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A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.

ABSTRACT: Radiculopathy, a painful neuroinflammation that can accompany intervertebral disc herniation, is associated with locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF?). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in the local delivery of anti-inflammatory drugs to treat this pathology as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antagonist of TNF? in multiple cell types and tissues, was chemically modified and conjugated to a thermally responsive elastin-like polypeptide (ELP) to create an injectable depot for sustained, local delivery of curcumin to treat neuroinflammation. ELPs are biopolymers capable of thermally-triggered in situ depot formation that have been successfully employed as drug carriers and biomaterials in several applications. ELP-curcumin conjugates were shown to display high drug loading, rapidly release curcumin in vitro via degradable carbamate bonds, and retain in vitro bioactivity against TNF?-induced cytotoxicity and monocyte activation with IC50 only two-fold higher than curcumin. When injected proximal to the sciatic nerve in mice via intramuscular (i.m.) injection, ELP-curcumin conjugates underwent a thermally triggered soluble-insoluble phase transition, leading to in situ formation of a depot that released curcumin over 4days post-injection and decreased plasma AUC 7-fold.

SUBMITTER: Sinclair SM

PROVIDER: S-EPMC3990405 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.

Sinclair S Michael SM Bhattacharyya Jayanta J McDaniel Jonathan R JR Gooden David M DM Gopalaswamy Ramesh R Chilkoti Ashutosh A Setton Lori A LA

Journal of controlled release : official journal of the Controlled Release Society 20130703 1

Radiculopathy, a painful neuroinflammation that can accompany intervertebral disc herniation, is associated with locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in the local delivery of anti-inflammatory drugs to treat this pathology as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antag ...[more]

PMID: 23830979

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Project description:Biochemical irritation of the dorsal root ganglion (DRG) after intervertebral disc herniation contributes to radiculopathy through tumor necrosis factor-alpha (TNFalpha)-mediated inflammation. Soluble TNF receptor Type II (sTNFRII) sequesters this cytokine, providing clinical benefit. Previous work involving conjugation of sTNFRII with thermally responsive elastin-like polypeptide (ELP) yielded a chimeric protein (ELP-sTNFRII) with in vitro anti-TNFalpha bioactivity. Furthermore, temperature-triggered ELP aggregation into a "depot" prolongs protein residence time following perineural injection. In this study the authors evaluated the inflammatory phenotype of DRG explants after TNFalpha stimulation, and assessed the abilities of sTNFRII or ELP-sTNFRII to attenuate these neuro-inflammatory changes.Rat lumbar DRGs (35 animals) were treated in 6 groups, as follows: control; TNFalpha (25 ng/ml); TNFalpha with low-(0.2 microg/ml) or high-dose (1 microg/ml) sTNFRII; and TNFalpha with low-(52.5 microg/ml) or high-dose (262.5 microg/ml) ELP-sTNFRII. After 24 hours, supernatant was evaluated for inflammatory cytokines (interleukin [IL]-1, IL-6, and IL-10); prostaglandin E2; and metabolites (glutamate, lactate, and pyruvate). Single-factor analysis of variance with post hoc Dunn analysis (alpha = 0.05) was used to assess treatment differences.Incubation of explants with TNFalpha caused metabolic stress reflected by an increased lactate/pyruvate ratio (1.8 +/- 0.5-fold) and extracellular glutamate (79 +/- 8% increase). Inflammatory activation was observed with heightened IL-6 release (5.2 +/- 1.4-fold) and prostaglandin E2 production (14 +/- 3-fold). An autoregulatory response occurred with an 11.8 +/- 0.6-fold increase in sTNFRI shedding. Treatment with high doses of sTNFRII or ELP-sTNFRII reversed all changes. Values are expressed as the mean +/- standard deviation.These results demonstrate that TNFalpha stimulation of DRG explants yields a phenotype of neurotoxic metabolite release and inflammatory mediator expression. Coincubation with either sTNFRII or ELP-sTNFRII antagonizes TNFalpha activity to abrogate these changes, suggesting potential for therapeutic intervention to treat peripheral nerve inflammatory disease.

Dataset Information

A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.

Publications

A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.

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