Shavi Gopal Venkatesh, Sreenivasa Reddy Meka, Raghavendra Ramesh, Nayak Usha Yogendra, Kumar Averineni Ranjith, Deshpande Praful Balavant, Udupa Nayanabhirama, Behl Gautam, Dave Vivek, Kushwaha Kriti
a South Eastern Applied Material Research Centre (SEAM) , WIT , Waterford , Ireland .
b Department of Pharmaceutics , Manipal College of Pharmaceutical Sciences, Manipal University , Manipal , Karnataka , India .
J Liposome Res. 2016;26(1):28-46. doi: 10.3109/08982104.2015.1029493. Epub 2015 Apr 8.
The aim of present study was to develop conventional and PEGylated (long circulating), liposomes containing anastrozole (ANS) for effective treatment of breast cancer. ANS is a third-generation non-steroidal aromatase inhibitor of the triazole class used for the treatment of advanced and late-stage breast cancer in post-menopausal women. Under such disease conditions the median duration of therapy should be prolonged until tumor regression ends (>31 months). Liposomes were prepared by the thin film hydration method by using ANS and various lipids such as soyaphosphatidyl choline, cholesterol and methoxy polyethylene glycol distearoyl ethanolamine in different concentration ratios and evaluated for physical characteristics, in vitro drug release and stability. Optimized formulations of liposome were studied for in vitro cytotoxic activity against the BT-549 and MCF-7 cell lines and in vivo behavior in Wistar rats. Preformulation studies, both Fourier transform infrared study and differential scanning calorimetry analysis showed no interaction between the drug and the excipients used in the formulations. The optimized formulations AL-07 and AL-09 liposomes showed encapsulation efficiencies in the range 65.12 ± 1.05% to 69.85 ± 3.2% with desired mean particle size distribution of 101.1 ± 5.9 and 120.2 ± 2.8 nm and zeta potentials of -43.7 ± 4.7 and -62.9 ± 3.5 mV. All the optimized formulations followed Higuchi-matrix release kinetics and when plotted in accordance with the Korsemeyer-Peppas method, the n-value 0.5 < n < 1.0 suggests an anomalous (non-Fickian) transport. Likewise, the PEGylated liposomes showed greater tumor growth inhibition on BT-549 and MCF-7 cell lines from in vitro cytotoxicity studies (p < 0.05). Pharmacokinetic study of conventional and PEGylated liposomes in Wistar rats demonstrated a 3.33- and 20.28-fold increase in AUC(0-∞) values when compared to pure drug (p < 0.001). Among the formulations, PEGylated liposomes showed encouraging results by way of their long circulation and sustained delivery properties for effective treatment of breast cancer.
本研究的目的是开发常规脂质体和聚乙二醇化（长循环）脂质体，其包裹阿那曲唑（ANS）用于有效治疗乳腺癌。ANS是一种用于治疗绝经后妇女晚期和晚期乳腺癌的第三代三唑类非甾体芳香酶抑制剂。在这种疾病情况下，治疗的中位持续时间应延长至肿瘤消退结束（>31个月）。通过薄膜水化法，使用ANS和各种脂质（如大豆磷脂酰胆碱、胆固醇和不同浓度比例的甲氧基聚乙二醇二硬脂酰乙醇胺）制备脂质体，并对其物理特性、体外药物释放和稳定性进行评估。研究了脂质体的优化配方对BT-549和MCF-7细胞系的体外细胞毒性活性以及在Wistar大鼠体内的行为。处方前研究，傅里叶变换红外光谱研究和差示扫描量热分析均表明药物与制剂中使用的辅料之间无相互作用。优化后的AL-07和AL-09脂质体配方的包封率在65.12±1.05%至69.85±3.2%范围内，平均粒径分布理想，分别为101.1±5.9和120.2±2.8nm，ζ电位分别为-43.7±4.7和-62.9±3.5mV。所有优化配方均遵循Higuchi矩阵释放动力学，按照Korsemeyer-Peppas方法绘制时，n值为（0.5 < n < 1.0）表明为非菲克（异常）转运。同样，聚乙二醇化脂质体在体外细胞毒性研究中对BT-549和MCF-7细胞系显示出更大的肿瘤生长抑制作用（p < 0.05）。对Wistar大鼠体内常规脂质体和聚乙二醇化脂质体的药代动力学研究表明，与纯药物相比，AUC(0-∞)值分别增加了3.33倍和20.28倍（p < 0.001）。在这些制剂中，聚乙二醇化脂质体因其长循环和持续递送特性，在有效治疗乳腺癌方面显示出令人鼓舞的结果。
