Zhao Xiaojing, Chen Qi, Liu Wei, Li Yusang, Tang Hebin, Liu Xuhan, Yang Xiangliang
College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People's Republic of China ; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Department of Pharmacology, College of Pharmacy, South-Central University for Nationalities, Wuhan, People's Republic of China.
Int J Nanomedicine. 2014 Dec 30;10:257-70. doi: 10.2147/IJN.S73322. eCollection 2015.
Liver cancer is a leading cause of cancer deaths worldwide. The combination therapy of cytotoxic and chemosensitizing agents loaded in nanoparticles has been highlighted as an effective treatment for different cancers. However, such studies in liver cancer remain very limited. In our study, we aim to develop a novel lipid nanoparticles loaded with doxorubicin (DOX) (an effective drug for liver cancer) and curcumin (Cur) (a chemosensitizer) simultaneously, and we examined the efficacy of chemotherapy in liver cancer. DOX and Cur codelivery lipid nanoparticles (DOX/Cur-NPs) were successfully prepared using a high-pressure microfluidics technique, showing a mean particle size of around 90 nm, a polydispersity index <0.3, and a zeta potential <-10 mV. The encapsulation efficacy was >90% for both DOX and Cur. The blank lipid nanoparticles were nontoxic, as determined by a cell cytotoxicity study in human normal liver cells L02 and liver cancer cells HepG2. In vitro DOX release studies revealed a sustained-release pattern until 48 hours in DOX/Cur-NPs. We found enhanced cytotoxicity and decreased inhibitory concentration (IC)50 in HepG2 cells and reduced cytotoxicity in L02 cells treated with DOX/Cur-NPs, suggesting the synergistic effects of DOX/Cur-NPs compared with free DOX and DOX nanoparticles (NPs). The optimal weight ratio of DOX and Cur was 1:1. Annexin-V-fluorescein isothiocyanate/propidium iodide double staining showed enhanced apoptosis in HepG2 cells treated with DOX/Cur-NPs compared with free DOX and DOX-NPs. An in vivo experiment showed the synergistic effect of DOX/Cur-NPs compared with DOX-NPs on liver tumor growth inhibition. Taken together, the simultaneous delivery of DOX and Cur by DOX/Cur-NPs might be a promising treatment for liver cancer.
肝癌是全球癌症死亡的主要原因之一。负载细胞毒性和化学增敏剂的纳米颗粒联合疗法已被视为治疗不同癌症的有效方法。然而，此类针对肝癌的研究仍然非常有限。在我们的研究中，我们旨在开发一种同时负载阿霉素（DOX，一种治疗肝癌的有效药物）和姜黄素（Cur，一种化学增敏剂）的新型脂质纳米颗粒，并研究其对肝癌的化疗效果。利用高压微流控技术成功制备了DOX和Cur共递送脂质纳米颗粒（DOX/Cur-NPs），其平均粒径约为90 nm，多分散指数<0.3，zeta电位<-10 mV。DOX和Cur的包封率均>90%。通过对人正常肝细胞L02和肝癌细胞HepG2进行细胞毒性研究，确定空白脂质纳米颗粒无毒。体外DOX释放研究表明，DOX/Cur-NPs中的DOX呈持续释放模式，直至48小时。我们发现，DOX/Cur-NPs处理的HepG2细胞的细胞毒性增强，抑制浓度（IC）50降低，而L02细胞的细胞毒性降低，这表明与游离DOX和DOX纳米颗粒（NPs）相比，DOX/Cur-NPs具有协同作用。DOX和Cur的最佳重量比为1:1。膜联蛋白V-异硫氰酸荧光素/碘化丙啶双染显示，与游离DOX和DOX-NPs相比，DOX/Cur-NPs处理的HepG2细胞凋亡增加。体内实验表明，与DOX-NPs相比，DOX/Cur-NPs对肝肿瘤生长具有协同抑制作用。综上所述，DOX/Cur-NPs同时递送DOX和Cur可能是一种有前景的肝癌治疗方法。
