Development of Cancer-Targeted Single Photon Emission Computed Tomography/Fluorescence Dual Imaging Probe Based on Polyoxazoline AITranslate

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DOI：https://doi.org/10.1021/acsapm.8b00238

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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 (111In) 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 111In, the biodistribution of 111In-DOTA-POZ-ICG was evaluated using mice inoculated with colon 26 tumors. In this biodistribution study, the tumor uptake levels of 111In 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 111In-DOTA-POZ-ICG. Furthermore, autoradiographic studies showed that the localization of radioactivity (111In) corresponded to ICG positive regions which were close to blood vessels, suggesting that the tumor uptake of 111In-DOTA-POZ-ICG occurred via the EPR effect. In summary, the intense, high-contrast tumor uptake of 111In-DOTA-POZ-ICG was demonstrated. Furthermore, intratumoral colocalization of radioactivity and fluorescence was observed; thus, the potential of 111In-DOTA-POZ-ICG as a nuclear/fluorescence dual imaging probe for tumors was demonstrated.