While the transplantation of cellular material such as islets and hepatocytes shows significant clinical promise, a substantial portion of the cellular material does not survive the first 48 hours post-transplant, in a large part due to an acute inflammatory response. We have previously demonstrated the benefit of the sustained localized delivery of the anti-inflammatory drug TAK-242 (Resatorvid) in a murine islet transplant model, where the cellular material was modified via an ex vivo surface conjugation with a slow-releasing prodrug prior to implantation. While this drug delivery method did significantly improve islet transplant outcomes, the linker design was not ideal for the delivery of TAK-242 as the prodrug release was complicated by a competing decomposition of the active drug. As such, we have recently explored two prodrugs that incorporate a self-immolative spacer between the β-eliminative trigger and drug, thus separating the labile TAK-242 sulfonamide from the electron-withdrawing carbamate trigger. The addition of these spacers creates a two-stage release mechanism that can be modulated to provide a range of half-lives, while also leading to more complex kinetics. This presentation will describe the synthesis of two classes of TAK-242 prodrugs, studies of the drug release kinetics, and preliminary experiments exploring their application in hepatocyte transplantation.

Synthesis and characterization of improved β-eliminative linkers for the bioconjugation and sustained release of TAK-242 (resatorvid)

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