Polymer-initiating Caveolae-mediated Endocytosis and GSH-responsive MiR-34a Gene Delivery System for Enhanced Orthotopic Triple Negative Breast Cancer Therapy.

Gene therapy based on miRNAs has broad application prospects in the treatment of tumors. However, due to degradation and ineffective release during intracellular transport, current gene delivery vectors used for miRNAs limited their actual transfection efficiency. This study developed a novel non-viral vector PEI-SPDP-Man (PSM) that could simultaneously target cellular uptake pathways and intracellular responsive release for miR-34a. PSM was synthesized by connected mannitol (Man) to branched polyethylenimine (PEI) using a disulfide bond. The prepared PSM/miR-34a gene delivery system can induce and enter to tumor cells through caveolae-mediated endocytosis to reduce the degradation of miR-34a in lysosomes. The disulfide bond was sensed at high concentration of glutathione (GSH) in the tumor cells and miR-34a was released, thereby reducing the expression of Bcl-2 and CD44 to suppress the proliferation and invasion of tumor cells. In vitro and in vivo experiments showed that through the targeted cellular uptake and the efficient release of miR-34a, an effective anti-tumor and anti-metastasis profiles for the treatment of orthotopic triple negative breast cancer were achieved. This strategy of controlling intracellular transport pathways by targeting cellular uptake pathways in the gene therapy was an approach that could be developed for highly effective cancer therapy. This article is protected by copyright. All rights reserved.