The Immunosuppressive Activity of Polymeric Micellar Formulation of Cyclosporine A: In Vitro and In Vivo Studies
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We have previously developed micelles of methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) as vehicles for the solubilization and delivery of cyclosporine A (CsA). These micelles were able to reduce the renal uptake and nephrotoxicity of CsA. The purpose of the current study was to test the efficacy of polymeric micellar formulation of CsA (PM-CsA) in suppressing immune responses by either T cells or dendritic cells (DCs). The performance of PM-CsA was compared to that of the commercially available formulation of CsA (Sandimmune®). Our results demonstrate that PM-CsA could exert a potent immunosuppressive effect similar to that of Sandimmune® both in vitro and in vivo. Both formulations inhibited phenotypic maturation of DCs and impaired their allostimulatory capacity. Furthermore, both PM-CsA and Sandimmune® have shown similar dose-dependent inhibition of in vitro T cell proliferative responses. A similar pattern was observed in the in vivo study, where T cells isolated from both PM-CsA-treated and Sandimmune®-treated mice have shown impairment in their proliferative response and IFN-γ production at similar levels. These results highlight the potential of polymeric micelles to serve as efficient vehicles for the delivery of CsA.
KEY WORDScyclosporine A dendritic cells polymeric micelles T cells
The authors would like to thank Elaine Moase for proof reading the manuscript. The authors would like to acknowledge financial support by research grant from Natural Sciences and Engineering Council of Canada (STPGP 336987).
- 13.Geng L, Dong S, Fang Y, Jiang G, Xie H, Shen M, et al. Cyclosporin a up-regulates B7-DC expression on dendritic cells in an IL-4-dependent manner in vitro, which is associated with decreased allostimulatory capacity of dendritic cells. Immunopharmacol Immunotoxicol. 2008;30(2):399–409.PubMedCrossRefGoogle Scholar
- 16.Aliabadi HM, Elhasi S, Mahmud A, Gulamhusein R, Mahdipoor P, Lavasanifar A. Encapsulation of hydrophobic drugs in polymeric micelles through co-solvent evaporation: the effect of solvent composition on micellar properties and drug loading. Int J Pharm. 2007;329(1–2):158–65.PubMedCrossRefGoogle Scholar
- 23.Akool el S, Doller A, Babelova A, Tsalastra W, Moreth K, Schaefer L, et al. Molecular mechanisms of TGF beta receptor-triggered signaling cascades rapidly induced by the calcineurin inhibitors cyclosporin A and FK506. J Immunol. 2008;181(4):2831–45.Google Scholar
- 24.Li B, Sehajpal PK, Khanna A, Vlassara H, Cerami A, Stenzel KH, et al. Differential regulation of transforming growth factor beta and interleukin 2 genes in human T cells: demonstration by usage of novel competitor DNA constructs in the quantitative polymerase chain reaction. J Exp Med. 1991;174(5):1259–62.PubMedCrossRefGoogle Scholar