Multifunctional amphiphilic peptide dendrimer as nonviral gene vectors for effective cancer therapy via combined gene/photodynamic therapies.

Gene therapy holds great promise for treatment of gene-associated diseases. However, safe and successful clinical application urgently requires further advancement of constructing efficient delivery systems. Herein, three amphiphilic peptide dendrimers (TTC-L-KRR/KKK/KHH), containing the natural amino acid residues (lysine K, arginine R, and histidine H) and AIE-based photosensitizer (tetraphenylethenethiophene modified cyanoacrylate, TTC) modified with alkyl chain (L), have been designed and prepared for improving therapeutic potency via the combination of gene therapy (GT) and photodynamic therapy (PDT). All three compounds possessed typical aggregation-induced emission (AIE) characteristics and ultralow critical micelle concentrations (CMCs). The liposomes consisting of amphiphilic peptide dendrimers and dioleoylphosphatidylethanolamine (DOPE) can effectively bind DNA into nanoparticles with appropriate sizes, regular morphology and good biocompatibility. Among them, liposomes TTC-L-KKK/DOPE exhibited the highest transfection efficiency up to 5.7-fold as compared with Lipo2000 in HeLa cells. Meanwhile, rapid endocytosis, successful endo/lysosomal escape, gene release and rapid nuclear delivery of DNA revealed the superiority of liposomes TTC-L-KKK/DOPE during gene delivery process. More importantly, efficient reactive oxygen species (ROS) generation by TTC-L-KKK/DOPE led to effective PDT, thus improving therapeutic potency via combining with p53 mediated-gene therapy. Our work brought novel insight and direction for the construction of bio-safe and bio-imaging liposome as the multifunctional nonviral gene vectors for the effective combined gene/photodynamic therapies.