Cationic Dendrimer Nanoformulation Improves Therapeutic Efficacy of Pro-Anabolic and Anti-Catabolic Therapeutics in Osteoarthritis

Abstract Purpose Osteoarthritis (OA) is a debilitating disease characterized by degeneration of articular cartilage with no clinically approved treatment available to date despite the multitude of approaches that have been proposed. Two fundamentally different therapeutic strategies are pro-anabolic and anti-catabolic treatments. However, one of the major challenges to developing a successful intervention for OA is the fast clearance of the therapeutics from the joint space, which makes evaluating these proposed strategies difficult. In this work, we utilize a modular cationic dendrimer nanoformulation conjugated with therapeutic proteins which grants them longer retention in joint space and makes comparison of the approaches possible. Methods Dendrimer conjugated with insulin-like growth factor-1 (dend-IGF1) and interleukin-1 receptor antagonist (dend-IL1RA) were used as representative pro-anabolic and anti-catabolic therapeutics, respectively. Preservation of bioactivity of the final formulations was tested in vitro and ex vivo , and the therapeutic efficacy was tested in vivo in a post-traumatic OA model in rats. Results Studies in a rat model revealed that both therapeutics when conjugated to the dendrimers show improved pharmacokinetics and inhibited OA progression in vivo . Furthermore, dend-IL1RA showed significant efficacy in pain mitigation as well. This work supports the concept that dendrimer-protein conjugates provided an extended half-life within cartilage tissue that can greatly enhance the treatment efficacy of different types of biologic treatments. Conclusion Therefore, not only do the formulations studied in this work present promising avenues for OA treatment, but they also open up the possibility of exploring other therapeutics to treat anionic avascular tissues, such as meniscus or cornea, using this platform technology. Lay Summary More than 650 million people worldwide suffer from osteoarthritis (OA), but unfortunately, there is no clinically approved treatment, and the only standard of care is pain management. Although there are two leading mechanisms of treatment that can be used, one being using pro-anabolic drugs to repair cartilages and the other one being using anti-catabolic drugs that prevents cartilage degradation, these drugs get rapidly cleared from the knee joints after injection. Therefore, in this study, we attached insulin-like growth factor-1 (IGF-1) which is a pro-anabolic drug and interleukin-1 receptor antagonist (IL-1RA) which is an anti-catabolic drug to a positively charged polymer that can stick to the cartilage via charge-charge interaction to prevent these drugs from being rapidly cleared. Our findings reveal that by doing so, the drugs were able to stay within the joint space longer and was able to delay OA progression. Especially, IL-1RA – polymer conjugate was able to significantly reduce pain as well.