Nanotechnology Core C

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

Nanotechnology (Core C) Summary A major unmet medical need to improve long-term organ transplant outcomes is the development of safer and more effective immunosuppressive regimens. One such approach is the design of innovative nanodelivery platforms that release immune therapeutics within specific immune cell types or graft tissue sites, with controlled release over time. Our Core team has formulated first-in-class nanotherapeutics, from a diverse range of small molecules (CNI, rapamycin, and mycophenolate mofetil) to mAbs, including anti-IL-6, with the ultimate goal of promoting transplant tolerance. We have also extensively worked around various conjugation strategies to decorate the surface of nanoparticles (NPs) with Abs and peptides to achieve targeted delivery. Targeted drug delivery has already entered clinical practice for various diseases, nonetheless, the vast majority of these efforts have been devoted to cancer. This technology has not yet been applied in clinical transplantation. Amongst virtually all clinical disorders where nanodelivery is being tested, transplantation remains unique, where the organ can be accessed directly by perfusion of the graft with nanotherapeutics. Our hypothesis is that nanodelivery of specific therapeutics, i.e, the mechanistic target of rapamycin inhibitor (TORi) rapamycin directly to dendritic cells in situ using anti-DEC205 (Project 1), or anti-IL-6 systemically or directly to the graft (Project 2) will promote immune regulation and consequently extend renal allograft survival/allow immunosuppressive drug (IS) withdrawal in NHP. Our Specific Aims are 1) to characterize and synthesize nanocarriers of anti- rhesus IL-6 and rapamycin, and 2) to conjugate the surface of NP with anti-DEC205 mAb (to target DCs specifically). The Core will function to fulfil its Specific Aims as a critical component of a collaborative multidisciplinary team, to synthesize, validate and provide sufficient quantities of essential NP to both Projects, including NPs labeled with various fluorophores to study NP distribution kinetics and cell/tissue trafficking. The Core will interact with both the Administrative Core (Core A) and the Transplant Pathology and Tissue Imaging Core (Core B). The Core Leader (Dr Abdi) will participate in scheduled meetings of the P01, as detailed in Core A. If successful, our paradigm-shifting nanotechnology delivery platform will have a high impact on the design of strategies to extend graft survival /allow IS withdrawal.