In vitro and in vivo evaluation of a novel 99mTc(CO)3-pyrazolyl conjugate of cyclo-(Arg-Gly-Asp-D-Tyr-Lys)
In vitro and in vivo evaluation of a novel 99mTc(CO)3-pyrazolyl conjugate of cyclo-(Arg-Gly-Asp-D-Tyr-Lys)
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DOI：
10.1021/bc060234t
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发表时间：
2007-03-01
影响因子：
4.7
通讯作者：
Smith, Charles J.
中科院分区：
文献类型：
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作者：
Alves, Susana;Correia, Joao D. G.;Smith, Charles J.
含有Arg-Gly-Asp氨基酸序列(单字母编码=RGD)的放射性标记多肽已被广泛研究，以靶向肿瘤细胞和新生血管上调的整合素受体。整合素是细胞表面的跨膜糖蛋白，以α-β异源二聚体形式存在。已知α(V)β(3)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，在血管生成过程中，α(V)β(3)和α(V)β(5)亚型在新生血管中表达。因此，使用基于RGD的多肽靶向载体对体内成像血管生成和肿瘤形成有一定的推动作用。在本研究中，我们报道了一种新的环状RGD类似物[Arg-Gly-Asp-D-Tyr-Lys(PZ)](PZ=3，5-Me-2-pz(CH2)(2)N((CH2)(3)COOH)-(CH2)(2)NH2))的设计和合成，该环可标记[TC-99m(CO)(3)(H2O)(3)](+)金属水离子。体外放射化学评价表明，新的~(99m)Tc-RGD~(99)m-RGD偶联物具有高放射性标记产率(~gt；=95%)和高比活度的简便合成方法。对α(V)β(3)受体阳性的人M21黑色素瘤癌细胞的体外内化和阻断试验表明，该结合物具有以高特异性和选择性靶向整合素受体的能力。在正常CF-1小鼠体内的药代动力学研究表明，药物从血液中迅速排出，主要通过/通过肾-尿路系统排泄。在荷人黑色素瘤α(V)β(3)受体阳性或阴性的小鼠体内，示踪剂的受体特异性摄取在注射后1h分别为2.50+/-0.29和0.71+/-0.08%ID/g。
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 alpha beta heterodimers. The alpha(v)beta(3) integrin is known to be overexpressed in many tumor types and is expressed at lower levels in normal tissues. Furthermore, alpha(v)beta(3) and alpha(v)beta(5) 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-Me-2-pz(CH2)(2)N((CH2)(3)COOH)-(CH2)(2)NH2) that can be radiolabeled with the [Tc-99m(CO)(3)(H2O)(3)](+) metal aquaion. Radiochemical evaluation of this new conjugate in vitro indicated a facile radiosynthesis of the new Tc-99m-RGD conjugate with high radiolabeling yields (>= 95%) and high specific activities. In vitro internalization and blocking assays in alpha(v)beta(3) 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 alpha(v)beta(3) 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 alpha(v)beta(3) integrin positive (M21) and negative (M21L) tumors at 1 h postinjection (p.i.), respectively.