THU0463 Polymeric Nanoparticles with Thermally Responsive Dual Release Profiles for Combined Therapy of Osteoarthritis

Background

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.

Objectives

In this study, we report the synthesis and characterization of the core-shell nanoparticles (F127/COS/KGN_DCF) 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.

Methods

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.

Results

The nanoparticles (F127/COS/KGN_DCF) 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_DCF 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_DCF nanoparticles was found to be negligible. Inflammation in U937 macrophage-like cells and chondrocytes was more effectively suppressed by the F127/COS/KGN_DCF 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.

Conclusions

These results suggested that thermally responsive F127/COS/KGN_DCF nanoparticles could provide useful dual-function therapeutics to quench the inflammation and regenerate damaged tissue when combined with cryotherapy.

References

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.

Acknowledgements

This work was supported by a grant from the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (NRF-2013R1A1A2062978).

Disclosure of Interest

None declared