Oncolytic adenovirus coated with stimuli responsive block copolymer mPEG-b-poly(His) induces tumor microenvironment-specific antitumor efficacy

Abstract

Adenovirus (Ad) has shown great promise in cancer gene therapy. Ad coated with cationic polymers have already been shown to enhance transduction, but it showed nonspecific binding with cells, resulted in evoked side effect. To overcome these hurdles, in this study adenovirus coated with pH sensitive poly(His) polymer through ionic interaction for passive tumor targeting. We have characterized the effect of polymer concentration on particle size distribution, zeta potential, transduction efficiency, and structural properties. Remarkable enhanced transduction efficiency was observed in cells treated with Ad/poly(His) nanocomplex compared to naked Ad at low pH. In addition, cellular trafficking using time lapse total internal reflection fluorescence showed that the Ad/poly(His) nanocomplex was significantly enhanced cellular uptake at lower pH, in contrast to neutral pH. The biodistribution study confirmed that the Ad/poly(His) nanocomplex can effectively accumulate at the tumor site by the EPR effect and exhibited 3.3-fold higher luciferase expressions in tumor than the naked Ad. Additionally, MTT assay and cancer cell xenografts studies showed that polymer coated nanocomplex exhibited high cancer cell killing effect and also inhibited the tumor growth. Furthermore, poly(His)-coated Ad complex was not significantly inhibited by serum, in contrast to naked Ad. Moreover, Ad/poly(His) nanocomplex significantly reduced the innate immune response in contrast to naked Ad, as assessed by interleukin-6 cytokine release from macrophage cells in vivo. These results suggest that the stimuli-responsive Ad/poly(His) nanocomplex has potential to targeting tumors.