School of Materials Science and Engineering and Department of Nanobio Materials and Electronics, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, Republic of Korea.
J Control Release. 2011 Dec 20;156(3):398-405. doi: 10.1016/j.jconrel.2011.07.017. Epub 2011 Jul 19.
Previously, the optical imaging of chitosan-functionalized, Pluronic-based nano-carriers by Cy5.5 conjugation revealed a good tumor targeting characteristic of the nano-carriers in vivo [J. Control. Release, 147 (2010) 109-117]. However, in spite of the relatively strong signal from tumor site, they also showed strong fluorescence signals from other organs, especially liver. Thus, for the detection of pathological sites, the direct use of the Cy5.5-conjugated nano-carriers is limited due to significant background signals associated with non-specific delivery of the probes. To overcome this limitation, in this study, we prepared hydrocyanine-conjugated and chitosan-functionalized Pluronic-based nano-carriers (Hydrocyanine-NC) that can detect ROS in pathological sites. The reduction of cyanine to hydrocyanine of the nano-carriers resulted in complete disappearance of fluorescence emission, and the fluorescence could be recovered by ROS-induced re-oxidization. Hydrocyanine-NC could detect various ROS including superoxide anion (O(2)(-)) and hydroxyl radical (OH(-)) in a dose-dependent manner. Hydrocyanine-NC was also stable in serum-containing media and did not show acute cytotoxicity. Hydrocyanine-NC developed strong fluorescence by the intracellular ROS formation in LPS-stimulated macrophage cells in vitro. As an in-vivo inflammation site imaging, SCC7 tumor-bearing mice were optically monitored after the i.v. injection of the dye-conjugated nano-carriers. When non-reduced, cyanine-conjugated and chitosan-functionalized Pluronic-based nano-carriers (Cyanine-NC) were injected, strong fluorescence emission was observed from the abdominal area as well as from the tumor site, and it remained over 2days. In contrast, in the case of Hydrocyanine-NC, the initially very weak fluorescence emission from the abdominal area disappeared over time whereas the fluorescence emission from the tumor site was similar to that of Cyanine-NC. Therefore, the re-oxidation of Hydrocyanine-NC by ROS in vivo specifically eliminated the background signals from non-specific delivery of the probes, but it produced fluorescence emission strong enough to monitor the target inflammation site selectively.
先前，通过 Cy5.5 缀合将壳聚糖功能化的 Pluronic 基纳米载体的光学成像表明，纳米载体在体内具有良好的肿瘤靶向特性[J. Control. Release, 147 (2010) 109-117]。然而，尽管肿瘤部位的信号相对较强，但它们也显示出其他器官（尤其是肝脏）的强烈荧光信号。因此，对于病理性部位的检测，由于与探针的非特异性递送相关的背景信号，直接使用 Cy5.5 缀合的纳米载体受到限制。为了克服这一限制，在本研究中，我们制备了氢氰酸缀合的壳聚糖功能化的 Pluronic 基纳米载体（Hydrocyanine-NC），该纳米载体可以检测病理性部位的 ROS。纳米载体的氰基还原为氢氰酸会导致荧光发射完全消失，而荧光可以通过 ROS 诱导的再氧化恢复。Hydrocyanine-NC 可以以剂量依赖的方式检测各种 ROS，包括超氧阴离子（O(2)(-))和羟基自由基（OH(-))。Hydrocyanine-NC 在含血清的介质中稳定，并且没有表现出急性细胞毒性。Hydrocyanine-NC 在体外 LPS 刺激的巨噬细胞中通过细胞内 ROS 形成产生强烈的荧光。作为体内炎症部位成像，在静脉注射染料缀合的纳米载体后，通过光学监测 SCC7 荷瘤小鼠。当注射非还原的氰基缀合的和壳聚糖功能化的 Pluronic 基纳米载体（Cyanine-NC）时，从腹部区域以及肿瘤部位观察到强烈的荧光发射，并且在 2 天以上保持不变。相比之下，在 Hydrocyanine-NC 的情况下，腹部区域最初非常弱的荧光发射随时间的流逝而消失，而肿瘤部位的荧光发射与 Cyanine-NC 相似。因此，体内 ROS 对 Hydrocyanine-NC 的再氧化特异性地消除了探针非特异性递送的背景信号，但产生了足够强的荧光发射，可选择性地监测靶炎症部位。
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