The effect of surface modification of adenovirus with an arginine-grafted bioreducible polymer on transduction efficiency and immunogenicity in cancer gene therapy
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Abstract
Adenoviral vectors offer many advantages for cancer gene therapy, including high transduction
efficiency, but safety concerns related to severe immunogenicity and other side effects
have led to careful reconsideration of their use in human clinical trials. To overcome
these issues, a strategy of generating hybrid vectors that combine viral and non-viral
elements as more intelligent gene carriers has been employed. Here, we coated adenovirus
(Ad) with an arginine-grafted bioreducible polymer (ABP) via electrostatic interaction.
We examined the effect of ABP-coated Ad complex at various ABP molecules/Ad particle
ratios. Enhanced transduction efficiency was observed in cells treated with cationic
ABP polymer-coated Ad complex compared to naked Ad. We also examined the coating of
Ad with ABP polymers at the optimal polymer ratio using dynamic light scattering and
transmission electron microscopy. In both high and low coxsackie virus and adenovirus
receptor (CAR)-expressing cells, ABP-coated Ad complex produced higher levels of transgene
expression than cationic polymer 25K PEI. Notably, high cytotoxicity was observed
with 25K PEI-coated Ad complex treatment, but not with ABP-coated Ad complex treatment.
In addition, ABP-coated Ad complex was not significantly inhibited by serum, in contrast
to naked Ad. Moreover, ABP-coated Ad complex significantly reduced the innate immune
response relative to naked Ad, as assessed by interleukin-6 (IL-6) cytokine release
from macrophage cells. Overall, our studies demonstrate that Ad complex formed with
ABP cationic polymer may improve the efficiency of Ad and be a promising tool for
cancer gene therapy.
(c) 2009 Elsevier Ltd. All rights reserved.