Impact of the amount of PEG on prodrug nanoassemblies for efficient cancer therapy

PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles (prodrug-SANPs). However, the impacts of the amount of PEG on the self-assemble stability, cellular uptake, pharmacokinetics, and antitumor efficacy of prodrug-SANPs are still unknown. Herein, selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug. Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG (W(prodrug)/W(DSPE-mPEG2000) = 10:0, 9:1, 8:2, 7:3 and 6:4), and defined as Pure drug NPs, 9:1NPs, 8:2NPs, 7:3 NPs and 6:4 NPs, respectively. Interestingly, 8:2 NPs formed the most compact nanostructure, thus improving the self-assemble stability and pharmacokinetics behavior. In addition, the difference of these prodrug-SANPs in cellular uptake was investigated, and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details. The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product. Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.