Trimodal Gadolinium-Gold Microcapsules Containing Pancreatic Islet Cells Restore Normoglycemia in Diabetic Mice and Can Be Tracked by Using US, CT, and Positive-Contrast MR Imaging

Abstract

Purpose:To develop microcapsules that immunoprotect pancreatic islet cells for treatment of type I diabetes and enable multimodal cellular imaging of transplanted islet cells. Materials and Methods:All animal experiments were approved by the institutional animal care and use committee. Gold nanoparticles functionalized with DTDTPA (dithiolated diethylenetriaminepentaacetic acid):gadolinium chelates (GG) were coencapsulated with pancreatic islet cells by using protamine sulfate as a clinical-grade alginate cross linker. Conventional poly-Llysine-cross-linked microcapsules and unencapsulated islets were included as controls. The viability and glucose responsiveness of islet cells were assessed in vitro, and in vivo insulin (C-peptide) secretion was monitored for 6 weeks in (streptozotocin-induced) diabetic mice with ( n = 7) or without ( n = 8) intraabdominally engrafted islet cells. Five nondiabetic mice were included as controls. Differences between samples were calculated by using a nonparametric Wilcoxon Mann-Whitney method. To adjust for multiple comparisons, a signifi cance level of P , .01 was chosen. Generalized estimating equations were used to model cell function over time. Three mice with engrafted capsules were imaged in vivo with high-fi eld-strength (9.4-T) magnetic resonance (MR) imaging, micro-computed tomography (CT), and 40-MHz ultrasonography (US). Results:Encapsulated human pancreatic islets were functional in vitro for at least 2 weeks after encapsulation. Blood glucose levels in the diabetic mice transplanted with GG-labeled encapsulated mouse b TC6 insulinoma cells returned to normal within 1 week after transplantation, and normoglycemia was sustained for at least 6 weeks without the use of immunosuppressive drugs. GG microcapsules could be readily visualized with positive-contrast high-fi eld-strength MR imaging, micro-CT, and US both in vitro and in vivo. Conclusion:Cell encapsulation with GG provides a means of trimodal noninvasive tracking of engrafted cells.

Clinical imaging in regenerative medicine

“…Gadolinium chelates used in MRI have potential disadvantages, including risk of nephrogenic systemic fibrosis in patients with renal insufficiency 113 and obscuring of the imaging signal in patients with hemosiderosis 114 . Instead, fluorine-19 MRI of perfluorocarbon-labeled islets appears to be a more promising approach because of lack of toxicity and the absence of background fluorine-19 signal in tissues 115, 116, 117 .…”

Imaging of Hydrogel Microsphere Structure and Foreign Body Response Based on Endogenous X-Ray Phase Contrast

“…Magnetic resonance imaging (MRI), absorption-based X-ray CT, and ultrasound (US) imaging may enable identification of cell/graft location either alone or in combination. [55][56][57][58][59][60][61] To enhance image contrast, an additional agent is often incorporated within the cells or the alginate microbeads. Contrast agents that have been explored include iron oxide nanoparticles, 55,58,61 gold nanoparticles, 55,61 and perfluorocarbon (PFC) nanoparticles.…”

Gold Nanoparticles as X-Ray, CT, and Multimodal Imaging Contrast Agents: Formulation, Targeting, and Methodology

“…The capsule allowed the pancreatic cells to maintain normal glucose levels for 6-7 weeks when injected into diabetic mice. Particles were tracked using CT and US [132]. The previously mentioned study by Zhang used a silica shell rather than a carbon-based one but it was still able to achieve an acceptable signal due to the nonlinear scattering caused by the embedded gold and manganese oxide particles [125].…”