1. Theranostic molecular imaging of islet transplantation for type 1 diabetes
Type 1 diabetes (T1D) results from destruction of insulin-producing pancreatic beta cells by autoimmunity. Pancreatic islet transplantation (Tx) has recently emerged as a clinical modality to achieve normoglycemia in T1D patients. In spite of some success, there are still two major problems: inability to monitor islet grafts non-invasively and graft failure due to islet damage. Therefore, it is critical to establish a non-invasive method to monitor the fate of islets directly in a clinical setting. We have previously shown that pancreatic islets can be labeled using dextran coated iron oxide nanoparticles and monitored after Tx under the kidney capsule and in the liver using magnetic resonance imaging (MRI) both in small animals and in non-human primates.
Further than that, we deliver nucleic therapeutics concurrent with the nanoparticles and label islets prior to transplantation. So far, we have used small interfering RNA targeted caspase-3 (to protect islets from apoptosis) and beta 2 microglobulin (B2M), one of the major components involved in immune rejection by T cells (to protect islet from immune rejection) in small animals, and large animals’ experiments are ongoing.
2. Endogenous pancreatic beta-cells drug delivery
Treatment of T1D is hampered in part by inefficient drug delivery to insulin producing islet beta-cells. We have developed a new iron oxide-based magnetic nanoparticle conjugated to exendin-4 (which is a targeting ligand for pancreatic islet beta-cells) for MR imaging of pancreatic beta-cells. The results of our study demonstrate preferential uptake of exendin-4 conjugated nanoparticles by a beta-cell cell line in vitro and by pancreatic beta-cells in vivo after intravenous injection. Furthermore, accumulation of this beta-cells targeting probes in the pancreas of diabetic animals was significantly reduced compared with healthy control, as reflected by the changes of transverse relaxation time on in vivo MRIs due to reduced beta-cell mass in these animals.
We also have tested intra-pancreatic ductal nanoparticles delivery to endogenous islet cells and monitored using MRI. We expect to utilize this exendin-4 conjugated nanoparticles as a nanodrug delivery vehicle, together with this intra-pancreatic ductal injection as a selective nanodrug delivery pathway, which could aid in development of personalized therapeutic intervention strategies for T1D.
3. Stem cell transplantation for type 1 diabetes therapy
Stem cell differentiation technology has greatly advanced in recent years. In vitro differentiation protocols that convert pluripotent stem cells into pancreatic β-cells have been developed. Studies that have recently advanced to Phase I trials successfully demonstrate application of human embryonic stem cell (hESC)-derived pancreatic progenitors for restoring normoglycemia of T1D patients. We have differentiated human iPSCs -L1(iPSC) derived from healthy human fibroblasts using a sendai virus into Stem cell derived β-cells (SC-β-cells). We propose to further sort these differentiated SC-β-cells and label them with theranostic iron oxide nanoparticles for in vivo test. These grafts cells will be monitored with a novel imaging modality: magnetic particle imaging.