In vivo study of the tissue distribution and immunosuppressive response of cyclosporin a-loaded polyester micro- and nanospheres

Abstract

In an attempt to elucidate the biopharmaceutical and clinical interest of new formulations of cyclosporin A (CyA) based on poly(d,l-lactide-co-glycolide) (PLGA) micro- and nanospheres, different in vivo studies were performed. On the one hand, tritium-labeled CyA was loaded into the microspheres (30 and 1 μm) and nano-spheres (0.2 μm) or diluted into a commercial injectable solution and then injected subcutaneously into mice. CyA kinetic profiles in blood and several tissues, i.e, liver, spleen, kidney, and adipose, were determined and compared for up to 21 days. The close relation observed between blood and tissue CyA profiles and the absence of significant differences between the distribution patterns of encapsulated CyA and the free drug led us to the following conclusions. First, subcutaneously injected microspheres and nanospheres act as a “depot,” from which CyA releases, attaining the blood and tissue compartments in the free form. Second, in addition to prolonging the residence time of the drug in the blood circulation, a single dose of microencapsulated CyA provides increased levels of the peptide in these tissues for up to several weeks. On the other hand, the immunosuppressive response after intraperitoneal injection of a single dose of the above-mentioned formulations was evaluated. Humoral immunosuppressive responses within day 0 and within day 7 postadministration were related to the in vivo kinetic profiles. Thus, nanospheres and 1-μm microspheres displayed a higher response at early times (0–24 h), while 30-μm microspheres led to an important level of immunosuppression at a later date (day 7). Consequently, these controlled release systems modulate the inununosuppression in terms of duration and intensity, suggesting their utility as promising CyA forms to achieve long-term immunosuppressive therapy.