Nanotherapeutics for combined immunesuppression in organ transplantation
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DESCRIPTION (provided by applicant): Solid organ transplantation is an effective therapy for several end-stage diseases. Its success has been driven by the development of immune suppressive medications that impair the immune response to the transplant. To avoid transplant rejection, combinations of these medications must be taken regularly. However, these medications induce undesirable side effects, such as hypertension and diabetes, as well as increased susceptibility to opportunistic infections and cancer. The development of drug delivery platforms that effectively deliver combination immune suppressants while avoiding drug-induced side effects would be transformative for the solid organ transplant field. We hypothesize that co-encapsulation of the commonly employed immune suppressive medications rapamycin and mycophenolic acid into FDA- approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles will prolong allograft survival and avoid the toxic side effects of the soluble administered drugs. In addition, one of our recent studies demonstrated that nanoparticles encapsulated with mycophenolic acid target dendritic cells and induce the upregulation of PD-L1, a negative costimulatory ligand, on these cells. As soluble administered rapamycin is known to impair the upregulation of activating costimulatory ligands on dendritic cells, we also hypothesize that co- encapsulation of rapamycin and mycophenolic acid will induce a pro immune tolerant phenotype in dendritic cells and enhance the development of transplant tolerance. To investigate whether combined encapsulation of rapamycin and mycophenolic acid within nanoparticles prolongs allograft survival, avoids toxic drug side effects and enhances the development of transplant tolerance, we will employ experimental murine transplant models after proof-of-concept studies have been completed in vitro, and both agents have been optimized for NP drug delivery. We expect that the anticipated results of our study will lay the foundation to a ground-breaking clinical study to deliver combination immune suppressants to organ transplant recipients via nanoparticles, which would be transformative to the solid organ transplant field.
