Song Shuangshuang, Chen Fen, Qi Huan, Li Fei, Xin Tiegang, Xu Jingwen, Ye Tiantian, Sheng Naicheng, Yang Xinggang, Pan Weisan
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, PO Box No. 122, 103 Wenhua Rd., Shenyang, 110016, People's Republic of China.
Pharm Res. 2014 Apr;31(4):1032-45. doi: 10.1007/s11095-013-1225-y. Epub 2013 Oct 24.
The objective of this work was to develop a multifunctional tumor-targeting nanocarrier based on the mechanism of CD44-mediated endocytosis and pH-induced drug release to improve the therapeutic efficacy of docetaxel (DTX).
Hyaluronic acid-coated docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) were prepared. The physiochemical properties and pH-dependent drug release of HA-CHEMS vesicles were evaluated. The HA-CHEMS vesicles were investigated for CD44-mediated internalization and in vitro cell viability using MCF-7,A549 and L929 cells.In addition,tissue distribution as well as antitumor efficacy was also evaluated in MCF-7 tumor-bearing mouse model.
The particle size and zeta potential of HA-CHEMS vesicles were 131.4 ± 6.2 nm and -13.3 ± 0.04 mV,respectively. The in vitro drug release results demonstrated a pH-responsive drug release under different pH conditions. In vitro cell viability tests suggested that the encapsulation of DTX in HA-CHEMS vesicles led to more than 51.6-fold and 46.3-fold improved growth inhibition in MCF-7 and A549 cell lines,respectively compared to Taxotere®. From the cell uptake studies,the coumarin 6-loaded HA-CHEMS vesicles enhanced intracellular fluorescent intensity in the CD44-overexpressing cell line (MCF-7). Biodistribution studies revealed selective accumulation of HA-CHEMS vesicles in the MCF-7 bearing BalB/c nude mice as a result of passive accumulation and active targeting (CD44-mediated endocytosis). Compared to Taxotere®,HA-CHEMS vesicles exhibited higher antitumor activity by reducing tumor volume (P < 0.05) and drug toxicity,demonstrating the success of the multifunctional targeting delivery.
This work corresponds to the preparation of a multifunctional tumor-targeted delivery system. Our investigation shows that hyaluronan-bearing docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) is a highly promising therapeutic system,leading to tumor regression after intravenous administration without visible toxicity.
本研究旨在基于CD44介导的内吞作用机制和pH诱导的药物释放，开发一种多功能肿瘤靶向纳米载体，以提高多西他赛（DTX）的治疗效果。
制备了透明质酸包被的载多西他赛胆固醇半琥珀酸酯囊泡（HA-CHEMS囊泡）。评估了HA-CHEMS囊泡的理化性质和pH依赖性药物释放。使用MCF-7、A549和L929细胞研究了HA-CHEMS囊泡的CD44介导的内化作用和体外细胞活力。此外，还在MCF-7荷瘤小鼠模型中评估了组织分布和抗肿瘤疗效。
HA-CHEMS囊泡的粒径和zeta电位分别为131.4±6.2nm和-13.3±0.04mV。体外药物释放结果表明，在不同pH条件下具有pH响应性药物释放。体外细胞活力测试表明，与泰索帝®相比，将DTX包裹在HA-CHEMS囊泡中分别使MCF-7和A549细胞系的生长抑制提高了51.6倍和46.3倍以上。从细胞摄取研究来看，载香豆素6的HA-CHEMS囊泡增强了CD44过表达细胞系（MCF-7）中的细胞内荧光强度。生物分布研究表明，由于被动积累和主动靶向（CD44介导内吞作用），HA-CHEMS囊泡在荷MCF-7的BalB/c裸鼠中选择性积累。与泰索帝®相比，HA-CHEMS囊泡通过减小肿瘤体积（P<0.05）和降低药物毒性表现出更高的抗肿瘤活性，证明了多功能靶向递送的成功。
本研究成功制备了一种多功能肿瘤靶向递送系统。我们的研究表明，载多西他赛的透明质酸胆固醇半琥珀酸酯囊泡（HA-CHEMS囊泡）是一种极具前景的治疗系统，静脉给药后可使肿瘤消退且无明显毒性。
