Targeted co‐delivery of paclitaxel and anti P‐gp shRNA by low molecular weight PEI decorated with L‐3,4‐dihydroxyphenylalanine

Abstract

Co‐delivery of small chemotherapeutic molecules and nucleic acid materials via targeted carriers has attracted great attention for treatment of resistant tumors and reducing adverse effects. In this study, a targeted carrier for co‐delivery was prepared based on low‐molecular weight polyethylenimine (LMW PEI). Paclitaxel (PTX) was covalently conjugated onto PEI via a succinate linker. The PEI conjugate was decorated with L‐DOPA in order to target large neutral amino acid transporter‐1 (LAT‐1) that is over‐expressed on various cancer cells. This PEI conjugate was complexed with human ABCB1 shRNA plasmid to down‐regulate the expression of P‐glycoprotein, as one of the major efflux pumps inducing resistance against chemotherapeutics. The formation of PEI conjugate enhanced the solubility of PTX and resulted in the condensation and protection of plasmid DNA in nanosized polyplexes. The results of targeted delivery into the cells demonstrated that PEI conjugate transferred the payloads to the cells over‐expressing LAT‐1 transporter, while the biological effects on the cells lacking the transporter was negligible. Also, shRNA‐mediated down‐regulation of P‐gp led to the increase of toxic effects on the cells over‐expressing P‐gp. This study suggests a promising approach for co‐delivery of small molecules and nucleic acid materials in a targeted manner for cancer therapy.