Development of Cancer-Targeted Single Photon Emission Computed Tomography/Fluorescence Dual Imaging Probe Based on Polyoxazoline
Development of Cancer-Targeted Single Photon Emission Computed Tomography/Fluorescence Dual Imaging Probe Based on Polyoxazoline
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DOI：
10.1021/acsapm.8b00238
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发表时间：
2019-05-01
影响因子：
5
通讯作者：
Mukai, Takahiro
中科院分区：
文献类型：
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作者：
Sano, Kohei;Bao, Ling;Mukai, Takahiro
聚恶唑啉(POZ)是由N-酰乙基亚胺组成的生物相容亲水性聚合物。我们以前的研究表明，POZ中的酰基可以部分水解生成的仲氨基上引入许多荧光染料，POZ的衍生物由于增强渗透性和保留力(EPR)效应可以在肿瘤组织中积聚。在本研究中，为了实现术前和术中肿瘤的无缝诊断，我们设计并合成了一种标记铟-111(In-111)和吲哚青绿(ICG)的POZ衍生物，并评价了其作为单光子发射计算机断层扫描和荧光成像双重成像探针的可行性。用盐酸对2-乙基-2-恶唑啉组成的POZ酰基进行部分水解，然后与DOTA(金属络合剂)偶联，然后进行ICG。用In-111标记DOTA-POZ-ICG后，研究In-111-DOTA-POZ-ICG在小鼠体内的分布。在此生物分布研究中，注射后24 h，In-111和ICG的肿瘤摄取水平相似，肿瘤与血液和肿瘤与肌肉的比率分别为1.8和6.7。体内荧光成像显示，注射In-111-DOTA-POZ-ICG后24 h，肿瘤清晰可见。此外，放射自显影研究表明，放射性(In-111)的定位对应于靠近血管的ICG阳性区域，提示肿瘤摄取西林-DOTA-POZ-ICG是通过EPR效应进行的。总之，证明了In-111-DOTA-POZ-ICG对肿瘤的高强度、高对比度摄取。此外，还观察到了瘤内放射性和荧光的共存，从而证明了In-111-DOTA-POZ-ICG作为肿瘤核/荧光双重成像探针的潜力。
Polyoxazolines (POZs) are biocompatible hydrophilic polymers composed of N-acylethylenimine. Our previous study showed that many fluorescence dyes could be introduced into the secondary amino groups yielded by partially hydrolyzing acyl groups in POZs and that POZ derivatives could accumulate in tumor tissues due to enhanced permeability and retention (EPR) effect. In this study, to achieve seamless preoperative and intraoperative tumor diagnosis, we newly designed and synthesized a POZ derivative labeled with indium-111 (In-111) and indocyanine green (ICG) and evaluated its feasibility as a dual imaging probe for single photon emission computed tomography and fluorescence imaging. We partially hydrolyzed the POZ acyl groups composed of 2-ethyl-2-oxazoline by reacting them with hydrochloric acid; then, the hydrolyzed POZ was conjugated with DOTA (a metal chelator), followed by ICG. After labeling DOTA-POZ-ICG with In-111, the biodistribution of In-111-DOTA-POZ-ICG was evaluated using mice inoculated with colon 26 tumors. In this biodistribution study, the tumor uptake levels of In-111 and ICG were similar 24 h after injection, and the tumor-to-blood and tumor-to-muscle ratios were 1.8 and 6.7, respectively. Using in vivo fluorescence imaging, the tumor was clearly detected 24 h after the injection of In-111-DOTA-POZ-ICG. Furthermore, autoradiographic studies showed that the localization of radioactivity (In-111) corresponded to ICG positive regions which were close to blood vessels, suggesting that the tumor uptake of IllIn-DOTA-POZ-ICG occurred via the EPR effect. In summary, the intense, high-contrast tumor uptake of In-111-DOTA-POZ-ICG was demonstrated. Furthermore, intratumoral colocalization of radioactivity and fluorescence was observed; thus, the potential of In-111-DOTA-POZ-ICG as a nuclear/fluorescence dual imaging probe for tumors was demonstrated.