Li Yingjia, Zhang Xia, Luo Wanxian, Wang Dongxiao, Yang Li, Wang Jianguo, Zhang Li, Zhang Shiyu, Luo Shuyi, Wang Ying
Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
Ultrasonics. 2018 Jul;87:82-90. doi: 10.1016/j.ultras.2018.02.003. Epub 2018 Feb 5.
The application of microbubble (MB)-assisted ultrasound (US) can combine the advantages of real-time imaging and targeted drug delivery. However, the drug loading capacity of MB is limited restricting its application in antitumor procedure. In contrast, nanoparticles (NPs) can carry drugs more efficiently, but adverse side effect induced by unspecific accumulation can not be ignored. Herein, we developed a dual-functionalized NP loaded MB to investigate its potential feasibility for tumor-targeted drug delivery. Firstly, we prepared NPs using heparin as backbone. Targeting ligand folate and cell-penetrating ligand Tat peptide were conjugated to the backbone to deliver paclitaxel (H-F-Tat-P NPs). Subsequently, the dual-functionalized NPs were incorporated with MBs via avidin-biotin linkage to fabricate H-F-Tat-P NPs loaded MBs (NPs-loaded MBs). The combined strategy can take profit of dual functionalities from NPs and sonoporation effect from MBs triggered by US. The prepared NPs have been characterized. The excellent cellular uptake of NPs were qualitative and quantitative analysis by flow cytometry and confocal microscope, the results indicated that it was attributed to not only dual functionalities but also US effect. Foremost, the NPs-loaded MBs combined with US exhibited significant cytotoxicity on both folate receptor (FR) overexpressing and deficiency cells. The combination of dual-functionalized NPs and MBs with US is expected to be a promising strategy for targeted anticancer drug delivery and ultrasound imaging simultaneously.
微泡（MB）辅助超声（US）的应用能够结合实时成像和靶向药物递送的优势。然而，微泡的载药量有限，这限制了其在抗肿瘤过程中的应用。相比之下，纳米颗粒（NPs）能够更高效地运载药物，但非特异性聚集所引发的不良副作用也不容忽视。在此，我们研发了一种负载微泡的双功能化纳米颗粒，以探究其用于肿瘤靶向药物递送的潜在可行性。首先，我们以肝素为骨架制备了纳米颗粒。将靶向配体叶酸和细胞穿透配体Tat肽偶联到骨架上，用于递送紫杉醇（H-F-Tat-P NPs）。随后，通过抗生物素蛋白-生物素连接将双功能化纳米颗粒与微泡结合，制备出负载微泡的H-F-Tat-P NPs（NPs负载微泡）。这种联合策略能够利用纳米颗粒的双重功能以及超声触发微泡产生的声孔效应。已对制备的纳米颗粒进行了表征。通过流式细胞术和共聚焦显微镜对纳米颗粒优异的细胞摄取进行了定性和定量分析，结果表明这不仅归因于双重功能，还归因于超声效应。最重要的是，负载微泡的纳米颗粒与超声联合使用时对叶酸受体（FR）过表达和缺乏的细胞均表现出显著的细胞毒性。双功能化纳米颗粒与微泡和超声的联合有望成为一种同时用于靶向抗癌药物递送和超声成像的有前景的策略。
