PEGylation of lipophilic SN38 prodrug with DSPE-mPEG2000 versus cremophor EL: comparative study for intravenous chemotherapy

Drug Delivery

Li Jia¹  Lu Yan¹  Chen Li¹  Xing Duan¹  Yaxin Zheng¹  Fuyue Liu¹  Anqin Li¹  Chunhan Luo¹  Yifang Gan¹  Jun Zeng² 

[1] School of Pharmacy, Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, Chengdu Medical College, Chengdu, China;School of Pharmacy, Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, Chengdu Medical College, Chengdu, China;Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, Chin;

关键词: SN38;    lipophilic prodrug;    nanomedicine;    Cremophor EL;    PEGylation;   

DOI  :  10.1080/10717544.2019.1587045

来源: publisher

【 摘 要 】

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-mPEG2000 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-mPEG2000/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-mPEG2000 in terms of the improvement of antitumor activity, but the enhanced toxicity warranted further attention in the future study.

【 授权许可】

CC BY