Chen Xiaoyuan, Park Ryan, Shahinian Anthony H, Bading James R, Conti Peter S
Department of Radiology, University of Southern California, Los Angeles, CA 90033, USA.
Nucl Med Biol. 2004 Jan;31(1):11-9. doi: 10.1016/j.nucmedbio.2003.07.003.
Tumor growth and metastasis are angiogenesis dependent. Overexpression of integrin alphavbeta3 in angiogenic vessels as well as various malignant human tumors suggests the potential of suitably labeled antagonists of this adhesion receptor for radionuclide imaging and therapy of tumors. Small head-to-tail cyclic peptides including the Arg-Gly-Asp (RGD) amino acid sequence have been radiolabeled and studied in preclinical animal models. However, the fast blood clearance, high kidney and liver uptake, and rapid washout from tumors make this type of tracer ineffective for clinical applications. In this study we modified the cyclic pentapeptide c(RGDyK) with monofunctional methoxy-PEG (mPEG, M.W. = 2,000) and labeled the RGD-mPEG conjugate with 125I. We studied the tumor targeting efficacy and in vivo pharmacokinetic properties of 125I-RGD-mPEG by means of direct tissue sampling and autoradiography in mice xenografted subcutaneously with U87MG glioblastoma. Compared to the 125I-RGD analog, this PEGylated RGD peptide revealed faster blood clearance, lower kidney uptake, and prolonged tumor uptake without compromising the receptor targeting ability.
肿瘤的生长和转移依赖于血管生成。整合素αvβ3在血管生成血管以及各种人类恶性肿瘤中过表达，这表明这种粘附受体的合适标记拮抗剂可能用于肿瘤的放射性核素显像和治疗。包含精氨酸-甘氨酸-天冬氨酸（RGD）氨基酸序列的小的头对尾环肽已被放射性标记，并在临床前动物模型中进行了研究。然而，这种示踪剂的快速血液清除、高肾脏和肝脏摄取以及从肿瘤中的快速洗脱使其在临床应用中无效。在本研究中，我们用单功能甲氧基聚乙二醇（mPEG，分子量 = 2000）修饰环五肽c(RGDyK)，并用125I标记RGD-mPEG偶联物。我们通过直接组织采样和放射自显影，在皮下接种U87MG胶质母细胞瘤的小鼠中研究了125I-RGD-mPEG的肿瘤靶向效能和体内药代动力学特性。与125I-RGD类似物相比，这种聚乙二醇化的RGD肽显示出更快的血液清除、更低的肾脏摄取以及延长的肿瘤摄取，同时不影响受体靶向能力。
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