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Molecularly engineered poly(ortho ester) microspheres for enhanced delivery of DNA vaccines

Abstract

Genetic vaccination using plasmid DNA presents a unique opportunity for achieving potent immune responses without the potential limitations of many conventional vaccines. Here we report the design of synthetic biodegradable polymers specifically for enhancing DNA vaccine efficacy in vivo. We molecularly engineered poly(ortho ester) microspheres that are non-toxic to cells, protect DNA from degradation, enable uptake by antigen-presenting cells, and release DNA rapidly in response to phagosomal pH. One type of microsphere of poly(ortho esters) that releases DNA vaccines in synchrony with the natural development of adaptive immunity, elicited distinct primary and secondary humoral and cellular immune responses in mice, and suppressed the growth of tumour cells bearing a model antigen. This polymer microparticulate system could, with further study, have implications for advancing the clinical utility of DNA vaccines as well as other nucleic-acid-based therapeutics against viral infections and cancer.

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Figure 1: Synthesis and characterization of POE microspheres encapsulating DNA plasmid.
Figure 2: Cytotoxicity of POE microspheres.
Figure 3: Quantification and conformation of plasmid DNA released from POE microspheres under different pH-buffered conditions.
Figure 4: Humoral and cellular immune response in mice immunized with model DNA vaccines.
Figure 5: Efficacy of DNA vaccination against tumour challenge in mice.

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Acknowledgements

The authors thank Daniel Anderson for valuable discussions and assistance and Frank Miskevich for assistance with confocal microscopy. This research was supported in part by a research grant from AP Pharma. C.W. would like to thank the National Institutes of Health for an individual National Research Service Award (1 F32 GM64921-01).

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Correspondence to Jorge Heller or Robert Langer.

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Jorge Heller and Hui-Rong Shen have equity in Pharma, Inc. All the other authors declare no competing financial interests.

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Wang, C., Ge, Q., Ting, D. et al. Molecularly engineered poly(ortho ester) microspheres for enhanced delivery of DNA vaccines. Nature Mater 3, 190–196 (2004). https://doi.org/10.1038/nmat1075

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