Fibroblast Growth Factor 7 Releasing Particles Enhance Islet Engraftment and Improve Metabolic Control Following Islet Transplantation in Mice with Diabetes

Abstract

Transplantation of islets in Type 1 diabetes is limited by poor islet engraftment into the liver, with 2-3 donor pancreases required per recipient. We aimed to condition the liver to enhance islet engraftment to improve long-term graft function. Diabetic mice received a non-curative islet transplant (n=400 islets) via the hepatic portal vein (HPV) with Fibroblast Growth Factor 7 loaded galactoslyated poly(DL-lactide-co-glycolic acid) (FGF7-GAL-PLGA) particles; 26μm diameter particles specifically targeted the liver, promoting hepatocyte proliferation in short-term experiments: in mice receiving 0.1mg FGF7-GAL-PLGA particles (60ng FGF7) versus vehicle, cell proliferation was induced specifically in the liver with greater efficacy and specificity than subcutaneous FGF7 (1.25mg/kg ×2 doses; ~75μg FGF7). Numbers of engrafted islets and vascularisation were greater in liver sections of mice receiving islets and FGF7-GAL-PLGA particles versus mice receiving islets alone, 72 hours post-transplant. More mice (6 out of 8) that received islets and FGF7-GAL-PLGA particles normalised blood glucose concentrations by 30- days post-transplantation, versus 0 of 8 mice receiving islets alone with no evidence of increased proliferation of cells within the liver at this stage and normal liver function tests. This work shows liver targeted FGF7-GAL-PLGA particles achieve selective FGF7 delivery to the liver promoting islet engraftment to help normalise blood glucose levels with a good safety profile.

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open access article

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Citation

Salamah, M.A., Qutachi, O., Starkey Lewis, P.J., Bond, A., Noble, J., Burgoyne, P., Morton, N., Carter, R., Mann, J., Ferreira-Gonzales, S., Alvarez-Paino, M., Forbes, S.J., Shakesheff, K.M., Forbes, S. (2021) Fibroblast Growth Factor 7 Releasing Particles Enhance Islet Engraftment and Improve Metabolic Control Following Islet Transplantation in Mice with Diabetes. American Journal of Transplantation, 21, 9, pp 2950-2963

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Research Institute

Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)