The effect of surface modification of adenovirus with an arginine-grafted bioreducible polymer on transduction efficiency and immunogenicity in cancer gene therapy.
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.
Kim
Pyung-Hwan
PH
Graduate Program for Nanomedical Science and Technology, Yonsei University, Seoul, Republic of Korea.
Kim
Tae-Il
TI
Yockman
James W
JW
Kim
Sung Wan
SW
Yun
Chae-Ok
CO
D000256:Adenoviridae / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D001120:Arginine / Q000378:metabolism* / Q000494:pharmacology; D002412:Cations; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015316:Genetic Therapy; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects; D008027:Light; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D011073:Polyamines / Q000378:metabolism* / Q000494:pharmacology; D011094:Polyethyleneimine / Q000494:pharmacology; D011991:Receptors, Virus / Q000378:metabolism; D015203:Reproducibility of Results; D012542:Scattering, Radiation; D044967:Serum; D013499:Surface Properties / Q000187:drug effects; D014161:Transduction, Genetic / Q000379:methods*
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D002412:Cations; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011073:Polyamines; D011991:Receptors, Virus; C534803:arginine-grafted bioreducible poly(disulfide amine)polymer; D011094:Polyethyleneimine; D001120:Arginine