Radioiodination of rhenium cyclized α-melanocyte-stimulating hormone resulting in enhanced radioactivity localization and retention in melanoma
Radioiodination of rhenium cyclized α-melanocyte-stimulating hormone resulting in enhanced radioactivity localization and retention in melanoma
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DOI：
10.1158/0008-5472.can-03-0193
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发表时间：
2004-02-15
期刊：
影响因子：
11.2
通讯作者：
Jurisson, SS
中科院分区：
文献类型：
--
作者：
Cheng, Z;Chen, JQ;Jurisson, SS
放射性卤代α-黑素细胞刺激激素（α-MSH）类似物被提出用于黑色素瘤成像和潜在的放射疗法，因为α-MSH受体在小鼠和人黑色素瘤细胞系上都过表达。然而，用放射性卤化的α-MSH肽在荷瘤小鼠中进行的生物分布研究显示，由于内化后放射性卤化复合物的溶酶体降解，肿瘤放射性洗脱非常快，这显著降低了治疗功效（R. Stein等人，癌症研究所，55：3132- 3139，1995; P.K. Garg等人，生物缀合物化学，6：493-501，1995）。黑色素瘤靶向金属肽ReO[Cys（3，4，10），D-Phe（7）] alpha-MSH 3 -13（ReCCMSH）被证明具有高肿瘤吸收和保留特性（J. Chen等人，癌症研究所，60：5649-5658，2000）。因此，三种肽Ac-Lys-ReCCMSH（Arg（11））、Ac-D-Lys-ReCCMSH（Arg（11））和[Nle（4），D-Phe（7）] a-MSH（NDP）（用于比较），用N-琥珀酰亚胺基4-[I-125]碘苯甲酸酯标记（I-125-PIB），并在体外和体内进行评价，以开发具有高肿瘤摄取、保留和良好的生物分布特性。体外细胞结合和内化数据显示，在培养的B16/F1黑色素瘤细胞中，约90%的放射性碘标记肽在2小时时被内化。细胞保留研究表明，受体结合的放射性碘标记的线性α-MSH类似物NDP从细胞中非常快速地释放到培养基中，而对于Ac-Lys（I-125-3-或4-碘苯甲酸酯（IBA））-ReCCMSH（Arg（11））和Ac-D-Lys（I-125-IBA）-ReCCMSH（Arg（11）），显著量的细胞相关放射性保留在细胞中。体外数据清楚地表明，β-环化显著增强了细胞中的肽捕获，D-氨基酸掺入也是如此。这两种效应的组合导致4 h时Ac-D-Lys（I-125-IBA）-ReCCMSH（Arg（11））的放射性保留相对于I-125-IBA-NDP增加2.9倍。体内研究也表明Ac-D-Lys（I-125-IBA）-ReCCMSH（Arg（11））在肿瘤中表现出极高的放射性蓄积和延长的保留。Ac-D-Lys（I-125-HIA）-ReCCMSH（Arg（11））和Ac-Lys（I-125-IBA）-ReCCMSH（Arg“）在注射后24小时与I-125-IBA-NDP相比显示出高得多的肿瘤摄取[分别为7.18%注射剂量/克（ID/g）、4.92%HIA/g和0.26%ID/g]。与I-125-IBA-NDP和Ac-Lys（I-125-IBA）-ReCCMSH（Arg“）相比，Ac-D-Lys（I-125-IBA）-ReCCMSH（Arg（11））也显示出非常快的全身清除和低的正常组织中的非特异性放射性蓄积。注射后24 h，Ac-D-Lys（I-125-IBA）-ReCCMSH（Arg（11））的肿瘤：血液比为34.3，而Ac-Lys（I-125-IBA）-ReCCMSH（Arg（11））和I-125-IBA-NDP的肿瘤：血液比分别为4.3和2.0。生物分布数据清楚地表明，双环化和D-Lys掺入增强了放射性标记的肿瘤定位和保留。因此，Ac-D-Lys-ReCCMSH（Arg（11））是额外治疗研究的极好候选物。
Radiohalogenated alpha-melanocyte-stimulating hormone (alpha-MSH) analogs were proposed for melanoma imaging and potential radiotherapy because alpha-MSH receptors are overexpressed on both mouse and human melanoma cell lines. However, biodistribution studies in tumor-bearing mice with radiohalogenated alpha-MSH peptides showed very rapid tumor radioactivity wash out due to lysosomal degradation of the radiohalogenated complex after internalization, which decreased the therapeutic efficacy significantly (R. Stein et al., Cancer Res., 55: 3132-3139,1995; P. K. Garg et al., Bioconjugate Chem., 6: 493-501, 1995.). The melanoma-targeting metallopeptide ReO[Cys(3,4,10),D-Phe(7)]alpha-MSH3-13 (ReCCMSH) was shown to possess high tumor uptake and retention properties (J. Chen et al., Cancer Res., 60: 5649-5658, 2000). Therefore, three peptides, Ac-Lys-ReCCMSH(Arg(11)), Ac-D-Lys-ReCCMSH(Arg(11)), and [Nle(4),D-Phe(7)]alpha-MSH (NDP) (for comparison), labeled with N-succinimidyl 4-[I-125]iodobenzoate (I-125-PIB), were prepared and evaluated in vitro and in vivo to develop radiohalogenated a-MSH peptide analogs with high tumor uptake, retention, and favorable biodistribution characteristics. In vitro cell binding and internalization data showed that approximately 90% of radioiodinated peptides were internalized at 2 h in cultured B16/Fl melanoma cells. Cellular retention studies showed that the receptor-bound radioiodinated linear a-MSH analog NDP was released from the cells into the medium very quickly, whereas significant amounts of cell-associated radioactivity remained in the cells for Ac-Lys(I-125-3- or 4-iodobenzoate (IBA))-ReCCMSH(Arg(11)) and Ac-D-Lys(I-125-IBA)-ReCCMSH(Arg(11)). The in vitro data clearly demonstrate that rhenium cyclization significantly enhanced peptide trapping in the cells, as did D-amino acid incorporation. The combination of these two effects resulted in a 2.9-fold increase in the retention of radioactivity for Ac-D-Lys(I-125-IBA)-ReCCMSH(Arg(11)) relative to I-125-IBA-NDP at 4 h. In vivo studies also showed that Ac-D-Lys(I-125-IBA)-ReCCMSH(Arg(11)) exhibited extremely high radioactivity accumulation and prolonged retention in the tumor. Ac-D-Lys(I-125-HIA)-ReCCMSH(Arg(11)) and Ac-Lys(I-125-IBA)-ReCCMSH(Arg'') exhibited much higher tumor uptake at 24 h after injection compared with I-125-IBA-NDP [7.18% injected dose/gram (ID/g), 4.92% H)/g, and 0.26% ID/g, respectively]. Ac-D-Lys(I-125-IBA)-ReCCMSH(Arg(11)) also showed very fast whole body clearance and low nonspecific radioactivity accumulation in normal tissues compared with I-125-IBA-NDP and Ac-Lys(I-125-IBA)-ReCCMSH(Arg''). A tumor:blood ratio of 34.3 was observed for Ac-D-Lys(I-125-IBA)-ReCCMSH(Arg(11)) at 24 h postinjection, whereas values of 4.3 and 2.0 were observed for Ac-Lys(I-125-IBA)-ReCCMSH(Arg(11)) and I-125-IBA-NDP, respectively. The biodistribution data clearly demonstrate that both rhenium cyclization and D-Lys incorporation enhanced the tumor localization and retention of the radiolabel. Therefore Ac-D-Lys-ReCCMSH(Arg(11)) is an excellent candidate for additional therapeutic studies.