Abstract
Despite the success of recombinant adenovirus serotype 5 (Ad5) and dioleoyltrimethylaminopropane:cholesterol (DOTAP:Chol) liposomes as viral and nonviral vectors in clinical trials, these vectors still suffer from drawbacks such as high immunogenicity and low transfection efficiency, respectively. To address these issues, some researchers have synthesized DOTAP:Chol/Ad5 hybrid vectors hoping to combine the unique features of the individual vectors. While this method shows promise, the limitations associated with Ad5 were not completely ameliorated. The objective of the present study was to use PEGylated liposomes to improve upon these previous studies, with the aim of maintaining high transduction efficiency and reducing the immune response. PEGylated DOTAP:Chol liposomes were synthesized at different molar ratios of polyethylene glycol (PEG) (0 to 0.04), and its effects on transduction efficiency and immunogenicity of Ad5 were studied. Coating of Ad5 with PEGylated liposomes was confirmed using transmission electron microscopy and dynamic light scattering, and these techniques indicated that the size of the complexes was ~ 140 nm. Transduction efficiency was enhanced nearly 100-fold in CAR-negative cells treated with PEGylated liposome/Ad5 complexes compared to unmodified Ad5. In addition, PEGylated liposome/Ad5 complexes significantly reduced the humoral and innate immune responses relative to native Ad5 as assessed by antiAd5 antibodies and IL-6 production by macrophage cells. Moreover, PEGylation decreased the cytotoxicity and hemolytic activity of the liposomes. In conclusion, the transduction efficiency, biocompatibility, and immunogenicity of DOTAP:Chol/Ad5 complexes were significantly improved by including an optimum amount of a PEG-lipid.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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This work was supported in part by a Scientist Development Grant from the American Heart Association (09SDG2250712) and a National Science Foundation Career Award (Division of Materials Research 1352535).
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Vupputuri, S., Tayebi, L., Hikkaduwa Koralege, R.S. et al. Polyethylene glycol–modified DOTAP:cholesterol/adenovirus hybrid vectors have improved transduction efficiency and reduced immunogenicity. J Nanopart Res 23, 37 (2021). https://doi.org/10.1007/s11051-020-05134-9
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DOI: https://doi.org/10.1007/s11051-020-05134-9