Abstract
Type 1 diabetes (T1D) is characterized by immune-mediated destruction of insulin-producing beta cells resulting in severe hyperglycemia if untreated. Prior work has shown that islet microvasculature becomes hyperpermeable during presymptomatic T1D, allowing for ‘nanobubble (NB)’ submicron ultrasound contrast agents to accumulate in immune-infiltrated islets, which can be quantified using ultrasound contrast. We investigated the utility of these lipid-shelled NBs as peptide delivery vehicles to provide islet-targeted delivery, for acoustically driven therapeutic release and where therapeutic delivery can be visualized in real-time with ultrasound. We developed this platform to enhance efficacy of insulin peptide mimotopes, which can promote the expansion of anti-inflammatory regulatory T cells (Tregs) and prevent T1D in mice. We modified insulin B:9-23 peptides with a palmitoyl fatty acid tail to incorporate in the NB lipid shell. NBs accumulated specifically in NOD islets and not in other abdominal organs or NOD-SCID (control) islets (p < 0.0001). We found that palmitoylation enhanced peptide retention in NBs (p < 0.001) and is essential for delivery to NOD islets (p < 0.0001), where the extent of peptide delivery correlates with extent of insulitis (p < 0.05). Peptide incorporation did not affect NB echogenicity (in vitro and in vivo), ability to burst, and size distribution. Palmitoylation and incorporation in NBs does not affect the ability for peptide-pulsed antigen presenting cells to stimulate insulin-reactive T cells in vitro (p < 0.0001). Finally, NOD mice treated with peptide-NBs had a higher proportion of Tregs amongst insulin-reactive CD4+ T cells in islets, as compared to mice treated with NBs or peptide alone (p < 0.05). This serves as an important proof-of-principle for the usage of NBs for targeted peptide delivery and has the potential to improve therapeutic intervention in T1D. Disclosure M.Ciccaglione: None. K.Mcdaniel: None. A.W.Michels: Stock/Shareholder; Immnomolecular Therapeutics. A.A.Exner: None. R.K.Benninger: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102950, R01DK106412, P30DK116073, T32DK120520); National Center for Advancing Translational Sciences (TL1TR002533); JDRF (1-INO-2017-435-A-N); University of Colorado
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