Abstract
Transplantation of pancreatic islets into subcutaneous, neovascularized devices is one of the possibilities explored as part of our search for a cure of diabetes. We have recently reported that syngeneic transplantation in a subcutaneous prevascularized device can restore euglycemia and sustain long-term function in rats and that explanted grafts showed preserved islets and intense vascular networks. Because all of the transplanted tissue is localized within the device, if such a bioartificial pancreas approach is used, localized immunosuppression might provide sufficient protection against rejection to achieve long-term function, while also avoiding the serious systemic side effects and the susceptibility for opportunistic infections that are commonly associated with systemic immunosuppressive therapies as only much smaller and localized doses are needed. Soft steroids are obvious candidates because soft drugs are specifically designed to produce targeted local activity, but no systemic side effects due to prompt metabolic (preferably extrahepatic, e.g., hydrolytic) inactivation. However, local concentrations that are effective for immunosuppression, but non-toxic to insulin-producing β-cells have to be found, and nontrivial difficulties related to long-term local deliverability have to be addressed. Here, we report preliminary results obtained using in vitro studies with human islets used to establish a tentative therapeutic concentration range together with fully scaled three-dimensional finite element method (FEM)-based Comsol multiphysics computational models that were used to explore various possibilities to achieve and maintain these concentration levels within the device.
| Original language | English |
|---|---|
| Pages (from-to) | 226-232 |
| Number of pages | 7 |
| Journal | Pharmazie |
| Volume | 63 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2008 |
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ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry
- Chemistry(all)
- Molecular Medicine
- Pharmacology
- Pharmaceutical Science
Cite this
Soft corticosteroids for local immunosuppression : Exploring the possibility for the use of loteprednol etabonate for islet transplantation. / Bocca, N.; Pileggi, A.; Molano, Ruth; Marzorati, S.; Wu, W.; Bodor, N.; Ricordi, Camillo; Buchwald, Peter.
In: Pharmazie, Vol. 63, No. 3, 01.03.2008, p. 226-232.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Soft corticosteroids for local immunosuppression
T2 - Exploring the possibility for the use of loteprednol etabonate for islet transplantation
AU - Bocca, N.
AU - Pileggi, A.
AU - Molano, Ruth
AU - Marzorati, S.
AU - Wu, W.
AU - Bodor, N.
AU - Ricordi, Camillo
AU - Buchwald, Peter
PY - 2008/3/1
Y1 - 2008/3/1
N2 - Transplantation of pancreatic islets into subcutaneous, neovascularized devices is one of the possibilities explored as part of our search for a cure of diabetes. We have recently reported that syngeneic transplantation in a subcutaneous prevascularized device can restore euglycemia and sustain long-term function in rats and that explanted grafts showed preserved islets and intense vascular networks. Because all of the transplanted tissue is localized within the device, if such a bioartificial pancreas approach is used, localized immunosuppression might provide sufficient protection against rejection to achieve long-term function, while also avoiding the serious systemic side effects and the susceptibility for opportunistic infections that are commonly associated with systemic immunosuppressive therapies as only much smaller and localized doses are needed. Soft steroids are obvious candidates because soft drugs are specifically designed to produce targeted local activity, but no systemic side effects due to prompt metabolic (preferably extrahepatic, e.g., hydrolytic) inactivation. However, local concentrations that are effective for immunosuppression, but non-toxic to insulin-producing β-cells have to be found, and nontrivial difficulties related to long-term local deliverability have to be addressed. Here, we report preliminary results obtained using in vitro studies with human islets used to establish a tentative therapeutic concentration range together with fully scaled three-dimensional finite element method (FEM)-based Comsol multiphysics computational models that were used to explore various possibilities to achieve and maintain these concentration levels within the device.
AB - Transplantation of pancreatic islets into subcutaneous, neovascularized devices is one of the possibilities explored as part of our search for a cure of diabetes. We have recently reported that syngeneic transplantation in a subcutaneous prevascularized device can restore euglycemia and sustain long-term function in rats and that explanted grafts showed preserved islets and intense vascular networks. Because all of the transplanted tissue is localized within the device, if such a bioartificial pancreas approach is used, localized immunosuppression might provide sufficient protection against rejection to achieve long-term function, while also avoiding the serious systemic side effects and the susceptibility for opportunistic infections that are commonly associated with systemic immunosuppressive therapies as only much smaller and localized doses are needed. Soft steroids are obvious candidates because soft drugs are specifically designed to produce targeted local activity, but no systemic side effects due to prompt metabolic (preferably extrahepatic, e.g., hydrolytic) inactivation. However, local concentrations that are effective for immunosuppression, but non-toxic to insulin-producing β-cells have to be found, and nontrivial difficulties related to long-term local deliverability have to be addressed. Here, we report preliminary results obtained using in vitro studies with human islets used to establish a tentative therapeutic concentration range together with fully scaled three-dimensional finite element method (FEM)-based Comsol multiphysics computational models that were used to explore various possibilities to achieve and maintain these concentration levels within the device.
UR - http://www.scopus.com/inward/record.url?scp=41349115062&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41349115062&partnerID=8YFLogxK
U2 - 10.1691/ph.2008.7774
DO - 10.1691/ph.2008.7774
M3 - Article
C2 - 18444512
AN - SCOPUS:41349115062
VL - 63
SP - 226
EP - 232
JO - Die Pharmazie
JF - Die Pharmazie
SN - 0031-7144
IS - 3
ER -