目的:负载他莫昔芬(Tam)的脂质体表面修饰对药物细胞毒性和生物分布的影响,通过壳聚糖和/或聚乙二醇化官能化,被调查。
方法:负载Tam的混合纳米载体(负载Tam的niosomes,壳聚糖,聚乙二醇化的脂质体,和聚乙二醇化的壳聚糖)进行配制和表征。
结果:有/没有聚乙二醇化的壳聚糖化被证明可以选择性地增强在癌性酸性微环境中的Tam释放。细胞毒性活性研究表明,Tam负载的聚乙二醇化壳聚糖对MCF-7细胞系的IC50值(0.39、0.35和0.27倍)低于Tam负载的聚乙二醇化壳聚糖,装满Tam的niosomes,和载有Tam的壳聚糖体,分别。细胞周期分析表明,聚乙二醇化和/或壳聚糖化显着影响Tam诱导凋亡的效率,聚乙二醇化优先于壳聚糖化。Annexin-V/PI双重染色的分析表明,壳聚糖化纳米载体在增加细胞凋亡而不是坏死的发生率方面具有重要作用。此外,聚乙二醇化纳米载体增加细胞凋亡,以及总死亡和坏死百分比高于自由Tam显示的百分比。此外,Bax/Bcl-2比值和Caspase9的平均变化在Tam负载的PEG化脂质体处理的细胞中比在所有其他制剂中得到最好的改善.涉及DMBA诱导的乳腺癌大鼠的体内研究表明,聚乙二醇化具有最高的肿瘤生长抑制作用(84.9%)和乳腺肿瘤选择性,而壳聚糖在血液(62.3ng/ml)和肝组织(103.67ng/ml)中的积累趋势较低。来自用Tam负载的PEG化的脂质体处理的组的组织病理学样本显示出优于其他制剂的最佳改善。
结论:所有这些结果都总结了Tam-loadedniosome的聚乙二醇化和壳聚糖功能化在增强有效性方面的关键作用,可瞄准性,和安全。
OBJECTIVE: The effect of surface-modification of Tamoxifen (Tam)-loaded-niosomes on drug cytotoxicity and bio-distribution, via functionalization with chitosan and/or PEGylation, was investigated.
METHODS: Tam-loaded hybrid-nanocarriers (Tam-loaded niosomes, chitosomes, PEGylated niosomes, and PEGylated chitosomes) were formulated and characterized.
RESULTS: Chitosanization with/without PEGylation proved to selectively enhance Tam-release at the cancerous-acidic micromilieu. Cytotoxic activity study showed that Tam-loaded PEGylated niosomes had a lower IC50 value on MCF-7 cell line (0.39, 0.35, and 0.27 times) than Tam-loaded PEGylated chitosomes, Tam-loaded niosomes, and Tam-loaded chitosomes, respectively. Cell cycle analysis showed that PEGylation and/or Chitosanization significantly impact Tam efficiency in inducing apoptosis, with a preferential influence of PEGylation over chitosanization. The assay of Annexin-V/PI double staining revealed that chitosanized-nanocarriers had a significant role in increasing the incidence of apoptosis over necrosis. Besides, PEGylated-nanocarriers increased apoptosis, as well as total death and necrosis percentages more than what was shown from free Tam. Moreover, the average changes in both Bax/Bcl-2 ratio and Caspase 9 were best improved in cells treated by Tam-loaded PEGylated niosomes over all other formulations. The in-vivo study involving DMBA-induced-breast cancer rats revealed that PEGylation made the highest tumor-growth inhibition (84.9 %) and breast tumor selectivity, while chitosanization had a lower accumulation tendency in the blood (62.3 ng/ml) and liver tissues (103.67 ng/ml). The histopathological specimens from the group treated with Tam-loaded PEGylated niosomes showed the best improvement over other formulations.
CONCLUSIONS: All these results concluded the crucial effect of both PEGylation and chitosan-functionalization of Tam-loaded niosomes in enhancing effectiveness, targetability, and safety.