Sustained release of PI3K inhibitor from PHA nanoparticles and in vitro growth inhibition of cancer cell lines
Sustained release of PI3K inhibitor from PHA nanoparticles and in vitro growth inhibition of cancer cell lines
复制标题
PHA纳米颗粒持续释放PI3K抑制剂并抑制癌细胞系的体外生长
DOI：
10.1007/s00253-011-3101-1
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发表时间：
2011-03-01
影响因子：
5
通讯作者：
Hirsch, Emilio
中科院分区：
文献类型：
--
作者：
Lu, Xiao-Yun;Ciraolo, Elisa;Hirsch, Emilio
磷脂酰肌醇-3-激酶(PI3Ks)是一类保守的脂蛋白激酶家族，能在细胞外刺激下磷酸化磷脂酰肌醇的3-羟基。PI3K通路在多种人类肿瘤中均有表达，对癌细胞的生长和存活起着重要作用。最近已经发现了几种PI3K抑制剂，但一些体外高效的PI3K抑制剂在动物肿瘤模型中效果不佳，原因是体内的药物性质较差，如溶解性差、不稳定性和血浆清除速度快。在本研究中，我们开发了一种基于聚羟基烷酸纳米粒(NP)的PI3K抑制剂(TGX221)缓释系统，并将其用于阻断癌细胞株的增殖。TGX221从以PHA为基础的NP中逐渐释放，在NP-TGX221处理的细胞中，癌细胞的生长明显慢于阴性对照或接受游离TGX221的细胞。由于生物利用度差和体内半衰期有限是疏水性PI3K抑制剂的共同特征，我们的结果为其他PI3K阻滞剂的类似配方和癌症治疗的新策略开辟了道路。
The phosphoinositide-3-kinases (PI3Ks) are a conserved family of lipid kinases that phosphorylate the 3-hydroxyl group of phosphatidylinositols in response to extracellular stimuli. PI3K pathway is enrolled in different kinds of human cancer and plays a prominent role in cancer cell growth and survival. Several PI3K inhibitors have been recently identified but some PI3K inhibitors with high potency in vitro do not show satisfactory effects in animal cancer models because of the poor pharmaceutical properties in vivo such as poor solubility, instability, and fast plasma clearance rate. In this study, we developed a sustained release system of PI3K inhibitor (TGX221) based on polyhydroxyalkanoate nanoparticles (NP) and used it to block proliferation of cancer cell lines. TGX221 was gradually released from PHA-based NP and growth of cancer cell lines was significantly slower in NP-TGX221-treated cells than in either negative controls or in cells receiving free TGX221. Since poor bioavailability and limited in vivo half-life are common features of hydrophobic PI3K inhibitors, our results open the way to similar formulation of other PI3K blockers and to new strategies in cancer treatment.