Hyaluronan-Based Nanocarriers with CD44-Overexpressed Cancer Cell Targeting
Hyaluronan-Based Nanocarriers with CD44-Overexpressed Cancer Cell Targeting
复制标题
基于透明质酸的纳米载体与 CD44 过表达的癌细胞靶向
DOI：
10.1007/s11095-014-1393-4
复制
发表时间：
2014-11-01
影响因子：
3.7
通讯作者：
Pan, Weisan
中科院分区：
文献类型：
--
作者：
Song, Shuangshuang;Qi, Huan;Pan, Weisan
目的评价透明质酸纳米粒作为肿瘤靶向纳米系统用于CD44过表达肿瘤治疗的可能性。方法在水环境中将合成的两亲胆固醇琥珀酰透明质酸(Chol-Suc-HA)结合物自组装成多西紫杉醇(DTX)纳米粒。对Chol-Suc-HA-DTX纳米粒子的物化性能进行了表征。用四甲基偶氮唑蓝比色法和乳酸脱氢酶比色法检测Chol-Suc-HA-DTX纳米粒对MCF-7、4T1、A549和L929细胞的体外杀伤作用。此外，利用激光共聚焦显微镜和流式细胞仪对细胞摄取机制进行了研究。在SD大鼠和4T1荷瘤BALB/c小鼠体内进行了CHOL-Suc-HA-DTX纳米粒的体内动物实验，包括药代动力学评价、EX vivoNIRF成像观察的生物分布和抗肿瘤效果。结果不同疏水取代度(DS)的Chol-Suc-HA-DTX纳米粒具有高载药量、均匀的粒径分布和良好的体外稳定性。然而，疏水基团的取代度对Chol-Suc-HA-DTX纳米粒的血浆稳定性有显著影响。取代度越高，NPs越稳定。细胞摄取实验表明，Chol-Suc-HA-DTX纳米粒通过CD44受体介导的内吞作用进入癌细胞。与Taxotere®相比，Chol-Suc-HA-DTX纳米粒对CD44阳性的癌细胞(MCF-7、4T1、A549细胞)具有明显更高的细胞毒性。活体动物实验证实，具有较高取代度的Chol-Suc-HA-DTX纳米粒具有较长的循环时间、良好的肿瘤靶向性和高效的抗肿瘤作用，且全身毒性极低。结论具有合适取代度的Chol-Suc-HA纳米粒有望成为系统靶向治疗CD44过表达肿瘤的药物载体。
PurposeThe objective of the work was to evaluate the potential of hyaluronan-based nanoparticles as tumor-targeting nano-systems for CD44-overexpressed cancer therapy.MethodsThe synthesized amphiphilic cholesteryl succinoyl hyaluronan (Chol-Suc-HA) conjugates self-assembled into docetaxel(DTX)-loaded nanoparticles in the aqueous environment. The physiochemical properties of Chol-Suc-HA-DTX NPs were characterized. Thein vitrocytotoxicity of Chol-Suc-HA-DTX NPs against MCF-7, 4T1, A549 and L929 cells was evaluated using MTT and LDH assays. Moreover, the cellular uptake mechanism was investigated using the CLSM and flow cytometry. Thein vivoanimal experiments of Chol-Suc-HA-DTX NPs including pharmacokinetic evaluation, bio-distribution observed byEX vivoNIRF imaging and antitumor efficacy were also carried out in SD rats or 4T1 tumor-bearing BALB/c mice.ResultsThe self-assembled Chol-Suc-HA-DTX NPs with different degree of substitution (DS) of hydrophobic moiety exhibited high drug loading, uniform particle size distribution and excellentin vitrostability. However, the plasma stability of Chol-Suc-HA-DTX NPs was significantly influenced by the DS of hydrophobic moiety. The higher the DS was, the more stable the NPs were. Cellular uptake demonstrated that Chol-Suc-HA-DTX NPs were internalized into cancer cells via CD44 receptor-mediated endocytosis. Compared with Taxotere®, Chol-Suc-HA-DTX NPs displayed remarkably higher cytotoxicity to CD44-positive cancer cells (MCF-7, 4T1, A549 cells).In vivoanimal experiments confirmed that Chol-Suc-HA-DTX NPs with relatively high DS values exhibited prolonged circulation time, excellent tumor-targeting properties and efficient antitumor effects with extremely low systemic toxicity. In addition, blank Chol-Suc-HA NPs also slightly suppressed the tumor growth.ConclusionsChol-Suc-HA NPs with a suitable DS value portend to be promising drug vehicles for systemic targeting of CD44-overexpressed cancers.