title: Immunosuppressive nano-therapeutic micelles downregulate endothelial cell inflammation and immunogenicity.
abstract: In this study, we developed a stable, nontoxic novel micelle nanoparticle to attenuate responses of endothelial cell (EC) inflammation when subjected to oxidative stress, such as observed in organ transplantation. Targeted Rapamycin Micelles (TRaM) were synthesized using PEG-PE-amine and N-palmitoyl homocysteine (PHC) with further tailoring of the micelle using targeting peptides (cRGD) and labeling with far-red fluorescent dye for tracking during cellular uptake studies. Our results revealed that the TRaM was approximately 10 nm in diameter and underwent successful internalization in Human Umbilical Vein EC (HUVEC) lines. Uptake efficiency of TRaM nanoparticles was improved with the addition of a targeting moiety. In addition, our TRaM therapy was able to downregulate both mouse cardiac endothelial cell (MCEC) and HUVEC production and release of the pro-inflammatory cytokines, IL-6 and IL-8 in normal oxygen tension and hypoxic conditions. We were also able to demonstrate a dose-dependent uptake of TRaM therapy into biologic tissuesex vivo. Taken together, these data demonstrate the feasibility of targeted drug delivery in transplantation, which has the potential for conferring local immunosuppressive effects without systemic consequences while also dampening endothelial cell injury responses.
authors.affiliation: Department of Surgery, Division of Transplant, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. ; Tel: 01 843 792 8596; nadigsn@musc.edu.|Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA. ; Tel: 01 843 792 1716; atkinsoc@musc.edu.|South Carolina Investigators in Transplantation (SCIT), Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. ; Tel: 01 843 792 3553; nadigsn@musc.edu.
authors.forename: Satish N
authors.initials: SN
authors.lastname: Nadig
authors.affiliation: Department of Radiology & Radiological Science, Medical University of South Carolina, 68 President Street MSC 120, Charleston, SC 29425, USA. ; Tel: 01 843 876 2481; broomea@musc.edu.|Center for Biomedical Imaging (CBI), Medical University of South Carolina, 68 President Street MSC 120, Charleston, SC 29425, USA. ; Tel: 01 843 876 2481; broomea@musc.edu.
authors.forename: Suraj K
authors.initials: SK
authors.lastname: Dixit
authors.affiliation: Department of Surgery, Division of Transplant, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. ; Tel: 01 843 792 8596; nadigsn@musc.edu.
authors.forename: Natalie
authors.initials: N
authors.lastname: Levey
authors.affiliation: Department of Surgery, Division of Transplant, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. ; Tel: 01 843 792 8596; nadigsn@musc.edu.
authors.forename: Scott
authors.initials: S
authors.lastname: Esckilsen
authors.affiliation: Department of Radiology & Radiological Science, Medical University of South Carolina, 68 President Street MSC 120, Charleston, SC 29425, USA. ; Tel: 01 843 876 2481; broomea@musc.edu.|Center for Biomedical Imaging (CBI), Medical University of South Carolina, 68 President Street MSC 120, Charleston, SC 29425, USA. ; Tel: 01 843 876 2481; broomea@musc.edu.
authors.forename: Kayla
authors.initials: K
authors.lastname: Miller
authors.affiliation: Department of Surgery, Division of Transplant, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. ; Tel: 01 843 792 8596; nadigsn@musc.edu.
authors.forename: William
authors.initials: W
authors.lastname: Dennis
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA. ; Tel: 01 843 792 1716; atkinsoc@musc.edu.|South Carolina Investigators in Transplantation (SCIT), Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. ; Tel: 01 843 792 3553; nadigsn@musc.edu.
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.affiliation: Department of Radiology & Radiological Science, Medical University of South Carolina, 68 President Street MSC 120, Charleston, SC 29425, USA. ; Tel: 01 843 876 2481; broomea@musc.edu.|Center for Biomedical Imaging (CBI), Medical University of South Carolina, 68 President Street MSC 120, Charleston, SC 29425, USA. ; Tel: 01 843 876 2481; broomea@musc.edu.|South Carolina Investigators in Transplantation (SCIT), Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA. ; Tel: 01 843 792 3553; nadigsn@musc.edu.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Broome