Tumor-assoicated Enzyme-triggered Liposomal Codelivery Of Simvastatin And Paclitaxel For Overcoming EMT-assoicated Drug Resistance

Epithelial–mesenchymal transition(EMT)is closely associated with the development of drug resistance.This study developed a tumor-assoicated enzyme-responsive liposomal system for tumor-microenvironment-targeted codelivery of simvastatin and paclitaxel.The potential of EMT as a therapeutic target and the application for overcoming drug resistance in non-small cell lung cancer(NSCLC)therapy were investigated in this work.The NSCLC A549 T cells are highly resistant to paclitaxel.It was found that A549 T cells are characterized by EMT(e.g.,low-level E-cadherin and high-level vimentin),and the HMG-CoA inhibitor simvastatin can re-sensitize the A549 T cells to the paclitaxel treatment.The in-vitro study revealed simvastatin,a cholesterol-lowering drug,was able to reverse EMT-associated resistance to chemotherapy via lipid metabolism.It was revealed simvastatin can disrupt lipid rafts(cholesterol-rich domains)and suppress integrin-?3 and focal adhesion formation,thus inhibiting FAK signaling pathway and re-sensitizing the drug-resistant cancer cells to paclitaxel.Furthermore,simvastatin was able to re-polarize tumor-associated macrophages(TAM),promoting M2-to-M1 phenotype switch via cholesterol-associated LXR/ABCA1 regulation.The repolarization increased TNF-?,but attenuated TGF-? that,in turn,remodeled tumor microenvironment and suppressed EMT.For dual-action on both cancer cells and TAM,the tumor microenvironment-activatable multifunctional liposomes were developed for codelivery of simvastatin/paclitaxel.The liposomes were modified with the hairpin-structured,activatable cell-penetrating peptide that was specifically responsive to the tumor-associated protease legumain,and achieved an enhanced treatment efficacy.The in vivo study demonstrated the tumor-targeted delivery function and the enhanced treatment efficacy in a drug-resistant A549 T xenografted mouse model.The reversal of EMT and repolarization of TAM were also demonstrated in vivo.It provides a promising simvastatin-based nanomedicine strategy targeting cholesterol metabolism to reverse EMT and repolarize TAM to treat drug-resistant cancer.The elucidation of the molecular pathways(cholesterol/lipid raft/integrin ?3/FAK and cholesterol-associated LXR/ABCA1 regulation)for anti-EMT should of clinical significance for an old drug for a new application.