Li Jiejing, Jiang Beiqi, Lin Chao, Zhuang Zhigang
Department of Breast Surgery, Shanghai First Maternity and Infant hospital, Tongji University, Shanghai, People's Republic of China.
The Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, Shanghai, People's Republic of China.
Int J Nanomedicine. 2014 Dec 4;9:5667-82. doi: 10.2147/IJN.S70593. eCollection 2014.
Sentinel lymph node (SLN) mapping is a critical procedure for SLN biopsy and its diagnosis as tumor metastasis in clinical practice. However, SLN mapping agents used in the clinic frequently cause side effects and complications in the patients. Here, we report the development of a near-infrared (NIR) emitting polymeric nanogel with hydrodynamic diameter of ~28 nm - which is the optimal size for SLN uptake - for noninvasive fluorescence mapping of SLN in a mouse. This polymeric nanogel was obtained by coupling Cy7, an NIR dye, to the self-assembled nanogel from disulfide-linked dextran-deoxycholic acid conjugate with the dextran of 10 kDa, denoted as Dex-Cy7. Fluorescence imaging analysis showed that Dex-Cy7 nanogels had an enhanced photostability when compared to Cy7 alone. After intradermal injection of Dex-Cy7 nanogel into the front paw of a mouse, the nanogels were able to migrate into the mouse's axillary lymph node, exhibiting longer retention time and higher fluorescence intensity in the node when compared to Cy7 alone. An immunohistofluorescence assay revealed that the nanogels were localized in the central region of lymph node and that the uptake was largely by the macrophages. In vitro and in vivo toxicity results indicated that the dextran-based nanogels were of low cytotoxicity at a polymer concentration up to 1,000 μg/mL and harmless to normal liver and kidney organs in mice at an intravenous dose of 1.25 mg/kg. The results of this study suggest that NIR-emitting polymeric nanogels based on bioreducible dextran-deoxycholic acid conjugates show high potential as fluorescence nanoprobes for safe and noninvasive SLN mapping.
前哨淋巴结(SLN)定位是临床实践中进行SLN活检及其肿瘤转移诊断的关键步骤。然而,临床中使用的SLN定位剂经常会给患者带来副作用和并发症。在此,我们报告了一种近红外(NIR)发射的聚合物纳米凝胶的研发情况,其流体动力学直径约为28 nm,这是SLN摄取的最佳尺寸,用于在小鼠体内对SLN进行无创荧光定位。这种聚合物纳米凝胶是通过将近红外染料Cy7与由10 kDa葡聚糖的二硫键连接的葡聚糖 - 脱氧胆酸共轭物自组装形成的纳米凝胶偶联而获得的,记为Dex - Cy7。荧光成像分析表明,与单独的Cy7相比,Dex - Cy7纳米凝胶具有增强的光稳定性。将Dex - Cy7纳米凝胶皮内注射到小鼠前爪后,纳米凝胶能够迁移到小鼠的腋窝淋巴结,与单独的Cy7相比,在淋巴结中显示出更长的保留时间和更高的荧光强度。免疫组织荧光分析显示,纳米凝胶定位于淋巴结的中央区域,并且摄取主要通过巨噬细胞进行。体外和体内毒性结果表明,基于葡聚糖的纳米凝胶在聚合物浓度高达1000 μg/mL时细胞毒性较低,在静脉注射剂量为1.25 mg/kg时对小鼠的正常肝脏和肾脏器官无害。本研究结果表明,基于可生物还原的葡聚糖 - 脱氧胆酸共轭物的近红外发射聚合物纳米凝胶作为用于安全无创SLN定位的荧光纳米探针具有很高的潜力。
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