Wear particle-induced osteolysis is considered to be the major cause of aseptic implant loosening and clinical failure after total joint replacement. There is no FDA approved treatment for this devastating medical condition at present. Tofacitinib, a novel JAK inhibitor has already been proved by the FDA for adult patients with moderately to severely active RA who have had an inadequate response or intolerance to methotrexate. Recently, it was found that Tofacitinib could ameliorate wear particle-induced osteolysis when given orally in animal model. Its systemic side effects, however, may hamper the potential clinical translation of this novel therapy. To address this issue, Tofacitinib was conjugated to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer via a carbamate bond to form a macromolecular prodrug. We hypothesize that after endocytosis by inflammatory infiltrates at the lesion associated with wear particles, the prodrug will reside in the endosomal/lysosomal compartments, providing sustained-release of Tofacitinib as a drug depot. The free drug will then act in an autocrine/paracrine fashion to regulate the local inflammatory processes. The preliminary in vivo experiment showed that polymeric Tofacitinib prodrug could produce sustained inhibitory activity in the mouse calvarial osteolysis model, preventing wear particle induced osteolysis. This result suggests that the polymeric Tofacitinib prodrug we developed may have the potential to become a novel therapeutic intervention of peri-implant osteolysis and subsequent orthopaedic implant failure.

Development of polymeric prodrug of a Janus kinase (JAK) inhibitor for the improved treatment of particle-induced osteolysis associated with orthopaedic implant

248th National Meeting (2014)

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