Lin Yi, He Xiaodan, Zhou Dinglun, Li Li, Sun Jiawei, Jiang Xuehua
National Engineering Research Center for Biomaterials, Sichuan University Chengdu 610064 China
West China School of Pharmacy, Sichuan University Chengdu 610041 China.
RSC Adv. 2018 Jun 29;8(42):23768-23779. doi: 10.1039/c8ra03787f. eCollection 2018 Jun 27.
To date, the combinational cancer therapy of anticancer and antiangiogenic agents represents a promising strategy to improve antitumor outcomes in clinics. However, combination therapy with drugs having distinct properties, such as solubility, limits the likelihood of simultaneous delivery. In our study, we aimed to develop a codelivery nanoparticulate system of hydrophilic doxorubicin (DOX) and hydrophobic itraconazole (ITZ) using liposomes coated with Pluronic® P123 (ITZ/DOX-PLip). The prepared ITZ/DOX-PLip exhibited a unimodal size distribution and high loading efficiency with sustained release profiles. Furthermore, cytotoxicity against 4T1 murine breast cancer cells and cellular uptake results revealed that the inhibitory effect of ITZ/DOX-Plip on tumor growth was superior to that of free DOX or DOX-loaded liposome (DOX-Lip), which was primarily attributed to the significantly higher intercellular DOX content. Cytotoxicity against HUVEC and wound healing tests confirmed that ITZ and ITZ formulations could inhibit the growth and migration of endothelial cells. In addition, in xenograft 4T1 bearing BALB/c mice, biodistribution experiments revealed that higher drug accumulation in tumors and decreased distribution in heart were observed for ITZ/DOX-PLip as compared to free DOX. Remarkably, ITZ/DOX-PLip significantly reduced tumor volume, tumor weight, liver metastasis and microvessel density in comparison with the same dose of ITZ injection or DOX-Lip. Overall, this Pluronic® P123 modified liposome-based codelivery system represents a promising nano-platform for combination therapy in cancers.
迄今为止，抗癌药物与抗血管生成药物的联合癌症治疗是一种有望改善临床抗肿瘤效果的策略。然而，使用具有不同性质（如溶解性）的药物进行联合治疗限制了同时给药的可能性。在我们的研究中，我们旨在利用涂有普朗尼克®P123的脂质体（ITZ/DOX-PLip）开发一种亲水性阿霉素（DOX）和疏水性伊曲康唑（ITZ）的共递送纳米颗粒系统。制备的ITZ/DOX-PLip呈现单峰尺寸分布且具有高负载效率和缓释特性。此外，对4T1小鼠乳腺癌细胞的细胞毒性和细胞摄取结果表明，ITZ/DOX-Plip对肿瘤生长的抑制作用优于游离DOX或载DOX脂质体（DOX-Lip），这主要归因于细胞内DOX含量显著更高。对人脐静脉内皮细胞（HUVEC）的细胞毒性和伤口愈合试验证实，ITZ及其制剂可抑制内皮细胞的生长和迁移。此外，在荷4T1异种移植的BALB/c小鼠中，生物分布实验表明，与游离DOX相比，ITZ/DOX-PLip在肿瘤中的药物蓄积更高，在心脏中的分布减少。值得注意的是，与相同剂量的ITZ注射或DOX-Lip相比，ITZ/DOX-PLip显著降低了肿瘤体积、肿瘤重量、肝转移和微血管密度。总体而言，这种普朗尼克®P-123修饰的基于脂质体的共递送系统是一种有前景的癌症联合治疗纳米平台。
