1 research outputs found
Safety Profiles and Antitumor Efficacy of Oncolytic Adenovirus Coated with Bioreducible Polymer in the Treatment of a CAR Negative Tumor Model
Adenovirus
(Ad) vectors show promise as cancer gene therapy delivery
vehicles, but immunogenic safety concerns and coxsackie and adenovirus
receptor (CAR)-dependency have limited their use. Alternately, biocompatible
and bioreducible nonviral vectors, including arginine-grafted cationic
polymers, have been shown to deliver nucleic acids through a cell
penetration peptide (CPP) and protein transduction domain (PTD) effect.
We utilized the advantages of both viral and nonviral vectors to develop
a hybrid gene delivery vehicle by coating Ad with mPEG-PEI-<i>g</i>-Arg-S-S-Arg-<b>g</b>-PEI-mPEG (Ad/PPSA). Characterization
of Ad/PPSA particle size and zeta potential showed an overall size
and cationic charge increase in a polymer concentration-dependent
manner. Ad/PPSA also showed a marked transduction efficiency increase
in both CAR-negative and -positive cells compared to naked Ad. Competition
assays demonstrated that Ad/PPSA produced higher transgene expression
levels than naked Ad and achieved CAR-independent transduction. Oncolytic
Ad (DWP418)/PPSA was able to overcome the nonspecificity of polymer-only
therapies by demonstrating cancer-specific killing effects. Furthermore,
the DWP418/PPSA nanocomplex elicited a 2.24-fold greater antitumor
efficacy than naked Ad in vivo. This was supported by immunohistochemical
confirmation of Ad E1As accumulation in MCF7 xenografted tumors. Lastly,
intravenous injection of DWP418/PPSA elicited less innate immune response
compared to naked Ad, evaluated by interleukin-6 cytokine release
into the serum. The increased antitumor effect and improved vector
targeting to both CAR-negative and -positive cells make DWP418/PPSA
a promising tool for cancer gene therapy