Dexamethasone-containing PLGA superparamagnetic microparticles as carriers for the local treatment of arthritis.

Superparamagnetic iron oxide nanoparticles (SPIONs) are attractive materials that have been widely used in medicine for diagnostic imaging and therapeutic applications. In our study, SPIONs and the corticosteroid dexamethasone acetate (DXM) are co-encapsulated into PLGA microparticles for the aim of locally treating inflammatory conditions such as arthritis. The magnetic properties conferred by the SPIONs could help to maintain the microparticles in the joint with an external magnet. The aim of this study was to investigate the interaction between magnetic microparticles and human synovial fibroblasts in terms of microparticle uptake (FACS, confocal and optical microscopy), internalization mechanism (Prussian Blue staining, TEM, immunofluorescence), cell toxicity (MTT) and tissue reaction after intra-articular injection (histology). The results show that the microparticles have an excellent biocompatibility with synoviocytes and that they are internalized through a phagocytic process, as demonstrated by fluorescence-activated cell sorting and morphological analyses of cells exposed to microparticles. Histological analysis showed that the prepared microparticles did not induce any inflammatory reaction in the joint. This type of carrier could represent a suitable magnetically retainable intra-articular drug delivery system for treating joint diseases such as arthritis or osteoarthritis.

Magnetically retainable microparticles for drug delivery to the joint: efficacy studies in an antigen-induced arthritis model in mice.

INTRODUCTION: Conventional corticosteroid suspensions for the intra-articular treatment of arthritis suffer from limitations such as crystal formation or rapid clearance from the joint. The purpose of this study was to investigate an innovative alternative consisting of corticosteroid encapsulation into magnetically retainable microparticles. METHODS: Microparticles (1 or 10 microm) containing both superparamagnetic iron oxide nanoparticles (SPIONs) and dexamethasone 21-acetate (DXM) were prepared. In a preliminary study, we compared the persistence of microparticles of both sizes in the joint. A second study evaluated the influence of a subcutaneously implanted magnet near the knee on the retention of magnetic microparticles in the joint by in vivo imaging. Finally, the efficacy of 10-microm microparticles was investigated using a model of antigen-induced arthritis (AIA) in mice. Phosphate-buffered saline, DXM suspension, SPION suspension, blank microparticles and microparticles containing only SPIONs were used as controls. Arthritis severity was assessed using 99mTc accumulation and histological scoring. RESULTS: Due to their capacity of encapsulating more corticosteroid and their increased joint retention, the 10-microm microparticles were more suitable vectors than the 1-microm microparticles for corticosteroid delivery to the joint. The presence of a magnet resulted in higher magnetic retention in the joint, as demonstrated by a higher fluorescence signal. The therapeutic efficacy in AIA of 10-microm microparticles containing DXM and SPIONs was similar to that of the DXM suspension, proving that the bioactive agent is released. Moreover, the anti-inflammatory effect of DXM-containing microparticles was more important than that of blank microparticles or microparticles containing only SPIONs. The presence of a magnet did not induce a greater inflammatory reaction. CONCLUSIONS: This study confirms the effectiveness of an innovative approach of using magnetically retainable microparticles as intra-articular drug delivery systems. A major advantage comes from a versatile polymer matrix, which allows the encapsulation of many classes of therapeutic agents (for example, p38 mitogen-activated protein kinase inhibitors), which may reduce systemic side effects.

Dexamethasone-containing biodegradable superparamagnetic microparticles for intra-articular administration: physicochemical and magnetic properties, in vitro and in vivo drug release.

Compared with traditional drug solutions or suspensions, polymeric microparticles represent a valuable means to achieve controlled and prolonged drug delivery into joints, but still suffer from the drawback of limited retention duration in the articular cavity. In this study, our aim was to prepare and characterize magnetic biodegradable microparticles containing dexamethasone acetate (DXM) for intra-articular administration. The superparamagnetic properties, which result from the encapsulation of superparamagnetic iron oxide nanoparticles (SPIONs), allow for microparticle retention with an external magnetic field, thus possibly reducing their clearance from the joint. Two molecular weights of poly(lactic-co-glycolic acid) (PLGA) were used, 12 and 19 kDa. The prepared batches were similar in size (around 10 microm), inner morphology, surface morphology, charge (neutral) and superparamagnetic behaviour. The SPION distribution in the microparticles assessed by TEM indicates a homogeneous distribution and the absence of aggregation, an important factor for preserving superparamagnetic properties. DXM release profiles were shown to be quite similar in vitro (ca. 6 days) and in vivo, using a mouse dorsal air pouch model (ca. 5 days).

Co-encapsulation of dexamethasone 21-acetate and SPIONs into biodegradable polymeric microparticles designed for intra-articular delivery.

OBJECTIVE: Intra-articular drug delivery systems still suffer from too short-lasting effects. Magnetic particles retained in the joint using an external magnetic field might prolong the local release of an anti-inflammatory drug. For the purpose, superparamagnetic iron oxide nanoparticles (SPIONs) and dexamethasone 21-acetate (DXM) were co-encapsulated into biodegradable microparticles. METHODS: Poly(D,L-lactide-co-glycolide) microparticles embedding both SPIONs and DXM were prepared by a double emulsion technique. The formulation was optimized in two steps, a screening design and a full factorial design, aiming at 10-microm particle diameter and high DXM encapsulation efficacy. RESULTS: The most significant parameters were the polymer concentration, the stirring speed during solvent extraction and the extractive volume. Increasing the polymer concentration from 200 to 300 mg ml(-1), both the microparticle mean diameter and the DXM encapsulation efficacy increased up to 12 microm and 90%, respectively. The microparticles could be retained with an external magnet of 0.8 T placed at 3 mm. Faster DXM release was obtained for smaller microparticles. CONCLUSION: The experimental set-up offered the tools for tailoring a formulation with magnetic retention properties and DXM release patterns corresponding to the required specifications for intra-articular administration.