Luo Binhua, Liang Huageng, Zhang Shengwei, Qin Xiaojuan, Liu Xuhan, Liu Wei, Zeng Fuqing, Wu Yun, Yang Xiangliang
College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People's Republic of China ; College of Pharmacy, Hubei University of Science and Technology, Xianning, People's Republic of China.
Department of Urology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Int J Nanomedicine. 2015 Sep 16;10:5805-17. doi: 10.2147/IJN.S83582. eCollection 2015.
In the study reported here, a novel amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) copolymer was synthesized by ring-opening polymerization reaction. The perfluoropentane-filled PAEEP-PLLA nanobubbles (NBs) were prepared using the O1/O2/W double-emulsion and solvent-evaporation method, with the copolymer as the shell and liquid perfluoropentane as the core of NBs. The prepared NBs were further conjugated with lactoferrin (Lf) for tumor-cell targeting. The resulting Lf-conjugated amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) nanobubbles (Lf-PAEEP-PLLA NBs) were characterized by photon correlation spectroscopy, polyacrylamide gel electrophoresis, Fourier transform infrared spectroscopy, and transmission electron microscopy. The average size of the Lf-PAEEP-PLLA NBs was 328.4±5.1 nm, with polydispersity index of 0.167±0.020, and zeta potential of -12.6±0.3 mV. Transmission electron microscopy imaging showed that the Lf-PAEEP-PLLA NBs had a near-spherical structure, were quite monodisperse, and there was a clear interface between the copolymer shell and the liquid core inside the NBs. The Lf-PAEEP-PLLA NBs also exhibited good biocompatibility in cytotoxicity and hemolysis studies and good stability during storage. The high cellular uptake of Lf-PAEEP-PLLA NBs in C6 cells (low-density lipoprotein receptor-related protein 1-positive cells) at concentrations of 0-20 µg/mL indicated that the Lf provided effective targeting for brain-tumor cells. The in vitro acoustic behavior of Lf-PAEEP-PLLA NBs was evaluated using a B-mode clinical ultrasound imaging system. In vivo ultrasound imaging was performed on tumor-bearing BALB/c nude mice, and compared with SonoVue(®) microbubbles, a commercial ultrasonic contrast agent. Both in vitro and in vivo ultrasound imaging indicated that the Lf-PAEEP-PLLA NBs possessed strong, long-lasting, and tumor-enhanced ultrasonic contrast ability. Taken together, these results indicate that Lf-PAEEP-PLLA NBs represent a promising nano-sized ultrasonic contrast agent for tumor-targeting ultrasonic imaging.
在本文报道的研究中，通过开环聚合反应合成了一种新型两亲性聚（氨基乙基乙烯磷酸酯）/聚（L-丙交酯）（PAEEP-PLLA）共聚物。以该共聚物为壳、液态全氟戊烷为核，采用O1/O2/W双乳液和溶剂蒸发法制备了填充全氟戊烷的PAEEP-PLLA纳米气泡（NBs）。将制备的NBs进一步与乳铁蛋白（Lf）偶联用于肿瘤细胞靶向。通过光子相关光谱、聚丙烯酰胺凝胶电泳、傅里叶变换红外光谱和透射电子显微镜对所得的Lf偶联两亲性聚（氨基乙基乙烯磷酸酯）/聚（L-丙交酯）纳米气泡（Lf-PAEEP-PLLA NBs）进行了表征。Lf-PAEEP-PLLA NBs的平均尺寸为328.4±5.1 nm，多分散指数为0.167±0.020，zeta电位为-12.6±0.3 mV。透射电子显微镜成像显示，Lf-PAEEP-PLLA NBs具有近球形结构，相当单分散，且在纳米气泡内部的共聚物壳与液核之间有清晰的界面。Lf-PAEEP-PLLA NBs在细胞毒性和溶血研究中还表现出良好的生物相容性，并且在储存期间具有良好的稳定性。在0 - 20 μg/mL浓度下，Lf-PAEEP-PLLA NBs在C6细胞（低密度脂蛋白受体相关蛋白1阳性细胞）中具有较高的细胞摄取率，这表明Lf为脑肿瘤细胞提供了有效的靶向作用。使用B型临床超声成像系统评估了Lf-PAEEP-PLLA NBs的体外声学行为。对荷瘤BALB/c裸鼠进行了体内超声成像，并与商用超声造影剂声诺维（®）微泡进行了比较。体外和体内超声成像均表明，Lf-PAEEP-PLLA NBs具有强的、持久的和肿瘤增强的超声造影能力。综上所述，这些结果表明Lf-PAEEP-PLLA NBs是一种有前景的用于肿瘤靶向超声成像的纳米级超声造影剂。
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