-Hep III. The low tumor accumulation is likelynot due to receptor down-regulation, but rather due to the weak affinity of the radioligands for the31 integrin.