Sensitizing Chemotherapy for Glioma with Fisetin mediated by Microenvironment-responsive Nano-drug Delivery System

Abstract Background: Drug resistance has become an obstacle to successful cancer chemotherapies, with therapeutic agents effectively traversing the blood-brain barrier (BBB) remaining a great challenge. Results: A microenvironmentresponsiveness and active targeting nanomicelle was constructed to enhance the penetration of drugs, leading to improved therapeutic effects. Dynamic light scattering demonstrated that prepared nanomicelle had uniform size. The cRGD modification renders the nanomicelle with active targeting capabilities to traverse BBB for chemotherapy. The disulfide-bond-containing nanomicelle can be disintegrated in response to high concentration of endogenous glutathione (GSH) within the tumor microenvironment (TME) for tumor-specific drug release, resulting in more effective accumulation. Notably, the released fisetin further increased the uptake of doxorubicin by glioma cells and exerted synergistic effects to promote apoptosis, induce cellular G2/M cycle arrest, and inhibit cell proliferation and migration in vitro. Moreover, the nanomicelle showed favorable anti-glioma effects in vivo. Conclusions: Our study provides a new strategy to overcome drug resistance by utilizing a natural product to sensitize conventional chemotherapeutics with well-designed targeted nanodelivery systems for cancer treatment.