THU0463 Polymeric Nanoparticles with Thermally Responsive Dual Release Profiles for Combined Therapy of Osteoarthritis
Authors: M.L. Kang, J.-Y. Ko, J.E. Kim, G.-I. Im
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Osteoarthritis (OA) is a primarily noninflammatory and degenerative joint disease. However, there is growing evidence suggesting that synovial inflammation causes many of the signs and symptoms of OA [1]. It is therefore anticipated that inhibition of the inflammatory component of OA may offer an effective treatment for the disease. Regeneration of damaged cartilage is essential in long-term good result of OA therapy. However, current treatment options for OA are largely limited to either pain medication or joint replacement surgery. Kartogenin (KGN) is a recently characterized compound that promotes the selective differentiation of mesenchymal stem cells (MSCs) into chondrocytes and induces the regeneration of cartilage in OA [2]. KGN can be combined with anti-inflammatory small molecules such as diclofenac (DCF; MW =296.15 Da) in a delivery system to enhance the therapeutic effects for OA treatment. The combination can cause a rapid subsidence of inflammation and pain reduction from rapid release of DCF followed by regeneration of articular cartilage with the sustained release of KGN when used for intra-articular injection. <h3>Objectives</h3> In this study, we report the synthesis and characterization of the core-shell nanoparticles (F127/COS/KGN<sub>DCF</sub>) consisting of inner core DCF, and an outer shell of cross-linked carboxyl group-terminated pluronic F127 (F127–COOH)/chitosan oligosaccharide (COS)/KGN. The aims of this study were to (1) characterize the F127/COS/KGNDCF nanoparticles for independent dual release by thermal responsiveness, and (2) evaluate the F127/COS/KGNDCF nanoparticles as a dual drug delivery system for combined therapy. <h3>Methods</h3> KGN was conjugated covalently with COS before the nanoparticle synthesis by carbodiimide chemistry. The nanoparticles were synthesized by covalent cross-linking between COS and F127–COOH using EDC catalysis during emulsification/solvent evaporation method. <h3>Results</h3> The nanoparticles (F127/COS/KGN<sub>DCF</sub>) were ∼125 nm in size at 37°C and expanded to ∼442 nm when cooled to 4°C in aqueous solutions. Swelling and shrinking of the nanoparticles by thermal responsiveness was also controllable by the composition ratio of F127 or KGN to COS. The F127/COS/KGN<sub>DCF</sub> nanoparticles showed immediate and sustained release of DCF and KGN respectively, which was controlled independently by temperature change. The toxicity of the F127/COS/KGN<sub>DCF</sub> nanoparticles was found to be negligible. Inflammation in U937 macrophage-like cells and chondrocytes was more effectively suppressed by the F127/COS/KGN<sub>DCF</sub> nanoparticles treated with cold shock than those without cold shock treatment. Chondrogenic differentiation of bone marrow-derived mesenchymal stem cells was also enhanced by cold shock treatment of the nanoparticles. <h3>Conclusions</h3> These results suggested that thermally responsive F127/COS/KGN<sub>DCF</sub> nanoparticles could provide useful dual-function therapeutics to quench the inflammation and regenerate damaged tissue when combined with cryotherapy. <h3>References</h3> F. Berenbaum, Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!), Osteoarthr. Cartilage 21 (2013) 16-21. K. Johnson et al. A stem cell-based approach to cartilage repair, Science 336 (2012) 717-721. <h3>Acknowledgements</h3> This work was supported by a grant from the Bio &amp; Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (NRF-2013R1A1A2062978). <h3>Disclosure of Interest</h3> None declared