A complete substitutional analysis of VIP for better tumor imaging properties
A complete substitutional analysis of VIP for better tumor imaging properties
复制标题
DOI：
10.1002/jmr.565
复制
发表时间：
2002-05-01
影响因子：
2.7
通讯作者：
Volkmer-Engert, R
中科院分区：
文献类型：
--
作者：
Bhargava, S;Licha, K;Volkmer-Engert, R
由于许多肿瘤细胞过度表达血管活性肠肽（VIP）受体亚型1 (VPAC(1))， VIP-染料偶联物可作为体内成像的造影剂。然而，VIP在体内的蛋白水解降解限制了其诊断用途，并强调需要结构优化的VIP衍生物，改善药代动力学。在这里，我们在纤维素膜上应用平行纳米合成可切割肽来进行完整的VIP取代分析。用流式细胞术检测504种不同的vip染料类似物的细胞结合能力。他们详细分析了与VPAC(1)过表达细胞结合所必需的氨基酸位置。从取代分析结果中得到了一个广义的vip -染料结合基序，为进一步优化提供了参考点。一种[Arg8]- vip染料类似物在蛋白质水解降解方面表现出更高的稳定性，在小鼠中具有良好的肿瘤-组织对比，并且在体内具有更长的半衰期。版权所有:John Wiley Sons, Ltd。
Since numerous tumor cells overexpress the vasoactive intestinal peptide (VIP) receptor subtype 1 (VPAC(1)), VIP-dye conjugates would be useful as contrast agents for in vivo imaging. However, proteolytic degradation of VIP in vivo limits their diagnostic use and highlights the need for structurally optimized VIP derivatives with improved pharmacokinetics. Here, we applied parallel nano-synthesis of cleavable peptides on cellulose membranes to perform a complete VIP substitutional analysis. The resulting 504 different VIP-dye analogs were tested for cell binding by flow cytometry. They provided a detailed analysis of amino acid positions essential for binding to VPAC(1) overexpressing cells. A generalized VIP-dye binding motif derived from the substitutional analysis results served as a reference point for further optimization. An [Arg8]-VIP-dye analog showed increased stability towards proteolytic degradation, good tumor-to-tissue contrast in mice and a longer half-life in vivo. Copyright (C) 2002 John Wiley Sons, Ltd.