The Synthesis of a Charge-Based Conjugation System to Extend the Intra-Articular Resident Time of Osteoarthritis Therapeutics

Abstract

Osteoarthritis (OA) is a chronic inflammatory disease that affects the synovial joint structure, and there is no medication that can reduce or prevent the disease's development. The main obstacles for drugs that can slow the disease progression are penetrating the condensed cartilage network, retaining within the cartilage, and remaining within the synovial joint due to the continuous exchange of the synovial fluid. Therefore, various techniques and mechanisms of drug delivery systems have been investigated to increase the time of OA therapeutics inside the synovial joint. One of these strategies is the use of cationic delivery systems to be interacted electrostatically with the anionic cartilage components (proteoglycans and glycosaminoglycans), which will attach the carrier to the cartilage, assisting the drug to infiltrate through and retain within the cartilage as well as avoiding drug elimination during the synovial fluid exchange. In the current study, three cationic polymers, A5, A16, and A87, were chosen from the library of poly beta-amino polymers to be covalently conjugated to OA therapeutic (licofelone) in order to enhance the uptake and retention time of the drug within two ex-vivo cartilage models. Furthermore, the licofelone conjugated to A5, A16, and A87 has shown a significant increase in drug uptake and retention time inside the healthy and early simulated OA cartilage model compared to the licofelone alone. The A87-licofelone conjugate showed the highest uptake percentage of the conjugated licofelone in healthy cartilage (44 ± 4.3 % at 30 minutes) and in the OA model (26.6 ± 3.1 % at 25 minutes), while in both models, the unconjugated licofelone maximum uptake percentages were 1.4 ± 0.6 % and 1.7 ± 0.6 % at 30 minutes, respectively. Factors such as the quantity of the cartilage content, the degree of the positive charge, the intensity of the electrostatic interaction, and the quantity of licofelone conjugated to the polymers have influenced the percentage of conjugated licofelone within the cartilage. Moreover, the A87-licofelone conjugate showed no effect on the chondrocyte viability compared to untreated cells. The conjugation of licofelone to A87 has increased the uptake and retention of the drug without affecting its chemical structure and cytocompatibility.