Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
Department of Pharmaceutics, College of Pharmaceutical Sciences, Fujian Medical University, Fuzhou 350122, People's Republic of China.
Int J Nanomedicine. 2020 Apr 22;15:2751-2764. doi: 10.2147/IJN.S238536. eCollection 2020.
A multifunctional redox- and pH-responsive polymeric drug delivery system is designed and investigated for targeted anticancer drug delivery to liver cancer.
The nanocarrier (His-PAMAM-ss-PEG-Tf, HP-ss-PEG-Tf) is constructed based on generation 4 polyamidoamine dendrimer (G4 PAMAM). Optimized amount of histidine (His) residues is grafted on the surface of PAMAM to obtain enhanced pH-sensitivity and proton-buffering capacity. Disulfide bonds (ss) are introduced between PAMAM and PEG to reach accelerated intracellular drug release. Transferrin (Tf) was applied to achieve active tumor targeting. Doxorubicin (DOX) is loaded in the hydrophobic cavity of the nanocarrier to exert its anti-tumor effect.
The results obtained from in vitro and in vivo evaluation indicate that HP-ss-PEG-Tf/DOX complex has pH and redox dual-sensitive properties, and exhibit higher cellular uptake and cytotoxicity than the other control groups. Flow cytometry and confocal microscopy display internalization of HP-ss-PEG-Tf/DOX via clathrin mediated endocytosis and effective endosomal escape in HepG2 cancer cells. Additionally, cyanine 7 labeled HP-ss-PEG-Tf conjugate could quickly accumulate in the HepG2 tumor. Remarkably, HP-ss-PEG-Tf/DOX present superior anticancer activity, enhanced apoptotic activity and lower heart and kidney toxicity in vivo.
Thus, HP-ss-PEG-Tf is proved to be a promising candidate for effective targeting delivery of DOX into the tumor.
设计并研究了一种多功能的氧化还原和 pH 响应型聚合物药物传递系统，用于肝癌的靶向抗癌药物传递。
基于第四代聚酰胺胺树枝状大分子（G4 PAMAM）构建纳米载体（His-PAMAM-ss-PEG-Tf，HP-ss-PEG-Tf）。在 PAMAM 表面接枝适量的组氨酸（His）残基，以获得增强的 pH 敏感性和质子缓冲能力。在 PAMAM 和 PEG 之间引入二硫键（ss）以达到加速细胞内药物释放。转铁蛋白（Tf）被应用于实现主动肿瘤靶向。阿霉素（DOX）被装载在纳米载体的疏水性腔中以发挥其抗癌作用。
体外和体内评价结果表明，HP-ss-PEG-Tf/DOX 复合物具有 pH 和氧化还原双重敏感性，并且比其他对照组具有更高的细胞摄取率和细胞毒性。流式细胞术和共聚焦显微镜显示 HP-ss-PEG-Tf/DOX 通过网格蛋白介导的内吞作用内化，并在 HepG2 癌细胞中有效进行内涵体逃逸。此外，Cy7 标记的 HP-ss-PEG-Tf 缀合物能够快速积聚在 HepG2 肿瘤中。值得注意的是，HP-ss-PEG-Tf/DOX 在体内表现出优异的抗癌活性、增强的凋亡活性和较低的心脏和肾脏毒性。
因此，HP-ss-PEG-Tf 被证明是一种有前途的候选物，可有效将 DOX 靶向递送至肿瘤。
