Doxorubicin Nanomedicine Based On Ginsenoside Rg1 With Alleviated Cardiotoxicity And Enhanced Antitumor Activity

The doxorubicin（Dox）-induced cardiotoxicity largely limits its clinical use in cancer.In this study,self-assembled Dox@Rg1 nanoparticles were prepared by Flash Nano Precipitation（FNP）.The Dox@Rg1 nanoparticles were constructed by encapsulating Dox into a self-assembled Rg1.The self-assembled nanomedicine could take advantage of the enhanced permeability and retention effect（EPR）for passive targeted drug delivery.The Dox@Rg1 nanoparticles have a core-shell structure,in which hydrophobic Dox is stable in the hydrophobic core of Rg1 micelles,and the hydrophilic shell can improve the steric stabilization.The self-assembled Dox@Rg1 nanoparticle were further characterized and the cytotoxicity in vitro was studied.The anti-tumor effect of nanoparticles was estimated using the 4T1 tumor bearing mice and the cardiac toxicity was also investigated.The experimental results showed that compared with Dox,the Dox@Rg1 nanoparticles displayed more distribution in the tumor cells than cardiomyocytes,and their cytotoxicity to tumor cells increased,while their toxicity to cardiomyocytes decreased.It is worth mentioning that the Dox@Rg1 nanoparticles have possessed an enhanced tumor-targeting efficacy and antitumor effects and are less cardiotoxic than Dox.In experiments exploring the mechanisms involved,the results showed that Dox@Rg1nanoparticles induced reduced levels of myocardial cell apoptosis compared to Dox alone.Further studies found that Dox@Rg1 nanoparticles reduced the toxicity of Dox to cardiomyocytes and significantly inhibited cardiomyocyte apoptosis by inhibiting reactive oxygen species（ROS）production and down-regulating apoptosis factors over-expression,including caspase-3 and p53.In vivo experiments revealed that the Dox@Rg1 nanoparticles induced good tumor targeting ability in 4T1 tumor-bearing mice and improved the anti-tumor effect of Dox and reduced the exhibited no serious toxicity on heart.In conclusion,the successful preparation of Dox@Rg1 nanoparticles provides more ideas for the rational application of Dox in clinical treatment.