Fenretinide-polyethylene glycol (PEG) conjugate with improved solubility enhanced cytotoxicity to cancer cell and potent in vivo efficacy

Abstract

Fenretinide (4-HPR), a synthetic retinoid, has shown its antitumor activity in many tumor types with low cytotoxicity to normal cells and high clinical safety. However, the low water solubility limits its further biological applications. To increase solubility, 4-HPR was conjugated with methoxy polyethylene glycol carboxylic acid (mPEG_2K-COOH) by an ester linkage between the phenol hydroxyl of 4-HPR and the carboxyl of mPEG_2K-COOH. The 4-HPR-PEG_2K conjugate micelles had mean size of 76.70 ± 1.248 nm with a narrow distribution and a low critical micelle concentration. In vitro cytotoxicity studies showed the micelles have higher cytotoxicity to A2780s and MCF-7 cells. Its IC₅₀ was 4.7 and 4.1-fold lower than the free 4-HPR, respectively. Importantly, in vivo pharmacokinetic studies, the AUC of 4-HPR was found to be 2.3-fold higher in 4-HPR-PEG_2K micelles compared to free 4-HPR. And the 4-HPR-PEG_2K micelles had higher antitumor activity. Meanwhile, the histopathology analysis exhibited that the micellar treatment decreased the viability of A2780s cells and increased the level of induced apoptosis. Therefore, the enhanced activity of 4-HPR by the method of conjugation with mPEG_2K-COOH could hopefully provide new insights into the matter of ovarian cancer and breast cancer treatment.

Graphical Abstract

Keywords:

• Fenretinide
• prodrug-based micelles
• self-assembled micelles
• drug delivery
• PEGylation

Disclosure statement

The authors declare that they have no potential conflict of interest.

Additional information

Funding

This study was financially supported by the National Nature Science Foundation of China [No. 81202484 and No. 81600527].