Simultaneous Delivery of Therapeutic Antagomirs with Paclitaxel for the Management of Metastatic Tumors by a PH-responsive Anti-microbial Peptide-mediated Liposomal Delivery System

The roles of microRNAs (miRNAs) in the regulation of metastasis have been widely recognized in the recent years. Mir-10b antagomir (antagomir-10b) was shown to impede metastasis through the down-regulation of mir-10b; however, it could not stunt the growth of primary tumors. In this study we showed that the co-delivery of antagomir-10b with paclitaxel (PTX) by a novel liposomal delivery system modified with an anti-microbial peptide [D]-H6L9 (D-Lip) could significantly both hinder the migration of 4T1 cells and induce evident cellular apoptosis and cell death in the meantime. The histidines in the sequence of [D]-H6L9 allowed the peptide to get protonated under pH5.0 (mimicking the lysosome/endosome environment), and strong membrane lytic effect could thus be activated, leading to the escape of liposomes from the lysosomes and the decrease of of mir-10b expression. The in vivo and ex vivo fluorescence imaging showed that D-Lip could reach 4T1 tumors efficaciously. Incorporation of PTX did not influence the antagomir-10b delivery effect of D-Lip; for the in vivo tumor inhibition assay, compared with all the other groups, the combination of antagomir-10b and PTX delivered by D-Lip could prominently delay the growth of 4T1 tumors and reduce the lung metastases at the same time, and the expression of Hoxd10 in tumors was also significantly up-regulated. Taken together, these results demonstrated that D-Lip could act as a sufficient tool in co-delivering antagomir-10b and PTX.