Dataset Information

Intra-articular injection of rapamycin microparticles prevent senescence and effectively treat osteoarthritis.

ABSTRACT: Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Rapamycin-loaded in poly(lactic-co-glycolic acid) microparticles (RMPs) induced autophagy, prevented senescence, and sustained sulphated glycosaminoglycans production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra-articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen. Together, the study demonstrates the feasibility of using RMPs as a potential clinically translatable therapy to prevent the progression of post-traumatic OA.

SUBMITTER: Dhanabalan KM

PROVIDER: S-EPMC9842044 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Intra-articular injection of rapamycin microparticles prevent senescence and effectively treat osteoarthritis.

Dhanabalan Kaamini M KM Dravid Ameya A AA Agarwal Smriti S Sharath Ramanath K RK Padmanabhan Ashok Kumar AK Agarwal Rachit R

Bioengineering & translational medicine 20220505 1

Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelio ...[more]

PMID: 36684078

Similar Datasets

Project description:Rapid joint clearance of small molecule drugs is the major limitation of current clinical approaches to osteoarthritis and its subtypes, including post-traumatic osteoarthritis (PTOA). Particulate systems such as nano/microtechnology could provide a potential avenue for improved joint retention of small molecule drugs. One drug of interest for PTOA treatment is flavopiridol, which inhibits cyclin-dependent kinase 9 (CDK9). Herein, polylactide-co-glycolide microparticles encapsulating flavopiridol were formulated, characterized, and evaluated as a strategy to mitigate PTOA-associated inflammation through the inhibition of CDK9. Characterization of the microparticles, including the drug loading, hydrodynamic diameter, stability, and release profile was performed. The mean hydrodynamic diameter of flavopiridol particles was ∼15 µm, indicating good syringeability and low potential for phagocytosis. The microparticles showed no cytotoxicity in-vitro, and drug activity was maintained after encapsulation, even after prolonged exposure to high temperatures (60 °C). Flavopiridol-loaded microparticles or blank (unloaded) microparticles were administered by intraarticular injection in a rat knee injury model of PTOA. We observed significant joint retention of flavopiridol microparticles compared to the soluble flavopiridol, confirming the sustained release behavior of the particles. Matrix metalloprotease (MMP) activity, an indicator of joint inflammation, was significantly reduced by flavopiridol microparticles 3 days post-injury. Histopathological analysis showed that flavopiridol microparticles reduced PTOA severity 28 days post-injury. Taken altogether, this work demonstrates a promising biomaterial platform for sustained small molecule drug delivery to the joint space as a therapeutic measure for post-traumatic osteoarthritis. STATEMENT OF SIGNIFICANCE: Post-traumatic osteoarthritis (PTOA) begins with the deterioration of subchondral bone and cartilage after acute injuries. In spite of the prevalence of PTOA and its associated financial and psychological burdens, therapeutic measures remain elusive. A number of small molecule drugs are now under investigation to replace FDA-approved palliative measures, including cyclin-dependent kinase 9 (CDK9) inhibitors which work by targeting early inflammatory programming after injury. However, the short half-life of these drugs is a major hurdle to their success. Here, we show that biomaterial encapsulation of Flavopiridol (CDK9 inhibitor) in poly (lactic-co-glycolic acid) microparticles is a promising route for direct delivery and improved drug retention time in the knee joint. Moreover, administration of the flavopiridol microparticles reduced the severity of PTOA.

Project description:IntroductionIntra-articular (IA) injection of hyaluronic acid (HA) and corticosteroid (CS) is a common treatment for osteoarthritis (OA) of the knee. As a drug treatment for patients with depression, duloxetine has been shown in many studies to effectively relieve the pain of OA and improve function of the knee joint. However, evidence regarding the efficacy of IA injection of HA+CS combined with duloxetine for pain management in patients with OA of the knee is lacking. The aim of this study was to test the hypothesis that IA injection of HA+CS combined with duloxetine could achieve pain management superior to that of IA injection of HA+CS alone in patients experiencing knee OA pain.MethodsThis study will adopt a prospective, randomised, open-label blind endpoint study design. In total, 150 patients with OA of the knee will be enrolled in the study. The participants will be randomly allocated to receive either a single IA injection of HA+CS combined with duloxetine or a single IA injection of HA+CS alone, and both groups will complete a 24-week follow-up to assess pain and functional improvements. The primary outcome measure is the change in the weekly mean of the 24 hours average pain scores from baseline to the end of 24 weeks in patients with OA of the knee, and the secondary outcomes include the response to treatment, changes from baseline in the brief pain inventory, improvement in the Western Ontario and McMaster Universities Osteoarthritis index scores, patient global impression of improvement scale, Hospital Anxiety and Depression Scale and adverse events during the 24-week follow-up. The data will be analysed by the intention-to-treat principle.Ethics approval and disseminationThis study was approved by the institutional ethics committee of the Beijing Tiantan Hospital (approval number: KY 2019-086-02). The results of the study will be published in peer-reviewed journals, and the findings will be presented at scientific meetings.Trial registration numberClinicalTrials.gov Identifier: NCT04117893; Pre-results.

Project description:ObjectiveTo evaluate the therapeutic trajectory of intra-articular hyaluronic acid (IAHA) vs placebo for knee osteoarthritis (OA).DesignOur data sources include Medline, EMBASE, CINAHL, BIOSIS, Web of Science, Google Scholar, Cochrane database; hand searched reviews, manuscripts, and, supplements; author contacts for unpublished data. Randomized trials that reported effects of IAHA vs placebo on knee OA were selected based on inclusion criteria. We computed effect sizes for change from baseline at 4, 8, 12, 16, 20 and 24 weeks, using Bayesian random effects model. We performed multivariate analyses adjusting for correlation between time points. Meta-regressions were performed adjusting for potential confounders.ResultsThe 54 eligible trials included 7545 participants. The conduct and quality of these trials varied in number of aspects. The effect size (ES) favored IAHA by week 4 (0.31; 95% CI 0.17, 0.45), reaching peak at week 8 (0.46; 0.28, 0.65), and then trending downwards, with a residual detectable effect at week 24 (0.21; 0.10, 0.31). This therapeutic trajectory was consistent among the subset of high quality trials and on multivariate analysis adjusting for correlation between time points.ConclusionsOur meta-analysis highlights a therapeutic trajectory of IAHA for knee OA pain over 6 months post-intervention. With this additional perspective, we are able to infer that IAHA is efficacious by 4 weeks, reaches its peak effectiveness at 8 weeks and exerts a residual detectable at 24 weeks. On the other hand, the peak effect size (0.46; 0.28, 0.65), is greater than published effects from other OA analgesics [acetaminophen (ES=0.13; 0.04, 0.22); NSAIDs (ES=0.29; 0.22, 0.35); COX-2 inhibitors (ES=0.44; 0.33, 0.55)]. An effect size above 0.20 is considered to be clinically relevant on an individual patient basis in chronic pain conditions such as knee OA. Thus, its properties could have utility for certain clinical situations, or in combination with other therapies.

Dataset Information

Intra-articular injection of rapamycin microparticles prevent senescence and effectively treat osteoarthritis.

Publications

Intra-articular injection of rapamycin microparticles prevent senescence and effectively treat osteoarthritis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets