Release of Plasmid DNA-Encoding IL-10 from PLGA Microparticles Facilitates Long-Term Reversal of Neuropathic Pain Following a Single Intrathecal Administration
- 12 March 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Pharmaceutical Research
- Vol. 27 (5), 841-854
- https://doi.org/10.1007/s11095-010-0077-y
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.Keywords
This publication has 76 references indexed in Scilit:
- Immunological priming potentiates non-viral anti-inflammatory gene therapy treatment of neuropathic painGene Therapy, 2009
- Long-term control of neuropathic pain in a non-viral gene therapy paradigmGene Therapy, 2009
- Anti-inflammatory cytokine gene therapy decreases sensory and motor dysfunction in experimental Multiple Sclerosis: MOG-EAE behavioral and anatomical symptom treatment with cytokine gene therapyBrain, Behavior, and Immunity, 2009
- Size‐Dependent Endocytosis of NanoparticlesAdvanced Materials, 2009
- Role of Particle Size in Phagocytosis of Polymeric MicrospheresPharmaceutical Research, 2008
- Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in ratsBrain, Behavior, and Immunity, 2007
- Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioidsBrain, Behavior, and Immunity, 2007
- Intrathecal polymer-based interleukin-10 gene delivery for neuropathic painNeuron Glia Biology, 2006
- Alternative activation of macrophagesNature Reviews Immunology, 2003
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001