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

• Published in: Journal of controlled release Vol. 171; no. 1; pp. 38 - 47
• Main Authors: Sinclair, S. Michael, Bhattacharyya, Jayanta, McDaniel, Jonathan R., Gooden, David M., Gopalaswamy, Ramesh, Chilkoti, Ashutosh, Setton, Lori A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10-10-2013
• Subjects: Animals; Antagonists; anti-inflammatory agents; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacokinetics; biocompatible materials; biopolymers; Cell Line, Tumor; Conjugate; Curcumin; Curcumin - administration & dosage; Curcumin - chemistry; Curcumin - pharmacokinetics; cytotoxicity; Delayed-Action Preparations; drug carriers; Drug Delivery Systems; Drug depot; Elastin - chemistry; Elastin-like polypeptide; Female; Genetic Engineering; Hot Temperature; Humans; Inflammation - drug therapy; inhibitory concentration 50; Intervertebral Disc Displacement; intervertebral disks; Mice; Mice, Inbred C57BL; monocytes; nerve tissue; Neuroinflammation; Peptides - chemistry; phase transition; polypeptides; Sciatic Nerve - metabolism; Sustained release; tumor necrosis factor-alpha; U937 Cells; Sustained release; Neuroinflammation; Curcumin; Conjugate; Elastin-like polypeptide; Drug depot
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2013.06.032

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.
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