Laboratory of Nanomedicine, Institute of Life Sciences, Bhubaneswar, Orissa, India.
PLoS One. 2011;6(11):e26803. doi: 10.1371/journal.pone.0026803. Epub 2011 Nov 16.
Amongst all leukemias, Bcr-Abl positive chronic myelogenous leukemia (CML) confers resistance to native drug due to multi drug resistance and also resistance to p53 and fas ligand pathways. In the present study, we have investigated the efficacy of microtubule stabilizing paclitaxel loaded magnetic nanoparticles (pac-MNPs) to ascertain its cytotoxic effect on Bcr-Abl positive K562 cells. For active targeted therapy, pac-MNPs were functionalized with lectin glycoprotein which resulted in higher cellular uptake and lower IC(50) value suggesting the efficacy of targeted delivery of paclitaxel. Both pac-MNPs and lectin conjugated pac-MNPs have a prolonged circulation time in serum suggesting increased bioavailability and therapeutics index of paclitaxel in vivo. Further, the molecular mechanism pertaining to pac-induced cytotoxicity was analyzed by studying the involvement of different apoptotic pathway proteins by immunoblotting and quantitative PCR. Our study revealed simultaneous activation of JNK pathway leading to Bcr-Abl instability and the extrinsic apoptotic pathway after pac-MNPs treatment in two Bcr-Abl positive cell lines. In addition, the MRI data suggested the potential application of MNPs as imaging agent. Thus our in vitro and in vivo results strongly suggested the pac-MNPs as a future prospective theranostic tool for leukemia therapy.
在所有白血病中，Bcr-Abl 阳性慢性髓系白血病（CML）由于多药耐药性以及对 p53 和 fas 配体途径的耐药性，导致对天然药物产生耐药性。在本研究中，我们研究了载紫杉醇的磁性纳米颗粒（pac-MNPs）的疗效，以确定其对 Bcr-Abl 阳性 K562 细胞的细胞毒性作用。为了进行主动靶向治疗，将 pac-MNPs 与凝集素糖蛋白功能化，导致细胞摄取增加和 IC50 值降低，表明紫杉醇靶向递送的效果。pac-MNPs 和凝集素偶联的 pac-MNPs 在血清中的循环时间延长，提示紫杉醇的体内生物利用度和治疗指数增加。此外，通过免疫印迹和定量 PCR 研究不同凋亡途径蛋白的参与，分析了 pac 诱导细胞毒性的分子机制。我们的研究揭示了在两种 Bcr-Abl 阳性细胞系中，pac-MNPs 处理后 JNK 途径的同时激活导致 Bcr-Abl 不稳定和外源性凋亡途径。此外，MRI 数据表明 MNPs 作为成像剂的潜在应用。因此，我们的体内外结果强烈表明 pac-MNPs 是白血病治疗的一种有前途的治疗工具。
