P-Glycoprotein Antibody Functionalized Carbon Nanotube Overcomes the Multidrug Resistance of Human Leukemia Cells
P-Glycoprotein Antibody Functionalized Carbon Nanotube Overcomes the Multidrug Resistance of Human Leukemia Cells
复制标题
P-糖蛋白抗体功能化碳纳米管克服人类白血病细胞的多药耐药性
DOI：
10.1021/nn9011225
复制
发表时间：
2010-03-01
期刊：
影响因子：
17.1
通讯作者：
Zou, Hanfa
中科院分区：
文献类型：
--
作者：
Li, Ruibin;Wu, Ren'an;Zou, Hanfa
肿瘤多药耐药（Multidrug resistance，MDR）与肿瘤化疗、肿瘤干细胞、肿瘤转移有关，是肿瘤有效治疗的巨大障碍。多药耐药细胞P-糖蛋白（P-gp）的过度表达增加了抗癌药物的外排，是多药耐药的潜在机制之一。本工作合成了负载阿霉素（Dox）的P-gp（抗P-gp）功能化水溶性单壁碳纳米管（Ap-SWNTs）抗体Dox/Ap-SWNTs，用于挑战K562人白血病细胞的MDR。所制备的Ap-SWNTs不仅能够特异性识别多药耐药的人白血病细胞（K562 R），而且在近红外辐射（NIR）照射下，对靶细胞K562 R具有有效的载药量和可控的释放性能。流式细胞仪（FCM）和激光共聚焦显微镜（CLSM）检测Ap-SWNTs对K562 R细胞的识别能力。Ap-SWNTs与耐药K562 R细胞的结合亲和力约为1.5 × 10 - 6。23-比对药物敏感的K562 S细胞高4倍。CLSM结果表明，Ap-SWNTs能特异性定位于K562 R细胞膜上，并能显著增强K562 R细胞内Dox的荧光强度。Dox/Ap-SWNTs复合物对K562 R白血病细胞的细胞毒活性是目前临床上常用的游离Dox的2.4倍，对K562 R白血病细胞的增殖有明显的抑制作用（p < 0.05）。这些结果表明，Ap-SWNTs是一种很有前途的药物载体，用于克服由细胞膜上P-gp过表达诱导的MDR。载药单壁碳纳米管可用于抑制多药耐药细胞的增殖，破坏肿瘤干细胞，抑制肿瘤的转移。
Multidrug resistance (MDR), which is related to cancer chemotherapy, tumor stem cells, and tumor metastasis, is a huge obstacle for the effective cancer therapy. One of the underlying mechanisms of MDR is the increased efflux of anticancer drugs by overexpressed P-glycoprotein (P-gp) of multidrug resistant cells. In this work, the antibody of P-gp (anti-P-gp) functionalized water-soluble single-walled carbon nanotubes (Ap-SWNTs) loaded with doxorubicin (Dox), Dox/Ap-SWNTs, were synthesized for challenging the MDR of K562 human leukemia cells. The resulting Ap-SWNTs could not only specifically recognize the multidrug resistant human leukemia cells (K562R), but also demonstrate the effective loading and controllable release performance for Dox toward the target K562R cells by exposing to near-infrared radiation (NIR). The recognition capability of Ap-SWNTs toward the K562R cells was confirmed by flow cytometry (FCM) and confocal laser scanning microscopy (CLSM). The binding affinity of Ap-SWNTs toward drug-resistant K562R cells was ca. 23-fold higher than that toward drug-sensitive K562S cells. Additionally, CLSM indicated that Ap-SWNTs could specifically localize on the cell membrane of K562R cells and the fluorescence of Dox in K562R cells could be significantly enhanced after the employment of Ap-SWNTs as carrier. Moreover, the composite of Dox and Ap-SWNTs (Dox/Ap-SWNTs) expressed 2.4-fold higher cytotoxicity and showed the significant cell proliferation suppression toward K562R leukemia cells (p < 0.05) as compared with free Dox which is popularly employed in clinic trials. These results suggest that the Ap-SWNTs are the promising drug delivery vehicle for overcoming the MDR induced by the overexpression of P-gp on cell membrane. Ap-SWNTs loaded with drug molecules could be used to suppress the proliferation of multidrug resistant cells, destroy the tumor stem cells, and inhibit the metastasis of tumor.