Drug delivery in the anterior chamber of the eye for islet transplantation as a diabetic treatment
Date of Issue2018
Interdisciplinary Graduate School (IGS)
Transplantation of pancreatic islets restores β-cell mass, reduces exogenous insulin dependence and provides tight glycemic control for diabetic patients. However, the challenge of maintaining the functionality of grafted islets and preventing their mass loss in the long-term is yet to be addressed. A novel site Anterior Chamber of the Eye (ACE) is employed as potential clinical site of transplantation because islets transplanted easily engraft and re-vascularize well on the vessel-rich iris. In addition, it acts as a natural body window for non-invasive longitudinal studies of islets condition during the post-transplantation period. Grafted allogeneic islets, however, are subject to immune rejections. In mouse models, T-cells attack allograft islets and their mass gradually decreases to zero over 21 days post transplantation. To address the immune rejection locally, a microparticle drug delivery system that ensures sustained release of the immunosuppressive drug rapamycin inside ACE was developed. Rapamycin was encapsulated by microparticle formulations developed using biodegradable polymers of poly(lactic-co-glycolic acid) (PLGA), poly-L-lactide (PLLA) and polycaprolactone (PCL). These microparticles protected the encapsulated rapamycin from degradation. The investigation of in vitro release showed a mixture of two selected formulations at 1:1 ratio released rapamycin higher than the target rate for 30 days. The subsequent co-transplantation of rapamycin microparticles and islets to ACE was successfully performed on mice. These transplanted microparticles effectively delayed the rejection onset of islets grafts and prolong the grafted islets’ survival period significantly in comparison to controls. This project is the first few to transplant drug carriers into ACE and monitor islet interaction with microparticles in vivo. Building on the success of this model, a novel microparticle, Janus particle (JP), was proposed for encapsulating dual drugs, rapamycin and glibenclamide, to preserve islets grafts and stimulate insulin secretion, simultaneously. The challenge of drug-loaded JP fabrication was overcome after series investigations. The formation of drug-loaded JP can be defined thermodynamically that is strongly governed by the emulsion interfacial tensions in accordance with the classic equilibrium spreading coefficient. A mechanistic insight into the fabrication of drug-loaded JP was provided and laid the necessary foundation for dual drug loaded JP fabrication. In summary, the novel microparticles and novel approach of islet transplantation developed in this thesis would pave a path for an improved clinical treatment method for diabetes.