ROS Responsive Nanoparticles Encapsulated with Natural Medicine Remodel Autophagy Homeostasis in Breast Cancer.

ABSTRACT

In photodynamic therapy (PDT), elevated reactive oxygen species (ROS) activate tumor cell protective autophagy, therefore attenuating the antitumor function of therapy. Hence, inhibition of protective autophagy in tumors can improve the antitumor effect of PDT. Herein, an innovative nanotraditional Chinese medicine system ((TP+A)@TkPEG NPs), which remodeled autophagy homeostasis, was fabricated. A photosensitizer aggregation inducing emission (AIE) and autophagy modulator triptolide (TP, an active ingredient of Tripterygium wilfordii Hook F) were encapsulated into ROS-responsive nanoparticles to improve antitumor effect of PDT in treatment of triple negative breast cancer. We proved that (TP+A)@TkPEG NPs effectively elevated intracellular ROS levels, activated ROS-responsive release of TP and inhibited the proliferation of 4T1 cells in vitro. More importantly, it sharply reduced autophagy related genes transcription and proteins expression in 4T1 cells, then promote cell apoptosis. In addition, this nanoherb therapeutic system effectively orientated to tumor sites, achieved efficient inhibition of tumor, and extended the survival time of 4T1-bearing mice in vivo. Further results confirmed that (TP+A)@TkPEG NPs remarkably inhibit the expression level of autophagy related initiation gene (becline-1) and elongation protein (light chain 3B) in tumor microenvironment and then block PDT induced protective autophagy. In brief, this system can remodel autophagy homeostasis and serve as an innovative approach for treatment of triple negative breast cancer.