Summary
Objective
Blocking the interleukin-1 (IL-1) catabolic cascade following joint trauma can be
achieved using its receptor antagonist, IL-1Ra. However, its clinical translation
for osteoarthritis therapy has been unsuccessful due to its rapid joint clearance
and lack of targeting and penetration into deep cartilage layers at therapeutic concentrations.
Here, we target the high negative charge of cartilage aggrecan-glycosaminoglycans
(GAGs) by attaching cationic carriers to IL-1Ra. IL-1Ra was conjugated to the cartilage
targeting glycoprotein, Avidin, and a short length optimally charged cationic peptide
carrier (CPC+14). It is hypothesized that electro-diffusive transport and binding
properties of IL-1Ra-Avidin and IL-1Ra-CPC+14 will create intra-cartilage depots of
IL-1Ra, resulting in long-term suppression of IL-1 catabolism with only a single administration.
Design
IL-1Ra was conjugated to Avidin or CPC+14 using site specific maleimide linkers, and
confirmed using gel electrophoresis, high-performance liquid chromatography (HPLC),
and mass spectrometry. Intra-cartilage transport and retention of conjugates was compared
with native IL-1Ra. Attenuation of IL-1 catabolic signaling with one-time dose of
IL-1Ra-CPC+14 and IL-1Ra-Avidin was assessed over 16 days using IL-1α challenged bovine
cartilage and compared with unmodified IL-1Ra.
Results
Positively charged IL-1Ra penetrated through the full-thickness of cartilage, creating
a drug depot. A single dose of unmodified IL-1Ra was not sufficient to attenuate IL-1-induced
cartilage deterioration over 16 days. However, when delivered using Avidin, and to
a greater extent CPC+14, IL-1Ra significantly suppressed cytokine induced GAG loss
and nitrite release while improving cell metabolism and viability.
Conclusion
Charge-based cartilage targeting drug delivery systems hold promise as they can enable
long-term therapeutic benefit with only a single dose.
Keywords
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Article info
Publication history
Published online: February 03, 2023
Accepted:
January 17,
2023
Received:
July 28,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
