Graphene Oxide Functionalized Drug-Integrating Amphiphilic Nano-AssemblieS (GO-DIANAs) with High Potential Application in the Diabetes Treatment
Progetto Islet transplantation is a beta-cell replacement therapy used to treat patients with diabetes who lack the ability to secrete insulin, and it is currently performed only for patients with severe type 1 diabetes that suffer from hypoglycemia unawareness. In allogenic islet transplantation, up to 60% of islets are immediately lost following transplantation, due to inflammation from the instant blood-mediated inflammatory reaction (IBMIR). Furthermore, transplanted islets are targeted by the host immune attacks and systemic immunosuppression is needed to avoid rejection, which is a problem because it can lead to severe toxicity, and it impairs a subject`s ability to fend off infections. Therefore, we propose to develop a novel nanomaterial based immunotherapy to defend and nurish transplanted islets without using immunomodulatory drugs but using a combination of two nanomaterial platforms: our nanoparticles, known as Drug-Integrating Amphiphilic Nano-Assemblies (DIANAs) and 2D graphene-derived materials. DIANAs are made of poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) nanomicelles (nMIC) and/or poly(ethylene glycol)-oligo(ethylene sulfide) (PEG-OES) nanofibrils (nFIB), and here they will be functionalized with graphene oxide (GO-DIANAs). Graphene related materials have been intensively studied for their properties, modifications, and application potential. Biomedical applications are one of the main directions of research in this field. In the last few years, the research results were obtained especially related to delivery systems, cell interactions and antimicrobial properties. GO derived materials also promote adhesion of proteins of the extracellular matrix and, therefore, cell proliferation. Here we will prepare and analyze GO-DIANA nanoparticles made from the new PEG-PPS-GO and PEG-OES-GO block copolymers, which can still self-assemble in nanomicelles and nanofibrils, respectively. Importantly, the new combined GO-DIANAs have shown to inhibit activated murine T cells proliferation in vitro without presence of immunosuppressant drugs. Therefore, based on the already demonstrated ability of nMIC and nFIB to target inflammation sites, our goal is to fabricate GO-DIANA nanoparticles that provide local sustained immune-therapies without administration of toxic drugs. Being already demonstrated that the nFIB DIANAs can be aggregated with islet cells and retained in the transplant site, while the nMIC DIANAs can accumulate in the inflammation site after systemic injection, we will fabricate nanofibril GO-DIANAs for pre-transplant treatment of islets (Aim1), and nanomicelle GO-DIANAs for passive targeting of islet transplant site (Aim2) to enhance b-cell functionality and survival in vitro and in vivo. We expect those treatments to reduce or eliminate the need of systemic immunomodulatory therapies. Should the treatment not be effective enough we will load the nMIC and nFIB GO-DIANAs with drugs that we already showed to be efficiently carried and slow released from regular nMIC and nFIB DIANAs (e.g. Rapamycin, Dexamethasone). Hence, focusing on islet transplantation for treatment of type 1 diabetes, our novel GO nanoparticle-based strategies will be evaluated in diabetic murine models of islet transplantation as adds-on to the pancreatic islets before implantation or as targeted treatment, but it can be optimized for all kinds of cell and organ transplantations.