Radiotheranostic Agent 64Cu-cyclam-RAFT-c(-RGDfK-)4 for Management of Peritoneal Metastasis in Ovarian Cancer
Radiotheranostic Agent 64Cu-cyclam-RAFT-c(-RGDfK-)4 for Management of Peritoneal Metastasis in Ovarian Cancer
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DOI：
10.1158/1078-0432.ccr-20-1205
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发表时间：
2020-12-01
影响因子：
11.5
通讯作者：
Higashi, Tatsuya
中科院分区：
文献类型：
--
作者：
Jin, Zhao-Hui;Tsuji, Atsushi B.;Higashi, Tatsuya
目的：卵巢癌腹膜转移(OCPMs)是一组病理生理异质性的肿瘤，很少治愈。α(V)β(3)整合素(α(V)β(3))在肿瘤新生血管和卵巢癌细胞上高表达。在这里，我们使用两个临床相关的α(V)β(3)阳性的OCPM小鼠模型，研究了α(V)β(3)特异性放射性多肽-铜--甜蜜素-c(-RGDfK-)(4)的治疗潜力及其在肿瘤微环境中的分布。实验设计：建立了表达α(V)β(3)的卵巢癌裸鼠腹膜和皮下模型(IGR-OV1和NIH：OVCAR-3)。铜--RaftRGD静脉或腹腔给药。我们进行了瘤内分布、PET/CT成像和定量、生物分布分析和放射剂量测定，以及治疗效果和毒性研究。结果：腹腔给药是靶向铜--RaftRGD的OCPM的有效途径，具有良好的肿瘤穿透性。利用荧光替代物Cy5.5-RaftRGD，在我们独特的高分辨率多荧光分析中，我们发现Cu--RaftRGD的ITD与缺氧的ITD在空间上是不同的，但又是互补的。基于铜--RaftRGD的PET能够清晰地显示多个OCPM沉积物和腹水，生物分布分析表明肿瘤摄取与肿瘤大小(1.2-17.2 mm)呈负相关。铜--RaftRGD在放射治疗剂量(148MBq/0.357 nmol)下，通过抑制肿瘤细胞增殖和诱导细胞凋亡而显示出抗肿瘤活性，毒性可忽略不计。结论：综合以上结果，铜--RaftRGD具有同时靶向肿瘤新生血管和癌细胞的影像引导放射治疗OCPM的潜力。根据ITD的发现，我们认为，通过克服单一药物治疗所遇到的ITD的异质性，配对α(V)、β(3)和低氧靶向放射治疗可以提高治疗效果。
Purpose: Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. alpha(V)beta(3) integrin (alpha(V)beta(3)) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant alpha(V)beta(3)-positive OCPM mouse models, we studied the theranostic potential of an alpha(V)beta(3)-specific radiopeptide, Cu-64-cyclamRAFT-c(-RGDfK-) (4) (Cu-64-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment.Experimental Design: alpha(V)beta(3)-expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH: OVCAR-3) were established in nude mice. Cu-64-RaftRGD was administered either intravenously or intraperitoneally. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies.Results: Intraperitoneal administration was an efficient route for targeting Cu-64-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescence surrogate, Cy5.5-RaftRGD, in our unique high-resolution multifluorescence analysis, we found that the ITD of Cu-64-RaftRGD was spatially distinct from, but complementary to, that of hypoxia. Cu-64-RaftRGD-based PET enabled clear visualization of multiple OCPM deposits and ascites and biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2-17.2 mm). Cu-64-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, with negligible toxicity.Conclusions: Collectively, these results demonstrate the all-in-one potential of Cu-64-RaftRGD for imaging guided radiotherapy of OCPM by targeting both tumoral neovessels and cancerous cells. On the basis of the ITD finding, we propose that pairing alpha(V)beta(3)- and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.