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Release of Plasmid DNA-Encoding IL-10 from PLGA Microparticles Facilitates Long-Term Reversal of Neuropathic Pain Following a Single Intrathecal Administration

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Abstract

Purpose

Interleukin-10 (IL-10) is an anti-inflammatory molecule that has achieved interest as a therapeutic for neuropathic pain. In this work, the potential of plasmid DNA-encoding IL-10 (pDNA-IL-10) slowly released from biodegradable microparticles to provide long-term pain relief in an animal model of neuropathic pain was investigated.

Methods

PLGA microparticles encapsulating pDNA-IL-10 were developed and assessed both in vitro and in vivo.

Results

In vitro, pDNA containing microparticles activated macrophages, enhanced the production of nitric oxide, and increased the production of IL-10 protein relative to levels achieved with unencapsulated pDNA-IL-10. In vivo, intrathecally administered microparticles embedded in meningeal tissue, induced phagocytic cell recruitment to the cerebrospinal fluid, and relieved neuropathic pain for greater than 74 days following a single intrathecal administration, a feat not achieved with unencapsulated pDNA. Therapeutic effects of microparticle-delivered pDNA-IL-10 were blocked in the presence of IL-10-neutralizing antibody, and elevated levels of plasmid-derived IL-10 were detected in tissues for a prolonged time period post-injection (>28 days), demonstrating that therapeutic effects are dependent on IL-10 protein production.

Conclusions

These studies demonstrate that microparticle encapsulation significantly enhances the potency of intrathecally administered pDNA, which may be extended to treat other disorders that require intrathecal gene therapy.

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Abbreviations

Anti-IL-10-IgG:

anti-rat interleukin-10 IgG neutralizing antibody

CCI:

chronic constriction injury

CSF:

cerebrospinal Fluid

CT :

threshold cycle

GAPDH:

glyceraldehyde-6-phosphate dehydrogenase

IL-10:

interleukin-10

LAL:

limulus amebocyte lysate

LPS:

lipopolysaccharide

MHCII:

major histocompatibility complex-II

NO:

nitric oxide

pDNA:

plasmid DNA

PLGA:

poly (lactic-co-glycolic-acid)

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Acknowledgements

Funding for this work was provided by NIH grant DA018156, and E. Dengler was supported by NSF Grant DGE-0549500. The authors would like to acknowledge the expert assistance of Dr. Travis Hughes and Dr. Leslie Leinwand at the University of Colorado for consultations on plasmid DNA growth and characterization. We would also like to thank Avigen Inc. (Alameda, CA) for the purification of Anti-IL-10-IgG and Control-IgG antibodies used in this work and Jenny L. Wilkerson at the University of New Mexico for her assistance with surgical procedures.

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Authors and Affiliations

  1. Department of Chemical & Biological Engineering, University of Colorado at Boulder, 424 UCB, Boulder, Colorado, 80309, USA

    Ryan Gene Soderquist, Scott M. Johnson, Luke D. Amer, Courtney S. Young & Melissa J. Mahoney

  2. Department of Psychology and Neuroscience, & the Center for Neuroscience, University of Colorado at Boulder, 345 UCB, Boulder, Colorado, 80309, USA

    Evan M. Sloane, Lisa C. Loram, Jacqueline A. Harrison, Makenzie T. Lewis, Matthew G. Frank & Linda R. Watkins

  3. Department of Neurosciences, University of New Mexico School of Medicine, MSC08 4740, Albuquerque, New Mexico, 87131-0001, USA

    Ellen C. Dengler & Erin D. Milligan

  4. Division of Endocrinology, National Institute for Biological Standards and Control, South Mimms, Potters Bar, Herts, Eng 3QG, UK

    Stephen Poole

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  1. Ryan Gene Soderquist
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  2. Evan M. Sloane
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Corresponding author

Correspondence to Melissa J. Mahoney.

Additional information

Evan M. Sloane made a substantial contribution to the in vivo components of this work.

The authors wish to dedicate this work to Dr. Evan Sloane, who lost his life to cancer prior to the publication of this work.

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Soderquist, R.G., Sloane, E.M., Loram, L.C. et al. Release of Plasmid DNA-Encoding IL-10 from PLGA Microparticles Facilitates Long-Term Reversal of Neuropathic Pain Following a Single Intrathecal Administration. Pharm Res 27, 841–854 (2010). https://doi.org/10.1007/s11095-010-0077-y

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