Enhanced Chemotherapeutic Efficacy of Paclitaxel Nanoparticles Co-delivered with MicroRNA-7 by Inhibiting Paclitaxel-Induced EGFR/ERK pathway Activation for Ovarian Cancer Therapy.

Chemotherapy-induced activation of cell survival pathways leads to drug resistance. MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in many biological pathways. Paclitaxel (PTX) is one of the first-line chemotherapy drugs for ovarian cancer, and it induces the activation of the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) pathway that leads to tumor cell proliferation, survival, invasion, and drug resistance. MicroRNA-7 (miR-7) has the ability to suppress the EGFR/ERK pathway. To sensitize chemotherapy, we developed monomethoxy(poly(ethylene glycol))-poly(d,l-lactide- co-glycolide)-poly(l-lysine) nanoparticles for the simultaneous co-delivery of PTX and miR-7. The resulting PTX/miR-7 nanoparticles (P/MNPs) protect miRNA from degradation, possess a sequential and controlled release of drugs, improve the transfection efficiency of miRNA, decrease the half-maximal inhibitory concentration of PTX, and increase the apoptosis of ovarian cancer cells. The chemotherapeutic efficacy of PTX is prominently enhanced in vitro and in vivo via the inhibition of PTX-induced EGFR/ERK pathway activation by miR-7. Our studies in P/MNPs reveal a novel paradigm for a dual-drug-delivery system of chemotherapeutics and gene therapy in treating cancers.