Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy
Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy
复制标题
DOI：
10.1016/j.ejps.2009.11.010
复制
发表时间：
2010-01-31
影响因子：
4.6
通讯作者：
Sahoo, Sanjeeb K.
中科院分区：
文献类型：
--
作者：
Misra, Ranjita;Sahoo, Sanjeeb K.
多柔比星（DOX）是一种在细胞核中具有细胞内作用位点的抗癌药物。对于高抗肿瘤活性，它应该有效地内化到癌细胞中并在细胞核中积累。在本研究中，我们制备了核定位信号缀合的阿霉素负载聚（D，L-丙交酯-共-乙交酯）纳米颗粒（NPs），以有效地将阿霉素递送到细胞核。这些纳米颗粒的物理化学表征表明，药物分子分散在球形和光滑表面的纳米颗粒。在体外条件下的NP（直径类似于226 nm，46%包封效率）表现出包封药物的持续释放（60天内释放63%）。细胞毒性结果显示，通过MTT法研究，NLS缀合的NPs在乳腺癌细胞系MCF-7中表现出比溶液中的药物（17.6 μ M/ml）和未缀合的NPs（7.9 μ M/ml）相对较低的IC 50值（2.3 μ M/ml）。通过共聚焦激光扫描显微镜（CLSM）和荧光分光光度计进行的细胞摄取研究表明，与溶液中的药物或未缀合的NP相比，NLS缀合的NP将更大量的药物靶向细胞核。流式细胞术实验结果显示，NLS缀合的NP显示出比天然DOX和未缀合的NP更大的细胞周期（G2/M期）阻断和凋亡。总之，这些结果表明，NLS缀合的阿霉素负载纳米粒可能是潜在的有用的新型药物递送系统用于乳腺癌治疗。(C)2009 Elsevier B. V.保留所有权利。
Doxorubicin (DOX) is an anticancer drug with an intracellular site of action in the nucleus. For high antitumour activity, it should be effectively internalized into the cancer cells and accumulate in the nucleus. In this study, we have prepared a nuclear localization signal conjugated doxorubicin loaded Poly (D,L-lactide-co-glycolide) nanoparticles (NPs), to deliver doxorubicin to the nucleus efficiently. Physicochemical characterization of these NPs showed that the drug is molecularly dispersed in spherical and smooth surfaced nanoparticles. NPs (similar to 226 nm in diameter, 46% encapsulation efficiency) under in vitro conditions exhibited sustained release of the encapsulated drug (63% release in 60 days). Cell cytotoxicity results showed that NLS conjugated NPs exhibited comparatively lower IC50 value (2.3 mu M/ml) than drug in solution (17.6 mu M/ml) and unconjugated NPs (7.9 mu M/ml) in breast cancer cell line MCF-7 as studied by MTT assay. Cellular uptake studies by confocal laser scanning microscopy (CLSM) and fluorescence spectrophotometer showed that greater amount of drug is targeted to the nucleus with NLS conjugated NPs as compared to drug in solution or unconjugated NPs. Flow cytometry experiments results showed that NLS conjugated NPs are showing greater cell cycle (G2/M phase) blocking and apoptosis than native DOX and unconjugated NPs. In conclusion, these results suggested that NLS conjugated doxorubicin loaded NPs could be potentially useful as novel drug delivery system for breast cancer therapy. (C) 2009 Elsevier B.V. All rights reserved.