BACKGROUND:
A series of endocannabinoid agonists with the ability to self-assemble into a variety of nanoassembled particles for the encapsulation and controlled release of drugs have been synthesised. Conjugation of a synovium targeting peptide, HAP-1 to the surface of the nanoparticles was added, facilitating their selective accumulation to the inflamed synovium. These targeted endocannabinoid-based nanoparticles were then evaluated for their anti-inflammatory effects in arthritic rats.
METHODS:
To study the effects of endocannabinoid-nanoparticles on inflammatory cytokine production in vitro, rheumatoid arthritis fibroblast like cells (RA-FLS cells) were stimulated with TNF-α alone, or in the presence of endocannabinoid-nanoparticles. Pro-inflammatory gene expression was measured by PCR. In-vivo, arthritic rats were injected intravenously with endocannabinoid-nanoparticles and blood samples collected by the lateral tail vein at various time intervals. Quantification of inflammatory cytokines in circulating rat plasma was determined using bead-based immunoassay.
RESULTS:
We have shown that cannabinoid receptors CB1 and CB2 are expressed by human fibroblast like synoviocytes (FLS), and are up-regulated in an inflammatory state. Incubation of endocannabinoid-nanoparticles suppressed IL-6, NF-Kb and MMP-1 cytokines in-vitro. Similarly in-vivo, circulating GM-CSF and IL-6 plasma levels, noted to be up-regulated in arthritic rats, were suppressed in the endocannabinoid-nanoparticle treated groups. Using HPLC endocannabinoid lipids, OEA and LEA, were highly expressed in joints of the nanoparticle injected rats and correlated with increases in endogenous PEA levels.
DISCUSSION:
Increasing evidence from preclinical studies supports the interest of the endocannabinoid system as an emerging therapeutic target for arthritic pain. We have shown that RA-FLS cells express endocannabinoid receptors which can regulate cytokine production in vitro and in vivo. The data suggests possible therapeutic potential in alleviating inflammation associated with arthritis.