Limitations of adenoviral (Ad) vectors for cancer gene therapy could be overcome by their combination with pharmaceutical technologies. Here we show that an enzyme-responsive liposomal formulation could significantly enhance the tumor cell transduction abilities and reduce the immunogenicity of Ad vectors. In the current research, the enzymatically cleavable PEG-lipids composed of a PEG/matrix metalloproteinase (MMP)-substrate peptide/cholesterol (PPC) were synthesized and characterized by (1)H NMR and TOF MS ES(+). The obtained MMP-cleavable lipids were inserted into the anionic liposomal Ad vectors (AL-Ad) by the post-insertion method. The results of in vitro infection assays indicated that the enzymatically cleavable formulation (PPC-AL-Ad) displayed a much higher gene expression than naked Ad5 and the non-cleavable PEG-lipid modified Ad vectors in tumor cells. More importantly, PPC-AL-Ad induces a lower production of neutralizing antibody and lower innate immune response, as well as significantly reduced liver toxicity in vivo. These findings suggest that PPC-AL-Ad is a promising system for gene delivery in tumor therapy.
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