Potent antitumor effect of intranasally administrable pH-sensitive and photothermal polymeric oncolytic adenovirus for the treatment of brain cancer

Abstract

Oncolytic viruses showed promising therapeutic effect against brain cancer in clinical trials. To further improve oncolytic viruses’ potency against brain cancer, combination of oncolytic virotherapy and photothermal therapy using an intranasally administrable nanohybrid system was developed. Specifically, near-infrared dye (IR780) was conjugated to pH-sensitive and arginine-grafted bioreducible polymer (PPA and PPA-IR780) then conjugated to surface of oncolytic adenovirus (oAd), generating oAd-PPA and oAd-PPA-IR780. The transduction efficiency of Ad-PPA or Ad-PPA-IR780 was enhanced under the acidic pH. Both oAd-PPA and oAd-PPA-IR780 exerted potent cancer killing effect under acidic pH that was enhanced after laser irradiation for oAd-PPA-IR780. Intranasal administration of oAd-PPA-IR780 into mice bearing orthotopic brain tumors led to effective oAd accumulation in both the cancerous and noncancerous brain regions, which was further enhanced by laser, ultimately inhibiting orthotopic GBM tumor growth. PPA-IR780 also successfully delivered other gene therapeutics, like siRNA and DNA, to the brain after intranasal administration. Collectively, these findings demonstrated that intranasally administered oAd-PPA-IR780 can noninvasively induce both oncolytic and photothermal therapeutic effect in a synergistic manner to regress GBM.