Development of Cartilage Penetrating Dendrimer for Osteoarthritis Treatment

Introduction:: Osteoarthritis is a disease characterized by degeneration of articular cartilage which leads to pain as well as decrease in mobility. It is estimated that 20 ~ 30 million people in the United States suffer from osteoarthritis and the economic cost is estimated to be about $60 billion per year. Although there have been prior efforts to address this disease, there is no FDA approved disease-modifying osteoarthritis drug to date. One of the major challenges is the fast clearance of the therapeutics when injected into the joint space. Therefore, there is a demand for new technology that can achieve both targeted delivery and enhanced retention in the joint cartilage.

Materials and Methods:: Cationic dendrimers conjugated with therapeutic proteins were designed which allows them to penetrate the negatively charged cartilage matrix and have sustained affect. Insulin-like growth factor-1 (IGF1) and IL-1 receptor antagonist (IL1RA) were used as anabolic and anti-catabolic therapeutic respectively, and polyamidoamine (PAMAM) was used as the cationic dendrimer. The PEGylated PAMAM was functionalized with DBCO and proteins were functionalized with azide. The final formulations (dend-IGF1, dend-IL1RA) were synthesized by DBCO-azide click chemistry. Preservation of bioactivities of the final formulations was tested in vitro and ex vivo. Pharmacokinetics were tested by intra-articularly injecting fluorescently labelled formulations and monitoring the retention using IVIS. The therapeutic efficacy was tested on a post-traumatic osteoarthritis rat model. Disease progression was assessed using pain measurements, computerized tomography (CT) scan, and histology evaluation.

Results, Conclusions, and Discussions:: Dend-IGF1 significantly increased cell proliferation and dend-IL1RA significantly inhibited IL-1 activity in vitro. In bovine cartilage explant ex vivo experiment, dend-IGF1 increased glycosaminoglycan synthesis and dend-IL1RA inhibited glycosaminoglycan loss. The half-lives of the dendrimer formulations in vivo were 7 times longer than their free-protein counterparts. Both of the formulations showed improved outcome in CT and histology evaluation, but only dend-IL1RA showed significant improvement in pain management.

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