title: 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 (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 antagonist of TNFα 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 TNFα-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.
authors.affiliation: Department of Biomedical Engineering, 136 Hudson Hall, Box 90281, Durham 27708, USA. michael.sinclair@alumni.duke.edu
authors.forename: S Michael
authors.initials: SM
authors.lastname: Sinclair
authors.forename: Jayanta
authors.initials: J
authors.lastname: Bhattacharyya
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: McDaniel
authors.forename: David M
authors.initials: DM
authors.lastname: Gooden
authors.forename: Ramesh
authors.initials: R
authors.lastname: Gopalaswamy
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chilkoti
authors.forename: Lori A
authors.initials: LA
authors.lastname: Setton
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003474:Curcumin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D004549:Elastin / Q000737:chemistry; D005260:Female; D005818:Genetic Engineering; D006358:Hot Temperature; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D007405:Intervertebral Disc Displacement; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000737:chemistry; D012584:Sciatic Nerve / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D010455:Peptides; D004549:Elastin; D003474:Curcumin
keywords: Conjugate; Curcumin; Drug depot; Elastin-like polypeptide; Neuroinflammation; Sustained release