Preparation and Biopharmaceutical Evaluation of Tacrolimus Loaded Biodegradable Nanoparticles for Liver Targeting

Abstract

Tacrolimus (TAC) is a potent immunosuppressant used in liver transplantation. Its use is however hindered by its systemic side effects, mainly nephrotoxcity. Since antigen presentation occurs in the graft and lymphatics, then by targeting TAC to the liver and spleen graft survival and decreased side effects could both be achieved. Simultaneous targeting to liver and spleen could be obtained via the reticuloendothelial system (RES). The objective of this study was to formulate RES attractive TAC-loaded nanoparticles that could ultimately increase TAC concentration in the liver and spleen and decrease it in the kidneys. Tacrolimus was incorporated into Poly(lactic acid) nanoparticles via the emulsion-solvent evaporation method. Poly lactide tacrolimus nanoparticles (PLA-TAC-NP) were extensively characterized by dynamic light scattering (DLS), transmission, scanning and atomic force microscopy (TEM, SEM and AFM) ensuring that they possessed the required characteristics rendering them RES attractive. Targeting efficiency of the formulated particles was assessed in-vitro by the evaluating their uptake by cultured human monocytes both qualitatively by TEM and quantitatively by HPLC-UV. DLS showed that particles had a mean diameter of 255 +/- 4.58 nm with unimodal distribution. Results were confirmed by SEM, AFM and TEM. Zeta Potential was -60.08 +/- 5.83 mV, whereas entrapment efficiency was 64.71 +/- 4.27%. TAC release pattern from PLA-NP was determined by the dialysis bag method showing 77 +/- 45.72% drug release within 4 days. PLA-TAC-NP phagocytosis was confirmed by TEM. The extent of phagocytosis was determined by HPLC analysis to be 80.48 +/- 11.61%. In conclusion, PLA-TAC-NP are promising carriers for TAC targeting to the liver and spleen via the reticuloendothelial system (RES).