Double hit strategy using pH-sensitive liposomes containing doxorubicin and pheophorbide-a for combination tumor therapy

Abstract

For successful combination therapy using nanoparticles, stable loading and targeted delivery of different drugs are important. Herein, we prepared pH-sensitive liposomes with hydrophilic doxorubicin (Dox) in the core and hydrophobic pheophobide-a (Pba) in the lipid membrane (pH-lipo-Dox-Pba). The liposomes provided high drug accumulation in tumor tissue, with an enhanced permeability and retention (EPR) effect and enhanced binding to tumor cells by cyclic Arg-Gly-Asp peptide (cRGD). After cellular uptake, Dox was released in response to the endo-lysosomal acidic pH and moved into the nucleus, while Pba remained in the cytosol. Therefore, a double hit strategy composed of a simultaneous attack on nucleus and cytosol could be achieved by chemo- and photodynamic therapy. High tumor accumulation of pH-lipo-Dox-Pba was observed after intravenous injection into 4T1 tumor-bearing mice. Effective suppression of tumor growth in the same mouse model demonstrated a synergetic effect of combination therapy enabled by the double hit strategy using pH-lipo-Dox-Pba.