Osteoarthritis and cartilage · 2025
Cartilage targeting cationic peptide carriers display deep cartilage penetration and retention in a rabbit model of post-traumatic osteoarthritis.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Boyer Timothy L, Chao Olivia, Hakim Bill, Childress Luke, Meslier Quentin A, Iyengar Suhasini M, Ondrechen Mary Jo, Porter Ryan M, Bajpayee Ambika G
Аннотация
OBJECTIVE: Drug delivery to cartilage is limited by its complex architecture and avascularity. Cationic peptide carriers (CPCs) have previously been optimized for improved cartilage transport and retention of drugs in vitro. In this study, we evaluated the kinetics, stability, and immunogenicity of CPCs after a single intra-articular injection using a rabbit knee injury model.
DESIGN: New Zealand White rabbits were administered a single dose of Cy5-labeled CPCs in knees receiving anterior cruciate ligament transection (ACLT) or Sham surgery. CPC biodistribution and retention within joint tissues and synovial fluid were evaluated 1 and 7 days after administration, and extra-articular kinetics were assessed in serum. Histology, immunohistochemistry, and reverse transcription quantitative polymerase chain reaction were performed to assess synovitis and protease activity. Proteolytic analysis of CPCs in the presence of arthritic enzymes was evaluated using synovial fluid size-exclusion filtration, Fluorescence Resonance Energy Transfer analysis, and computational molecular docking.
RESULTS: CPCs penetrated the full depth of sulfated glycosaminoglycan (sGAG)-rich tissues, notably cartilage, and were retained through the latest timepoint measured (one week) in both Sham and ACLT knees. Compared to ACLT, Sham knees had greater joint retention at Day 1 (1.6-fold) and Day 7 (1.8-fold). CPC intra-tissue concentration strongly correlated with tissue sGAG density, which did not considerably differ between surgical conditions at these timepoints. However, CPCs exhibited elevated vascular clearance and proteolytic fragmentation in inflammatory conditions. CPCs did not increase macrophage abundance, cytokine expression, or alter tissue morphology.
CONCLUSION: CPCs target the deep layers of cartilage, even in inflamed joints, and can be utilized to substantially improve intra-joint bioavailability of therapeutics.
DESIGN: New Zealand White rabbits were administered a single dose of Cy5-labeled CPCs in knees receiving anterior cruciate ligament transection (ACLT) or Sham surgery. CPC biodistribution and retention within joint tissues and synovial fluid were evaluated 1 and 7 days after administration, and extra-articular kinetics were assessed in serum. Histology, immunohistochemistry, and reverse transcription quantitative polymerase chain reaction were performed to assess synovitis and protease activity. Proteolytic analysis of CPCs in the presence of arthritic enzymes was evaluated using synovial fluid size-exclusion filtration, Fluorescence Resonance Energy Transfer analysis, and computational molecular docking.
RESULTS: CPCs penetrated the full depth of sulfated glycosaminoglycan (sGAG)-rich tissues, notably cartilage, and were retained through the latest timepoint measured (one week) in both Sham and ACLT knees. Compared to ACLT, Sham knees had greater joint retention at Day 1 (1.6-fold) and Day 7 (1.8-fold). CPC intra-tissue concentration strongly correlated with tissue sGAG density, which did not considerably differ between surgical conditions at these timepoints. However, CPCs exhibited elevated vascular clearance and proteolytic fragmentation in inflammatory conditions. CPCs did not increase macrophage abundance, cytokine expression, or alter tissue morphology.
CONCLUSION: CPCs target the deep layers of cartilage, even in inflamed joints, and can be utilized to substantially improve intra-joint bioavailability of therapeutics.