Adalimumab-polyelectrolyte nanocomplexes decelerate synovial drug clearance ex vivo

Intra-articular injections of biologicals, such as the TNF-α antibody adalimumab, can provide a locally concentrated and more effective therapy for osteoarthritis, with much less systemic side effects. These, however, suffer from an insufficient residence time in the joint cavity due to rapid elimination across the synovial membrane. The extracellular matrix of the synovium consists of a collagen network with enmeshed aggrecan galactosamine glycans, generating a high fixed negative charge density. This unique property can be exploited to design drug delivery systems that allow an extended residence time and thus action of the biological cargo in the joint. Here, we have demonstrated that by linking adalimumab to different molar equivalents of cationic diethylaminoethyl-dextran using avidin-mediated nanocomplexation, the flux of the antibody through porcine synovium could be decelerated from 53.3 ± 15.4 to 14.3 ± 7.2 pmol cm^-2 h^-1. Concurringly, using confocal laser scanning microscopy, immobilization of the complex in superficial tissue layers of the synovium was shown. The prepared nanocomplexes exhibited excellent intra-tissue stability, while retaining up to 84.4 ± 3.6% target recognition compared to free adalimumab. The nanocomplexes showed no significant toxicity for the synovial cells, maintaining a tissue viability of 86.7 ± 10.4% compared to treatment with adalimumab alone. Cell culture experiments revealed that compared to pure adalimumab, the nanocomplexes could suppress TNF-α and downregulate NF-κB at significantly lower concentrations (10 µg mL^-1vs. 300 µg mL^-1). This work highlights how electrostatic-driven material-tissue interactions can be exploited by avidin-biotin-linked cationic nanocomplexes to slow the ex vivo permeation of a protein drug across the synovial membrane without limiting the antibody's functionality.