Liposomes loaded with paclitaxel and modified with novel triphenylphosphonium-PEG-PE conjugate possess low toxicity, target mitochondria and demonstrate enhanced antitumor effects in vitro and in vivo.

Previously, stearyl triphenylphosphonium (STPP)-modified liposomes (STPP-L) were reported to target mitochondria. To overcome a non-specific cytotoxicity of STPP-L, we synthesized a novel polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugate with the TPP group attached to the distal end of the PEG block (TPP-PEG-PE). This conjugate was incorporated into the liposomal lipid bilayer, and the modified liposomes were studied for their toxicity, mitochondrial targeting, and efficacy in delivering paclitaxel (PTX) to cancer cells in vitro and in vivo. These TPP-PEG-PE-modified liposomes (TPP-PEG-L), surface grafted with as high as 8 mol% of the conjugate, were less cytotoxic compared to STPP-L or PEGylated STPP-L. At the same time, TPP-PEG-L demonstrated efficient mitochondrial targeting in cancer cells as shown by confocal microscopy in co-localization experiments with stained mitochondria. PTX-loaded TPP-PEG-L demonstrated enhanced PTX-induced cytotoxicity and anti-tumor efficacy in cell culture and mouse experiments compared to PTX-loaded unmodified plain liposomes (PL). Thus, TPP-PEG-PE can serve as a targeting ligand to prepare non-toxic liposomes as mitochondria-targeted drug delivery systems (DDS).