Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar (Mohali), Punjab 160062, India.
Mol Pharm. 2011 Aug 1;8(4):1140-51. doi: 10.1021/mp200011f. Epub 2011 May 25.
The present investigation reports an extensive evaluation of in vitro and in vivo anticancer efficacy of orally administered doxorubicin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Dox-NPs) in a breast cancer induced animal model. Spherically shaped Dox-NPs were prepared with an entrapment efficiency and particle size of 55.40 ± 2.30% and 160.20 ± 0.99 nm, respectively, and freeze-dried with 5% trehalose using stepwise freeze-drying. Cytotoxicity, as investigated on C127I cell line, revealed insignificant differences between the IC(50) of free Dox and Dox-NPs treated cells in the first 24 h, while higher cytotoxicity was demonstrated by Dox-NPs, following 72 h of incubation. Confocal laser scanning microscopy (CLSM) imaging corroborated that nanoparticles were efficiently localized into the nuclear region of C127I cells. The cellular uptake profile of Dox-NPs revealed both time and concentration dependent increases in the Caco-2 cell uptake as compared to the free Dox solution. Further, Dox-NPs significantly suppressed the growth of breast tumor in female Sprague-Dawley (SD) rats upon oral administration. Finally, orally administered Dox-NPs showed a marked reduction in cardiotoxicity when compared with intravenously injected free Dox as also evident by the increased level of malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine phosphokinase (CK-MB) and reduced levels of glutathione (GSH) and superoxide dismutase (SOD). The reduced cardiotoxicity of orally administered Dox-NPs was also confirmed by the major histopathological changes in the heart tissue after the treatments of intravenously injected free Dox and orally delivered Dox-NPs.
本研究报告了一种广泛的评价，即在乳腺癌诱导的动物模型中，口服多柔比星负载的聚（乳酸-共-乙醇酸）（PLGA）纳米粒（Dox-NPs）的体外和体内抗癌疗效。球形的 Dox-NPs 的包封效率和粒径分别为 55.40 ± 2.30%和 160.20 ± 0.99nm，并使用分步冷冻干燥法用 5%海藻糖冷冻干燥。在 C127I 细胞系上进行的细胞毒性研究表明，游离多柔比星和 Dox-NPs 处理细胞的 IC（50）在前 24 小时内没有显著差异，而在孵育 72 小时后，Dox-NPs 表现出更高的细胞毒性。共焦激光扫描显微镜（CLSM）成像证实，纳米粒有效地定位于 C127I 细胞的核区域。Dox-NPs 的细胞摄取谱表明，与游离多柔比星溶液相比，Caco-2 细胞摄取的时间和浓度依赖性均增加。此外，口服 Dox-NPs 可显著抑制雌性 Sprague-Dawley（SD）大鼠的乳腺癌生长。最后，与静脉注射游离多柔比星相比，口服 Dox-NPs 可显著降低心脏毒性，这也可以通过丙二醛（MDA）、乳酸脱氢酶（LDH）和肌酸磷酸激酶（CK-MB）水平的升高和谷胱甘肽（GSH）和超氧化物歧化酶（SOD）水平的降低来证明。口服 Dox-NPs 的心脏毒性降低也通过静脉注射游离多柔比星和口服递送 Dox-NPs 治疗后的心脏组织的主要组织病理学变化得到证实。
