Alves Susana, Correia João D G, Gano Lurdes, Rold Tammy L, Prasanphanich Adam, Haubner Roland, Rupprich Marco, Alberto Roger, Decristoforo Clemens, Santos Isabel, Smith Charles J
Department of Radiology, Department of Internal Medicine, and The Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, Missouri 65211, USA.
Bioconjug Chem. 2007 Mar-Apr;18(2):530-7. doi: 10.1021/bc060234t.
Radiolabeled peptides containing the Arg-Gly-Asp amino acid sequence (single letter code = RGD) have been studied extensively to target integrin receptors upregulated on tumor cells and neovasculature. Integrins are cell surface transmembrane glycoproteins that exist as alphabeta heterodimers. The alphavbeta3 integrin is known to be overexpressed in many tumor types and is expressed at lower levels in normal tissues. Furthermore, alphavbeta3 and alphavbeta5 subtypes are expressed in neovasculature during angiogenesis. Thus, there is some impetus to image angiogenesis and tumor formation in vivo using RGD-based peptide targeting vectors. In this study, we report the design and development of a new cyclic RGD analogue cyclo-[Arg-Gly-Asp-d-Tyr-Lys(PZ)] (PZ = 3,5-Me2-pz(CH2)2N((CH2)3COOH)(CH2)2NH2) that can be radiolabeled with the [99mTc(CO)3(H2O)3]+ metal aquaion. Radiochemical evaluation of this new conjugate in vitro indicated a facile radiosynthesis of the new 99mTc-RGD conjugate with high radiolabeling yields (>or=95%) and high specific activities. In vitro internalization and blocking assays in alphavbeta3 receptor-positive, human M21 melanoma cancer cells showed the ability of this conjugate to target the integrin receptor with high specificity and selectivity. In vivo pharmacokinetic studies in normal CF-1 mice showed rapid clearance from blood with excretion primarily via/through the renal-urinary system. In vivo accumulation of radioactivity in mice bearing either alphavbeta3 receptor-positive or negative human melanoma tumors showed receptor specific uptake of tracer with accumulations of 2.50 +/- 0.29 and 0.71 +/- 0.08% ID/g in alphavbeta3 integrin positive (M21) and negative (M21L) tumors at 1 h postinjection (p.i.), respectively.
含有精氨酸 - 甘氨酸 - 天冬氨酸氨基酸序列（单字母代码 = RGD）的放射性标记肽已被广泛研究，用于靶向肿瘤细胞和新生血管上上调的整合素受体。整合素是作为αβ异二聚体存在的细胞表面跨膜糖蛋白。已知αvβ3整合素在许多肿瘤类型中过度表达，而在正常组织中表达水平较低。此外，αvβ3和αvβ5亚型在血管生成过程中在新生血管中表达。因此，使用基于RGD的肽靶向载体在体内成像血管生成和肿瘤形成具有一定的推动力。在本研究中，我们报告了一种新的环状RGD类似物环 - [精氨酸 - 甘氨酸 - 天冬氨酸 - d - 酪氨酸 - 赖氨酸（PZ）]（PZ = 3,5 - 二甲基 - 吡唑（CH2）2N（（CH2）3COOH）（CH2）2NH2）的设计和开发，它可以用[99mTc（CO）3（H2O）3]+金属水合离子进行放射性标记。这种新偶联物在体外的放射化学评估表明，新的99mTc - RGD偶联物易于进行放射性合成，具有高放射性标记产率（≥95％）和高比活度。在αvβ3受体阳性的人M21黑色素瘤癌细胞中进行的体外内化和阻断试验表明，这种偶联物能够以高特异性和选择性靶向整合素受体。在正常CF - 1小鼠中进行的体内药代动力学研究表明，该药物从血液中快速清除，主要通过肾 - 泌尿系统排泄。在携带αvβ3受体阳性或阴性人黑色素瘤肿瘤的小鼠中进行的体内放射性积累研究表明，在注射后1小时（p.i.），αvβ3整合素阳性（M21）和阴性（M21L）肿瘤中示踪剂的受体特异性摄取分别为2.50±0.29和0.71±0.08％ID / g。
