Prolonged inhibition of inflammation in osteoarthritis by triamcinolone acetonide released from a polyester amide microsphere platform

Abstract

Controlled biomaterial-based corticosteroid release might circumvent multiple injections and the accompanying risks, such as hormone imbalance and muscle weakness, in osteoarthritic (OA) patients. For this purpose, microspheres were prepared from an amino acid-based polyester amide (PEA) platform and loaded with triamcinolone acetonide (TAA). TAA loaded microspheres were shown to release TAA for over 60days in PBS. Furthermore, the bioactivity lasted at least 28days, demonstrated by a 80-95% inhibition of PGE production using TNFα-stimulated chondrocyte culture, indicating inhibition of inflammation. Microspheres loaded with the near infrared marker NIR780-iodide injected in healthy rat joints or joints with mild collagenase-induced OA showed retention of the microspheres up till 70days after injection. After intra-articular injection of TAA-loaded microspheres, TAA was detectable in the serum until day seven. Synovial inflammation was significantly lower in OA joints injected with TAA-loaded microspheres based on histological Krenn scores. Injection of TAA-loaded nor empty microspheres had no effect on cartilage integrity as determined by Mankin scoring. In conclusion, the PEA platform shows safety and efficacy upon intra-articular injection, and its extended degradation and release profiles compared to the currently used PLGA platforms may render it a good alternative. Even though further in vivo studies may need to address dosing and readout parameters such as pain, no effect on cartilage pathology was found and inflammation was effectively lowered in OA joints.

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing

“…In rodent models commonly used in the first stage of preclinical development of novel therapies, synovial fluid sampling over time is impossible and very small quantities of plasma are available for analysis. In the current study, plasma TAA levels in the first 2 days reflected the initial burst release of TAA‐loaded PEA occurring in vitro (Rudnik‐Jansen et al, ). The area under the curve (AUC) of the plasma levels, indirectly showing loss from the synovial cavity and hence delivery by the MSs, was approximately 10 times smaller for the MS‐based versus the bolus formulation of 0.7‐mg TAA.…”

“…Moreover, the IA release of a dose of 60‐mg TAA from a PLGA MS platform, equivalent to the lowest dosage used in the current study, was shown to be safe in knee OA patients (Bodick et al, ). Also in a different, collagenase‐induced, rat model of OA, the extended release of TAA by PEA MSs did not show any effects on cartilage integrity nor induced tissue calcification (Rudnik‐Jansen et al, ). Given the absence of effects in previous studies of unloaded PEA MSs in OA animals, the MS platform per se is not likely to have contributed to the effects found either (Janssen et al, ; Rudnik‐Jansen et al, ), nor would have their combination with TAA bolus, given the absence of effects of either when administered separately.…”

“…Also in a different, collagenase‐induced, rat model of OA, the extended release of TAA by PEA MSs did not show any effects on cartilage integrity nor induced tissue calcification (Rudnik‐Jansen et al, ). Given the absence of effects in previous studies of unloaded PEA MSs in OA animals, the MS platform per se is not likely to have contributed to the effects found either (Janssen et al, ; Rudnik‐Jansen et al, ), nor would have their combination with TAA bolus, given the absence of effects of either when administered separately. Together with the lack of effect of the bolus in OA animals and of TAA‐releasing PEA MSs in non‐operated healthy animals, our observations rather point towards an interaction of extended release of TAA with the pathological processes occurring in the ACLT + pMMx OA model.…”

“…However, whether the drug was released for the full period of 16 weeks after injection, as was demonstrated before in vitro (Rudnik‐Jansen, Woike, et al, ), cannot be stated with certainty. PEA MSs loaded with a hydrophobic near IR dye were shown to still contain dye up until 70 days after injection in a rat OA model (Rudnik‐Jansen et al, ), suggesting that release continued until at least the first 10 weeks. Moreover, in knee OA patients treated with a PLGA‐based platform releasing TAA (Kraus et al, ), TAA was detected in the synovial fluid of knee OA patients up to 12 weeks after IA injection, but not in bolus injected joints.…”

“…PEA MSs were prepared as described before (Rudnik‐Jansen et al, ); 20‐, 30‐, and 45‐wt% TAA was dispersed in polymer/solvent solution, and particles were formed at 8,000 rpm with an Ultra‐Turrax homogenizer and poured into a hardening bath afterwards. Particles were stirred over night at ambient temperature, cooled prior to washing, and snap frozen with liquid nitrogen prior to freeze‐drying.…”