In vivo imaging of insulin‐secreting human pancreatic ductal cells using MRI reporter gene technique: A feasibility study

Abstract

Purpose The purpose of this study was to investigate the feasibility of in vivo imaging of human pancreatic ductal cells by OATP1B3 reporter gene under MRI. Methods A human cell line (PANC‐1) derived from the pancreatic ductal epithelium was used in this study. After transduction of OATP1B3, the cellular physiological functions and the ability of intracellular uptake of the MRI contrast medium (Gd‐EOB‐DTPA) were examined. Induced differentiation of the PANC‐1 cells into hormone‐secreting cells were performed to simulate pancreatic β‐like cells. The hormone‐secreting cells were implanted into rats and in vivo MRI was evaluated. Results The mRNA and proteins of OATP1B3 were highly expressed. No significant change of cellular physiological functions was found after the expression. After induced differentiation, the hormone secretion capacities of the OATP1B3‐expressing PANC‐1 cells were confirmed. Intra‐cellular uptake of Gd‐EOB‐DTPA was determined in vitro by inductively coupled plasma mass spectrometry and MRI. In vivo MRI of the OATP1B3‐expressing xenograft revealed an increased signal intensity after contrast enhancement. Conclusion OATP1B3 can be used as a safe and feasible in vivo MRI gene reporter for human pancreatic ductal cells.

Utility of Hepatic Transporters as Multimodal Gene Reporters for Cell‐Based Medicine

“…OATP1B3 and NTCP also specifically uptake another clinically approved near infrared dye—Indocyanine green (ICG)—which exhibits a maximum Excitation/Emission (Ex/Em) at 780/830 nm. [ 13–15 ] ICG is used intra‐operatively to monitor cardiac output, liver function, and ophthalmic angiography. Furthermore, tumors expressing NTCP and OATP1B3 showed ICG uptake in nude mice, which could be monitored for up to 72 to 96 h after ICG injection.…”

Human Organic Anion Transporting Polypeptide 1B3 Applied as an MRI-Based Reporter Gene

“…Recent progress has been made using OATP1a1 from mouse and OATP1B3 from humans as gadoxetic aciddependent MRI-reporters (19)(20)(21)(22). But these studies have focused on the imaging in animals, and the viral vector delivery method used in these studies may be potentially unsafe for humans for the following reasons.…”

“…Consequently, the normal liver parenchyma is selectively enhanced at the hepatobiliary phase (18). A few groups have used either mouse OATP1a1 or human OATP1B3 as MRI gene reporters by transfecting target cells with viral vectors (19)(20)(21)(22).…”

A primer on contrast agents for magnetic resonance imaging of post‐procedural and follow‐up imaging of islet cell transplant

“…showed that the cellular uptake of a GBCA Gd-EOB-DTPA could be increased by inducing increased expression of an organic anion transportation peptide OATP1B3, and subsequently increase signal intensity on MR imaging. [39] While both approaches utilized cell labeling through culture and reliance on cellular uptake of GBCA, other approaches included encapsulation with Gd-bound or Gdcontaining microstructures as has also been demonstrated with other contrast agents; encapsulation with Gd-Gold microcapsules, Gd-containing alginate nanoparticles, and Gd-silica alginate nanoparticles have all been used. [40][41][42] These approaches have been shown to be associated with no adverse effects up to 4 weeks post-implantation.…”

“…As discussed earlier, multiple groups have separately demonstrated the ability to prolong transplanted islet cell function by manipulating the size and structure of alginate capsules upon which islet cells are loaded prior to transplant. [39,42,68,75,[78][79][80][81] In 2011, Wang et al demonstrated an approach that involved synthesizing an MR-probe which consisted of a therapeutic siRNA in combination with magnetic iron oxide nanoparticles as a contrast agent. The therapeutic siRNA portion targeted the pro-apoptotic protein Caspase-3, and improved longevity of islets utilizing this method in animal studies.…”