化学学报 ›› 2014, Vol. 72 ›› Issue (4): 427-432.DOI: 10.6023/A13121248 上一篇    下一篇

研究论文

111In-CCPM-RGD纳米粒子的合成及其双模态分子显像研究

朱华a, 李囡a, 林新峰a, 洪业b, 杨志a   

  1. a 北京大学肿瘤医院暨北京市肿瘤防治研究所 核医学科 恶性肿瘤发病机制及转化研究教育部重点实验室 100142;
    b 中国原子能科学研究院同位素所 北京275信箱 102413
  • 收稿日期:2013-12-12 出版日期:2014-04-14 发布日期:2014-01-08
  • 通讯作者: 杨志 E-mail:pekyz@163.com; Tel.:0086-010-88196192 E-mail:pekyz@163.com
  • 基金资助:
    项目受国家自然科学基金(No.81071198,81172082,81371592)和北京自然科学基金(No.7132040)资助.

Design and Synthesis of 111In-CCPM-RGD Nanoparticles for Dual-modality Molecular Imaging

Zhu Huaa, Li Nana, Lin Xinfenga, Hong Yeb, Yang Zhia   

  1. a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142;
    b Isotope Department, China Institute of Atomic Energy, Beijing 102413
  • Received:2013-12-12 Online:2014-04-14 Published:2014-01-08
  • Supported by:
    Project supported by the National Natural Science Foundation of China (Nos. 81071198, 81172082, 81371592) and Beijing Natural Science Foundation (No. 7132040).

本研究以具有优良生物学性能的近红外核交联聚合胶束纳米粒子(NIRF-CCPM)为载体,将具有肿瘤靶向性的多肽RGD(精氨酸-甘氨酸-天冬氨酸)与该纳米粒子偶联,并通过放射性核素111In进行标记,放射性标记过程中,标记率96%,放化纯度大于99%. 111In-CCPM-RGD分子探针表现出良好的放射标记/光学性质. 体外稳定性研究表明,25 ℃条件下其在5%小牛血清缓冲液中静置72 h,依然保持有90%的稳定性. 同时采用核医学/光学显像两种影像手段评价了该双模态分子探针在U87肿瘤模型裸鼠体内的代谢情况:在静脉注射11.1 MBq 111In-CCPM-RGD纳米粒子24 h、72 h进行SPECT/CT的显像,其在肿瘤部位表现出特异性的浓集. 同时,其在NIRF的显像中表明相应肿瘤区域出现特异性富集. 111In-CCPM-RGD纳米粒子的设计、合成及初步生物学评价说明其同时兼具光学和核医学显像功能,是性能优良的新型双模态纳米分子探针,能够帮助提高肿瘤的诊断效能,为建立光学/核医学用于肿瘤靶向双模式成像奠定理论基础.

关键词: 近红外核交联聚合胶束纳米粒子, 肿瘤靶向, 双模态显像, 铟-111

The multi-modality probes are essential for multi-modality imaging. Dual labeled imaging probes allow the same target to be evaluated with two different modalities. Based on the structure of c-RGD peptide motif, some examples of multimodality agents have been reported in design of RGD for αvβ3 intergin positive tumor imaging. The aim of this study was to develop a dual-labeled nanoparticles for both single photon emission computed tomography (SPECT) and near-infrared fluorescence (NIRF) imaging of αvβ3. In this paper, c-RGD was conjugated to near-infrared fluorescence fluorophores (Cy7) entrapped polyethylene glycol-coated, core-crosslinked polymeric micelles (NIRF-CCPM) labeled with a radioisotope indium 111. The labeling efficiency was over 96%, the radio chemical purity was over 99% after purification. The in vitro stability tests were presented in 5% bull serum albumin (BSA) for 72 h at 25 ℃. Less than 10% 111In dissociation was detected by Radio-Thin-Layer Chromatography. 111In-CCPM-RGD seems to be a promising candidate for dual optical and nuclear imaging applications in tumor detection. Its structure was fully characterized. Serial SPECT imaging of human glioma U87 tumor-bearing nude mice revealed that tumor uptake of 111In-CCPM-RGD got a substantial growth from 24 h to 72 h after post-injection of 11.1 MBq nanoparticles, corroborated by in vivo NIRF imaging. Tumor uptake as measured by in vivo NIRF imaging by region of interest (ROI) with the unit of average radiant efficiency. The ROI of tumor NIRF imaging were 4.81×107 and 6.91×107 [p/sec/cm2/sr]/[μW/cm2] at 24 h, 72 h respectively. The in vivo SPECT imaging was general concordance with NIRF imaging. The combination of these nuclear and NIRF imaging technologies will significantly improve the accuracy in tumor diagnosis. The persistent, excellent, and αvβ3-specific uptake of 111In-CCPM-RGD in the tumor, observed by both SPECT and NIRF imaging, warrants further investigation and future clinical translation of such nanoparticles-based imaging agents.

Key words: core-crosslinked polymeric micelles, tumor target, dual-modality imaging, indium-111