Preclinical evaluation of a dual sstr2 and integrin αvβ3-targeted heterodimer [68Ga]-NOTA-3PEG4-TATE-RGD
Preclinical evaluation of a dual sstr2 and integrin αvβ3-targeted heterodimer [68Ga]-NOTA-3PEG4-TATE-RGD
复制标题
双 sstr2 和整合素 α(v)β(3) 靶向异二聚体 [Ga-68]-NOTA-3PEG(4)-TATE-RGD 的临床前评估
DOI：
10.1016/j.bmc.2019.115094
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发表时间：
2019-11-01
影响因子：
3.5
通讯作者：
Yao, Shaobo
中科院分区：
文献类型：
--
作者：
Liu, Bingnan;Zhang, Zhenzhong;Yao, Shaobo
目的：多种受体在多种类型的癌症中共表达。奥曲酸（TATE）和Arg-Gly-Asp（RGD）肽分别靶向生长抑素受体2（sstr 2）和整合素α（v）β（3）。方法：将TATE和RGD肽与1，4，7-三氮杂酰基壬烷-N '，N“，N”“-三乙酸（NOTA）通过谷氨酸和聚乙二醇（PEG）连接，然后用Ga-68离子标记3 PTATE-RGD，并将其与1，4，7-三氮杂酰基壬烷-N'，N”，N“"-三乙酸（NOTA）连接，制备了一种新型的异源二聚体NOTA-3 PEG（4）-TATE-RGD（3 PTATE-RGD），研究其对sstr 2和整合素α（v）β（3）的双重靶向性。结果：[Ga-68]-3 PTATE-RGD在细胞摄取和PET显像中与单体TATE和RGD具有相当的sstr 2和整合素α（v）β（3）结合亲和力。在竞争研究中，在过量的未标记的TATE或RGD的存在下，H69和A549肿瘤对[Ga-68]-3 PTATE-RGD的摄取分别被完全抑制。当TATE和RGD混合物与[Ga-68] 3 PTATE-RGD共注射时，阻断水平没有增加。结论：[Ga-68]-3 PTATE-RGD与单体TATE和RGD相比，具有更好的靶向性和更广的靶向性，可用于sstr 2和整合素α（v）β（3）相关肿瘤的检测。
Purpose: Multiple receptors are co-expressed in many types of cancers. Octreotate (TATE) and Arg-Gly-Asp (RGD) peptides target somatostatin receptor 2 (sstr2) and integrin alpha(v)beta(3), respectively. We developed and synthesized a heterodimer NOTA-3PEG(4)-TATE-RGD (3PTATE-RGD) and aimed to investigate its characteristics for dual-targeting sstr2 and integrin alpha(v)beta(3).Methods: TATE and RGD peptides and 1,4,7-triazacylononane-N',N '',N'''-triacetic acid (NOTA) were linked through a glutamate and polyethylene glycol (PEG) linker, then 3PTATE-RGD was labeled with Ga-68 ion. Receptor-binding characteristics and tumor-targeting efficacy were tested in vitro and in vivo using H69 and A549 lung cancer cell lines and tumor-bearing mice models.Results: [Ga-68]-3PTATE-RGD had comparable sstr2 and integrin alpha(v)beta(3)-binding affinity with monomeric TATE and RGD in cell uptake and PET imaging study, respectively. In the competition study, H69 and A549 tumor uptake of [Ga-68]-3PTATE-RGD was completed inhibited in the presence of an excess amount of unlabeled TATE or RGD, respectively. The blocked level didn't grow when both of TATE and RGD mixture was co-injected with [Ga-68]3PTATE-RGD. The pharmacokinetics of [Ga-68]-3PTATE-RGD is comparable with [Ga-68]-TATE and [Ga-68]- RGD, resulting in a larger application.Conclusion: [Ga-68]-3PTATE-RGD showed improved and wider tumor-targeting efficacy compared with monomeric TATE and RGD peptides, which warrants its further investigation in detection both of sstr2 and integrin alpha(v)beta(3)-related carcinomas.