a Division of Pulmonary and Critical Care Medicine , The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College , Chengdu , China.
b School of Pharmacy , Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, Chengdu Medical College , Chengdu , China.
Drug Deliv. 2019 Dec;26(1):354-362. doi: 10.1080/10717544.2019.1587045.
The lipophilic prodrug of hydrophobic drugs with well-designed molecular structures can form stable pure prodrug nanoparticles (NPs), but rapid NPs aggregation in plasma greatly restricted their direct use for intravenous chemotherapy. To address this, DSPE-mPEG and Cremophor EL are two of the most widely used lipophilic PEG derivatives to enhance their colloidal stability in plasma. However, their drug delivery performances have never been comparatively studied. Here, a redox-responsive lipophilic prodrug of SN38 was chosen as the model drug for such comparative investigations. We found that Cremophor EL/NPs having a small diameter (∼15 nm) and poor kinetic stability displayed an enhanced cell internalization, higher cytotoxicity and prolonged circulation time as compared with DSPE-mPEG/NPs. Most importantly, these superiorities further resulted in a much more potent antitumor activity in CT26 colorectal cancer xenograft, but the increased loss of body weight was also noted. These results suggested that Cremophor EL could be more advantageous than DSPE-mPEG in terms of the improvement of antitumor activity, but the enhanced toxicity warranted further attention in the future study.
疏水性药物的亲脂前药具有精心设计的分子结构，可以形成稳定的纯前药纳米颗粒（NPs），但前药纳米颗粒在血浆中迅速聚集极大地限制了它们在静脉化疗中的直接应用。为了解决这个问题，DSPE-mPEG 和 Cremophor EL 是两种最广泛使用的亲脂性 PEG 衍生物，用于增强它们在血浆中的胶体稳定性。然而，它们的药物递送性能从未进行过比较研究。在这里，选择 SN38 的氧化还原响应性亲脂前药作为模型药物进行此类比较研究。我们发现，与 DSPE-mPEG/NPs 相比，具有较小直径（约 15nm）和较差动力学稳定性的 Cremophor EL/NPs 表现出增强的细胞内化、更高的细胞毒性和更长的循环时间。最重要的是，这些优势进一步导致在 CT26 结直肠癌细胞异种移植中具有更强的抗肿瘤活性，但也注意到体重增加的损失。这些结果表明，在提高抗肿瘤活性方面，Cremophor EL 可能比 DSPE-mPEG 更有利，但增强的毒性需要在未来的研究中进一步关注。
