Intra-articular treatment with triamcinolone acetonide-loaded liposomes in the rat high-fat diet groove model

Abstract

Purpose: Local intra-articular injections with triamcinolone acetonide (TA) is favorable as an anti-inflammatory treatment. In animal (rat) models of OA it was shown that TA can reduce osteophyte formation and thus may be beneficial as a disease modifying treatment. To evaluate the potential for slow-release anti-inflammatory treatment in a model mimicking metabolically accelerated post-traumatic OA, we evaluated the effect of TA-loaded liposomes, in the high-fat diet groove model in rats. Methods: Thirty four male Wistar rats (Charles River) were fed a high-fat diet for 24 weeks where 60% of the kilocalories consist of fat (D12492i, 5.2kcal/g, Research Diets Inc., NJ, USA). In all animals, in both knees, grooves were applied to the cartilage of both femur condyles, in week 12. Then, in 1 week and 7 weeks post-surgery, they received an intra-articular injection with TA-loaded liposomes in their left knee. They received either 100 microgram (n=17) or 30 microgram TA (n=17). The right knee was used as a contralateral positive control and received either saline (n=8) or empty liposomes (n=26). To evaluate pain responses loading of the joints was monitored using a Dynamic Weight Bearing (DWB) test setup (Bioseb, France). Micro-CT scans were made using a Quantum FX μ-CT scanner (PerkinElmer, MA, USA) at baseline, pre-surgery and at the endpoint after 24 weeks. Results: An overall increase in weight was observed during the full length of the experiment for both treatment groups. However, after a single intra-articular injection with liposomes containing 100 microgram TA, significant weight loss was observed for at least 7 days (figure 1). After this period weight increased again and there was no significant difference in weight at the end of the study between the high-dose and the low-dose group. DWB showed a shift in weight towards the front paws and reduced rearing time shortly after surgery that normalized after treatment. But no difference between treatment groups was observed. MicroCT analysis showed significantly thinner lateral subchondral plate of the tibia at endpoint in the treated leg compared to the untreated (sham treated) leg (figure2). Histological examination showed minor inflammation and no differences between treatments, controls or treated and untreated legs. Conclusions: Rats are particularly sensitive to corticosteroids as single intra-articular injections with TA-loaded liposomes led to acute weight loss. This effect was previously observed with multiple (daily) injections of free TA, at the same concentration, suggesting the slow-release formulation is extremely potent. There was also an effect on lateral subchondral bone that was thinner in the treated legs compared to untreated legs. The TA-loaded liposomes seem to be tolerated well by the joint and further evaluation in an OA model is recommended. [Figure presented] [Figure presented]