Han Lingfei, Hu Lejian, Liu Fulei, Wang Xin, Huang Xiaoxian, Liu Bowen, Feng Feng, Liu Wenyuan, Qu Wei
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Asian J Pharm Sci. 2019 Sep;14(5):531-542. doi: 10.1016/j.ajps.2018.08.009. Epub 2018 Sep 24.
The application of paclitaxel (PTX) in clinic has been restricted due to its poor solubility. Several traditional nano-medicines have been developed to improve this defect, while they are still lack of tumor targeting ability and rapid drug release. In this work, an amphiphilic polymeric micelle of hyaluronic acid (HA) - all-trans-retinoid acid (ATRA) with a disulfide bond, was developed successfully for the co-delivery of PTX and ATRA. The combination chemotherapy of PTX and ATRA can strengthen the anti-tumor activity. Along with self-assembling to micelles in water, the delivery system displayed satisfying drug loading capacities for both PTX (32.62% ± 1.39%) and ATRA, due to directly using ATRA as the hydrophobic group. Rapid drug release properties of the PTX-loaded redox-sensitive micelles (HA-SS-ATRA) were confirmed under reducing condition containing GSH. Besides, HA-CD44 mediated endocytosis promoted the uptake of HA-SS-ATRA micelles by B16F10 cells. Due to these properties, cytotoxicity assay verified that PTX-loaded HA-SS-ATRA micelles showed concentration-dependent cytotoxicity and displayed obvious combination therapy of PTX and ATRA. Importantly, HA-SS-ATRA micelles could remarkably prolong plasma circulation time after intravenously administration. Therefore, redox-sensitive HA-SS-ATRA micelles could be utilized and explored as a promising drug delivery system for cancer combination chemotherapy.
由于紫杉醇（PTX）溶解度差，其在临床上的应用受到限制。已经开发了几种传统的纳米药物来改善这一缺陷，但它们仍然缺乏肿瘤靶向能力和快速药物释放性能。在这项工作中，成功开发了一种具有二硫键的透明质酸（HA）-全反式维甲酸（ATRA）两亲性聚合物胶束，用于PTX和ATRA的共递送。PTX和ATRA的联合化疗可以增强抗肿瘤活性。该递送系统在水中自组装形成胶束，由于直接使用ATRA作为疏水基团，其对PTX（32.62%±1.39%）和ATRA均显示出令人满意的载药能力。在含有谷胱甘肽（GSH）的还原条件下，证实了载PTX的氧化还原敏感胶束（HA-SS-ATRA）具有快速药物释放特性。此外，HA-CD44介导的内吞作用促进了B16F10细胞对HA-SS-ATRA胶束的摄取。由于这些特性，细胞毒性试验证实载PTX的HA-SS-ATRA胶束表现出浓度依赖性细胞毒性，并显示出PTX和ATRA明显的联合治疗效果。重要的是，HA-SS-ATRA胶束静脉给药后可显著延长血浆循环时间。因此，氧化还原敏感的HA-SS-ATRA胶束可作为一种有前景的癌症联合化疗药物递送系统加以利用和探索。
