title: Polylactide-cyclosporin A nanoparticles for targeted immunosuppression.
abstract: Polymeric nanoparticles (NPs), prepared via coprecipitation of drugs and polymers, are promising drug delivery vehicles for treating diseases with improved efficacy and reduced toxicity. Here, we report an unprecedented strategy for preparing polylactide-cyclosporine A (PLA-CsA) NPs (termed CsA-NPs) through CsA-initiated ring-opening polymerization of lactide (LA) followed by nanoprecipitation. The resulting CsA-NPs have sub-100 nm sizes and narrow particle size distributions, and release CsA in a sustained manner without a "burst"-release effect. Both free CsA and CsA-NPs displayed comparable suppression of T-cell proliferation and production of inflammatory cytokines in various T-cell assays in a dose-dependent manner. The IC(50) values for CsA and CsA-NPs were 27.5 and 72.0 ng/ml, respectively. As lymph nodes are the main loci for T-cell activation, we coupled dendritic cells (DCs) with CsA-NPs and successfully delivered CsA selectively to the lymph nodes. Our studies indicated that CsA-NPs could be internalized in the DCs with a sustained release of CsA to the culture medium, suppressing alloreactive T-cell proliferation. Allogeneic DCs loaded with CsA-NPs were able to migrate to the draining lymph nodes where the T-cell priming was significantly reduced without any systemic release. This innovative nanoparticulate CsA delivery technology constitutes a strong basis for future targeted delivery of immunosuppressive drugs with improved efficiency and reduced toxicity.
authors.affiliation: Transplant Research Center, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Jamil
authors.initials: J
authors.lastname: Azzi
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.forename: Robert
authors.initials: R
authors.lastname: Moore
authors.forename: Rong
authors.initials: R
authors.lastname: Tong
authors.forename: Najib
authors.initials: N
authors.lastname: El Haddad
authors.forename: Takurin
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Bechara
authors.initials: B
authors.lastname: Mfarrej
authors.forename: Sunmi
authors.initials: S
authors.lastname: Yang
authors.forename: Mollie
authors.initials: M
authors.lastname: Jurewicz
authors.forename: Takaharu
authors.initials: T
authors.lastname: Ichimura
authors.forename: Neal
authors.initials: N
authors.lastname: Lindeman
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D011091:Polyesters / Q000008:administration & dosage*
chemical_list: D007166:Immunosuppressive Agents; D011091:Polyesters; C033616:poly(lactide); D016572:Cyclosporine