Bioengineering localized and controlled drug delivery to actuate Enhanced Costimulation Blockade and promote long-term transplant survival

Abstract We recently demonstrated that a transient daily administration of the Jak-inhibitor Tofacitinib (Tofa) combined with CTLA4-Ig exerts what we call “enhanced costimulation blockade” and promotes long-term transplant survival in a mouse heart transplant model. To minimize the systemic exposure to Tofa and maximize its immune-modulatory effect, we explored two innovative drug delivery methods: a peptide-based hydrogel (Tofa-Hydro), and solid lipid nanoparticles (Tofa-SLN). Tofa-Hydro is a safe injectable hydrogel. A one-time application of Tofa-Hydro in the area surrounding the transplanted heart (combined with systemic CTLA4-Ig) rendered long-term graft survival (MST=127d Vs ‘CTLA4-Ig only’ MST=36, P<0.05). Importantly, application of Tofa-Hydro to a distal site ablated this synergistic improvement of survival, demonstrating the importance of the site of delivery. Tofa-SLN showed the unique property of accumulating in the lymphatics, reaching draining lymphoid tissues, and being taken up by immune cells. Tofa-SLN-conditioned dendritic cells were profoundly inhibited in their maturative response to LPS. These cells were less stimulatory for alloreactive T-cell and worked in concert with CTLA4-Ig to minimize T cell activation. Our results highlight two promising strategies for controlled and localized immune modulation. Injectable hydrogels allow a sustained localized delivery that requires a fraction of the dose of Tofa required when delivered systemic. Tofa-SLN can be passively directed to lymphoid tissues and effectively target and modulate antigen presenting cells. Overall, these strategies can maximize the immunomodulatory impact of Tofa while minimizing its toxic side-effects.