Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging.
PURPOSE: To develop novel immunoprotective alginate microcapsule formulations containing perfluorocarbons (PFCs) that may increase cell function, provide immunoprotection for xenografted cells, and simultaneously enable multimodality imaging. MATERIALS AND METHODS: All animal experiments were approved by an Institutional Animal Care and Use Committee. Cadaveric human islet cells were encapsulated with alginate, poly-l-lysine, and perfluorooctyl bromide (PFOB) or perfluoropolyether (PFPE). In vitro viability and the glucose-stimulation index for insulin were determined over the course of 2 weeks and analyzed by using a cross-sectional time series regression model. The sensitivity of multimodality (computed tomography [CT], ultrasonography [US], and fluorine 19 [(19)F] magnetic resonance [MR] imaging) detection was determined for fluorocapsules embedded in gel phantoms. C57BL/6 mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) islet-containing fluorocapsules and control mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) fluorocapsules without islets were monitored for human C-peptide (insulin) secretion during a period of 55 days. Mice underwent (19)F MR imaging at 9.4 T and micro-CT. Swine (n = 2) receiving 9000 PFOB capsules through renal artery catheterization were imaged with a clinical multidetector CT scanner. Signal intensity was evaluated by using a paired t test. RESULTS: Compared with nonfluorinated alginate microcapsules, PFOB fluorocapsules increased insulin secretion of encapsulated human islets, with values up to 18.5% (3.78 vs 3.19) at 8-mmol/L glucose concentration after 7 days in culture (P < .001). After placement of the immunoprotected encapsulated cells into mice, a sustained insulin release was achieved with human C-peptide levels of 19.1 pmol/L ± 0.9 (standard deviation) and 33.0 pmol/L ± 1.0 for PFPE and PFOB capsules, respectively. Fluorocapsules were readily visualized with (19)F MR imaging, US imaging, and CT with research- and clinical-grade imagers for all modalities. CONCLUSION: Fluorocapsules enhance glucose responsiveness and insulin secretion in vitro, enable long-term insulin secretion by xenografted islet cells in vivo, and represent a novel contrast agent platform for multimodality imaging.
Barnett, BP; Ruiz-Cabello, J; Hota, P; Liddell, R; Walczak, P; Howland, V; Chacko, VP; Kraitchman, DL; Arepally, A; Bulte, JWM
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