Ramasamy Thiruganesh, Sundaramoorthy Pasupathi, Ruttala Hima Bindu, Choi Yongjoo, Shin Woo Hyun, Jeong Jee-Heon, Ku Sae Kwang, Choi Han-Gon, Kim Hwan Mook, Yong Chul Soon, Kim Jong Oh
a College of Pharmacy , Yeungnam University , Gyeongsan , Republic of Korea.
b Department of Medicine , Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh , Pittsburgh , PA , USA.
Drug Deliv. 2017 Nov;24(1):1262-1272. doi: 10.1080/10717544.2017.1373163.
Since breast cancer is one of the most lethal malignancies, targeted strategies are urgently needed. In this study, we report the enhanced therapeutic efficacy of docetaxel (DTX) when combined with polyunsaturated fatty acids (PUFA) for effective treatment of multi-resistant breast cancers. Folic acid (FA)-conjugated PUFA-based lipid nanoparticles (FA-PLN/DTX) was developed. The physicochemical properties, in vitro uptake, in vitro cytotoxicity, and in vivo anticancer activity of FA-PLN/DTX were evaluated. FA-PLN/DTX could efficiently target and treat human breast tumor xenografts in vivo. They showed high payload carrying capacity with controlled release characteristics and selective endocytic uptake in folate receptor-overexpressing MCF-7 and MDA-MB-231 cells. PUFA synergistically improved the anticancer efficacy of DTX in both tested cancer cell lines by inducing a G2/M phase arrest and cell apoptosis. Combination of PUFA and DTX remarkably downregulated the expression levels of pro-apoptotic and anti-apoptotic markers, and blocked the phosphorylation of AKT signaling pathways. Compared to DTX alone, FA-PLN/DTX showed superior antitumor efficacy, with no signs of toxic effects in cancer xenograft animal models. We propose that PUFA could improve the therapeutic efficacy of anticancer agents in cancer therapy. Further studies are necessary to fully understand these findings and achieve clinical translation.
由于乳腺癌是最致命的恶性肿瘤之一，因此迫切需要靶向治疗策略。在本研究中，我们报告了多西他赛（DTX）与多不饱和脂肪酸（PUFA）联合使用时，对多耐药乳腺癌的治疗效果增强。我们制备了叶酸（FA）偶联的基于PUFA的脂质纳米粒（FA-PLN/DTX）。评估了FA-PLN/DTX的理化性质、体外摄取、体外细胞毒性和体内抗癌活性。FA-PLN/DTX能够在体内有效地靶向治疗人乳腺肿瘤异种移植瘤。它们在叶酸受体过表达的MCF-7和MDA-MB-231细胞中表现出高载药量、控释特性和选择性内吞摄取。PUFA通过诱导G2/M期阻滞和细胞凋亡，协同提高了DTX在两种受试癌细胞系中的抗癌效果。PUFA与DTX的联合使用显著下调了促凋亡和抗凋亡标志物的表达水平，并阻断了AKT信号通路的磷酸化。与单独使用DTX相比，FA-PLN/DTX在癌症异种移植动物模型中显示出更好的抗肿瘤效果，且没有毒性作用的迹象。我们认为PUFA可以提高抗癌药物在癌症治疗中的疗效。需要进一步研究以充分理解这些发现并实现临床转化。
