Purpose

SN-38 is an antineoplastic drug with a three orders of magnitude higher activity than its prodrug, irinotecan, a common chemotherapeutic of choice in the treatment of colorectal cancer. A considerable number of genes are known to alter their expression under the influence of free SN-38, but no studies have looked at the gene expression effects of SN-38 delivered via poly(D-L-lactide-co-caprolactone) (PLCL) nanoparticles yet.

Method

We evaluated changes to expression levels of genes encoding for ubiquitin D (UBD), fibroblast growth factor 3 (FGF3), histone (HIST), and regulator of cell cycle (RGCC) in SW-480 colon cancer cells in response to free SN-38 and two types of poloxamer-coated PLCL (PEO-PPO-PEO/PLCL) nanoparticles as carriers for SN-38, containing different conformations of the hydrophilic stealth corona: dense or collapsed.

Results

Both the free drug and the two drug-loaded nanoformulations upregulated UBD and RGCC and downregulated FGF3 and HIST, which was consistent with the pharmacological activity of SN-38. Still, there was a clear difference in gene expression levels in SW-480 cells depending on whether they were challenged with free SN-38 or with nanoparticles loaded with SN-38. Most critically, the delivery of SN-38 with the nanoparticles prolonged its mode of action and, in the case of genes such as UBD, FGF3, and HIST, provided for a more intense effect on gene expression alteration than that achieved by the drug alone.

Conclusions

Nanoparticles comprising the collapsed PEO-PPO-PEO corona produced a more intense effect on gene expression alteration than the nanoparticles with the dense PEO-PPO-PEO corona.

中文翻译：

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通过包含致密和塌陷的泊洛沙姆 Coronae 的聚 (DL-丙交酯-共-己内酯) 纳米颗粒递送 SN-38 的基因表达效应

目的

SN-38 是一种抗肿瘤药物，其活性比其前药伊立替康高三个数量级，伊立替康是治疗结直肠癌的常用化疗药物。已知相当多的基因在游离 SN-38 的影响下改变它们的表达，但没有研究关注通过聚 (DL-丙交酯-共-己内酯) (PLCL) 纳米颗粒传递的 SN-38 的基因表达影响然而。

方法

我们评估了 SW-480 结肠癌细胞中编码泛素 D ( UBD )、成纤维细胞生长因子 3 ( FGF3 )、组蛋白 ( HIST ) 和细胞周期调节因子 ( RGCC ) 的基因表达水平的变化，以响应游离 SN- 38 和两种类型的泊洛沙姆涂层 PLCL (PEO-PPO-PEO/PLCL) 纳米粒子作为 SN-38 的载体，包含不同构象的亲水隐形电晕：致密或塌陷。

结果

游离药物和两种载药纳米制剂均上调UBD和RGCC，下调FGF3和HIST，这与SN-38的药理活性一致。尽管如此，SW-480 细胞中的基因表达水平仍存在明显差异，这取决于它们是用游离 SN-38 攻击还是用负载有 SN-38 的纳米颗粒攻击。最关键的是，SN-38 与纳米颗粒的递送延长了其作用方式，并且对于UBD、FGF3和HIST等基因，对基因表达改变的影响比单独药物所达到的更强烈.

结论

与具有致密 PEO-PPO-PEO 电晕的纳米颗粒相比，包含塌陷的 PEO-PPO-PEO 电晕的纳米颗粒对基因表达改变产生更强烈的影响。