Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging.
OBJECTIVE
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.


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.


CONCLUSIONS
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
Brad P
BP
Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Johns Hopkins University School of Medicine, 720 Rutland Ave, 217 Traylor, Baltimore, MD 21205, USA.
Ruiz-Cabello
Jesús
J
Hota
Partha
P
Liddell
Robert
R
Walczak
Piotr
P
Howland
Valerie
V
Chacko
Vadappuram P
VP
Kraitchman
Dara L
DL
Arepally
Aravind
A
Bulte
Jeff W M
JW
D000464:Alginates / Q000494:pharmacology; D000818:Animals; D002214:Capsules / Q000494:pharmacology*; D003430:Cross-Sectional Studies; D005461:Fluorine; D005466:Fluorocarbons / Q000494:pharmacology*; D006801:Humans; D016381:Islets of Langerhans Transplantation; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D019047:Phantoms, Imaging; D012044:Regression Analysis; D013552:Swine; D014463:Ultrasonography / Q000379:methods; D055114:X-Ray Microtomography / Q000379:methods
D000464:Alginates; D002214:Capsules; D005466:Fluorocarbons; D005461:Fluorine