Intracellular Vitamin D to Combat Instant Blood-Mediated Inflammatory Reaction - PROJECT/SUMMARY ABSTRACT The objective of this proposal is to assess a nanotherapeutic for the treatment of islet transplantation associated instant-blood-mediated inflammatory reaction (IBMIR). Islet transplantation is a promising treatment for patients with type 1 diabetes and late-stage chronic pancreatitis. Isolated islets are infused into the patient’s liver in a minimally invasive manner via the portal vein. The goal of this procedure is to restore normoglycemia. Unfortunately, the IBMIR occurs when the islets contact blood and activate oxidative, inflammatory, and coagulation pathways. The cumulative oxidative thrombo-inflammatory stress causes islet necrosis and apoptosis. As a result, 50-70% of the transplanted islets are lost within the first 24 hours following infusion, making achieving insulin independence extremely difficult. Previous strategies to combat IBMIR include the use of anti-thrombotic drugs, such as heparin, which increases bleeding risk, or low molecular weight dextran sulfate, which prevents cell aggregation, but fails to combat inflammation and cytokine secretion that ultimately kills the islets or requires islet surface modification that complicates cell processing. There is a need for a therapeutic that combats oxidation, inflammation, and thrombosis associated with IBMIR without inducing bleeding. Vitamin D (aVD; 1, 25-Dihydroxyvitamin D3) is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant activity and a powerful inhibitor of nuclear factor kappa B (NF-κB)-dependent inflammation and coagulation. aVD acts via interaction with the intracellular vitamin D receptor (VDR). However, VDR interaction can be limited, as hydrophobic aVD has poor bioavailability and membrane permeability, both of which limit therapeutic efficacy. Targeted aVD delivery is further complicated by the ubiquitous nature of VDR, which is present in almost every cell. The highly cell-type specific results of aVD-VDR interaction can cause adverse effects, including toxicity if the wrong cell population is treated. Vesicular polymeric nanocarriers (i.e. polymersomes, PS) encapsulating vitamin D3 (aVD-PS) were found to enhance intracellular delivery of aVD within antigen-presenting cells, reducing inflammatory markers, including CD80/86 and MHC II. PS can be infused with the islets or targeted to the site of transplantation (the liver) via intravenous injection. Here, this proposal will investigate aVD-PS’s biocompatibility with and ability to combat oxidative thrombo-inflammation associated with IBMIR for the preservation of islets. The mechanisms by which aVD-PS mitigates oxidative stress, thrombosis and inflammation will also be assessed. The following aims will be achieved: 1) Assess the biocompatibility of aVD-PS with human islets and the effect of aVD-PS on coagulation under IBMIR conditions. 2) Assess the ability of aVD-PS to mitigate IBMIR in a murine islet transplantation model.
