Probing the fluorination effect on the self-assembly characteristics, in vivo fate and antitumor efficacy of paclitaxel prodrug nanoassemblies

Rationale: Small-molecule prodrug nanoassembly is emerging as an efficient platform for chemotherapy.The self-assembly stability plays a vital role on the drug delivery efficiency of prodrug nanoassembly.It is reported that fluoroalkylation could improve the self-assembly stability of amphiphilic polymers by utilizing the unique fluorination effect.But the application of fluoroalkylation on small-molecule prodrug nanoassembly has never been reported.Methods: Here, fluoro-modified prodrug was developed by conjugating paclitaxel with perfluorooctanol (F8-SS-PTX), and the paclitaxel-octanol prodrug (C8-SS-PTX) was used as control.The fluoro-mediated self-assembly mechanisms were illustrated using molecular dynamics simulation.In addition, the impacts of fluoroalkylation on the pharmacy characters, in vivo fate and antitumor effect of small-molecule prodrug nanoassembly were investigated in details.Results: Fluoroalkylation significantly improved the self-assembly stability of F8-SS-PTX NPs both in vitro and in vivo, which could be attributed to the fluoro-mediated hydrophobic force and halogen bonds.The AUC0-24h and tumor accumulation of F8-SS-PTX NPs was 6-fold and 2-fold higher than that of C8-SS-PTX NPs, respectively.As a result, F8-SS-PTX NPs exhibited much better antitumor effect than C8-SS-PTX NPs and Abraxane.Conclusion: Fluoroalkylation could improve the self-assembly stability, in vivo fate, and antitumor efficacy of small-molecule prodrug nanoassemblies, which could be an effective strategy for the rational design of advanced nanomedicines.