Evaluation of novel conjugated resveratrol polymeric nanoparticles in reduction of plasma degradation, hepatic metabolism and its augmentation of anticancer activity in vitro and in vivo

Resveratrol (RSV) is a natural product with multiple biological benefits including anticancer properties. Unfortunately, its biological benefits are limited by its low bioavailability and rapid hepatic metabolism and degradation in the body. The aim of this study was to develop an effective delivery system for RSV that would enhance the plasmatic stability and decrease the metabolism rate of RSV through a dual strategy of chemical modification and nanoparticle formulation. The effectiveness of this strategy was tested for the application of RSV anticancer treatment in a mouse cancer model. Chemical modification of RSV was achieved by conjugating RSV to a low molecular weight co-polymer mPEG-PLA. This conjugated RSV together with free RSV were formulated into mPEG-PLA nanoparticles (conjugated RSV NPs). These NPs showed a stable plasma stability profile and decreased liver metabolism rate compared to nanoparticles encapsulating free RSV in mPEG-PLA (encapsulated RSV NPs) and free RSV alone. However, in vitro cell studies using B16-F10 cancer cells showed that conjugated RSV NPs were less effective compared to encapsulated RSV NPs, possibly due to the lack of biotransformation of conjugated RSV to the active form RSV in the simple cell studies. To study the actual effect of our strategy, an in vivo C57BL/6J mouse model with subcutaneous B16-F10 melanoma using intraperitoneal administration was used to reveal the relationship between the improved plasma stability and reduced liver metabolism rate of RSV in conjugated RSV NPs, and suppression of the tumour growth in mice. In vivo, a better tumour suppression trend with conjugated RSV NPs was noted. Our study suggests that the use of chemical conjugation with NP formulation is an effective strategy to reduce the degradation and metabolism rate of RSV and consequently increase the antitumour activity of RSV in vivo. This strategy has potential to be further developed for the suppression of early growth of tumours with no side effects.