Sung Woo Hong

Surface modification of pancreatic islets using heparin-DOPA conjugate and anti-CD154 mAb for the prolonged survival of intrahepatic transplanted islets in a xenograft model

This study proposes a combination method of using 3,4-dihydorxy-l-phenylalanine (DOPA) conjugated heparin (heparin-DOPA) and a low dose of anti-CD154 monoclonal antibody (MR-1) treatment to improve the survival time of intrahepatic islet xenograft. To inhibit instant blood mediated inflammatory reactions, heparin-DOPA was directly grafted to the pancreatic islet surface. The surface coverage of heparin-DOPA, the viability and functionality of heparin-DOPA grafted islets were evaluated. In addition, the combined effect of grafted heparin-DOPA and a low dose of MR-1 (a T-cell targeting immunosuppressive drug) on the survival of islet was evaluated in a xenograft model. Both unmodified islets and heparin-DOPA grafted islets were completely rejected within 2 weeks after intraportal transplantation. However, when 0.1 mg/mouse of MR-1 was administered (at day 0, 2, 4, 6 of transplantation) to 11 mice that had heparin-DOPA grafted islets transplanted to, seven out of the recipients maintained normoglycemia over 60 days. Therefore, we propose that a developed combinatory immunoprotection protocol of surface modification of pancreatic islets using heparin-DOPA with a low dose of MR-1 can be effective in prolonging the survival rate of transplanted islets in a xenograft model.

Drug Release Behavior of Poly(ε-caprolactone)-b-Poly(acrylic acid) Shell Crosslinked Micelles below the Critical Micelle Concentration

To explore the potential of shell crosslinked micelle (SCM) as a drug carrier, the drug release behavior of poly(ε-caprolactone)-b-poly(acrylic acid) (PCL-b-PAA) SCMs was investigated. PCL-b-PAA was synthesized by ring opening polymerization of ε-caprolactone and atom transfer radical polymerization oftert-butyl acrylate, followed by selective hydrolysis oftert-butyl ester groups to acrylic acid groups. The resulting amphiphilic polymer was used to prepare SCMs by crosslinking of PAA corona via amidation chemistry. The drug release behavior of the SCMs was studied, using pyrene as a model drug, and was compared with that of non-crosslinked micelles, especially below the critical micelle concentration (CMC). When the shell layers were crosslinked, the drug release behavior of the SCMs was successfully modulated at a controlled rate compared with that of the non-crosslinked micelles, which showed a burst release of drug within a short time.

Molecularly engineered islet cell clusters for diabetes mellitus treatment.

Pancreatic islet transplantation is a promising method for curing diabetes mellitus. We proposed in this study a molecularly engineered islet cell clusters (ICCs) that could overcome problems posed by islet transplantation circumstances and hosts immune reactions. A gene containing highly releasable exendin-4, an insulinotropic protein, was delivered into single islet cells to enhance glucose sensitivity; thereafter, the cells were reaggregated into small size ICCs. Then the surface of ICCs was modified with biocompatible poly(ethylene glycol)-lipid (PEG) (C18) for preventing immune reactions. The regimen of ICCs with low doses of anti-CD154 mAb and tacrolimus could effectively maintain the normal glucose level in diabetic mice. This molecularly engineered PEG-Sp-Ex-4 ICC regimen prevented cell death in transplantation site, partly through improving the regulation of glucose metabolism and by preventing hypoxia- and immune response-induced apoptosis. Application of this remedy is also potentially far-reaching; one would be to help overcome islet supply shortage due to the limited availability of pancreas donors and reduce the immunosuppressant regimens to eliminate their adverse effects.

Layer-by-layer building up of heparin and glycol chitosan for rat pancreatic islet xenotransplantation to mouse

AbstractImmunoprotective strategies are being developed to improve the graft survival rate of islets. Heparin, which has been widely used due to its anti-coagulant and anti-inflammatory effects, holds great promise for use in preventing blood coagulation and related immune reactions. In this study, the layer-by-layer modification of islets using heparin and glycol chitosan as an immunoprotective remedy was examined in xenogeneic islet transplantation. The surface coverage of heparin and glycol chitosan was evaluated in vitro. The viability and functionality of layer-by-layer modified islets was evaluated using the CCK-8 assay and glucose-stimulated insulin secretion (GSIS) test, respectively. In addition, the effect of layer-by-layer on immunoprotection for transplanted islets was evaluated in a diabetic mouse model. Layer-by-layer modified islets were evenly covered with heparin and glycol chitosan. The viability of islets was not affected by the modification procedures up to the third layer modification. In addition, unmodified and layer-by-layer modified (three layers) islets transplanted into the recipients maintained a normal level of blood glucose for 9.0±0.6 and 9.0±0.5 days, respectively. However, when the recipients were administrated with FK506 and CTLA4-Ig, the median survival time of the unmodified and layer-by-layer modified islets (three layers) were 17±1.2 and 23.0±1.3 days, respectively. These results demonstrated that the combination of FK506 and CTLA4-Ig along with layer-by-layer modification using heparin and glycol chitosan showed highly improved synergic effects on the inhibition of inflammation and immune reactions.