Abstract
In this study, water-soluble chitosan lactate (CL) was reacted with lactobionic acid (LA), a disaccharide with remarkable affinity to hepatic asialoglycoprotein (ASGP) receptors, to form dual liver-targeting LA-modified-CL polymer for site-specific drug delivery to the liver. The synthesized polymer was used to encapsulate baicalin (BA), a promising bioactive flavonoid with pH-dependent solubility, into ultrahigh drug-loaded nanoparticles (NPs) via the ionic gelation method. The successful chemical conjugation of LA with CL was tested and the formulated drug-loaded LA-modified-CL-NPs were assessed in terms of particle size (PS), encapsulation efficiency (EE) and zeta potential (ZP) using full factorial design. The in vivo biodistribution and pharmacokinetics of the designed NPs were assessed using (99m)Tc-radiolabeled BA following oral administration to mice and results were compared to (99m)Tc-BA-loaded-LA-free-NPs and (99m)Tc-BA solution as controls. Results showed that the chemical modification of CL with LA was successfully achieved and the method of preparation of the optimized NPs was very efficient in encapsulating BA into nearly spherical particles with an extremely high EE exceeding 90%. The optimized BA-loaded-LA-modified-CL-NPs showed an average PS of 490 nm, EE of 93.7% and ZP of 48.1 mV. Oral administration of (99m)Tc-BA-loaded-LA-modified-CL-NPs showed a remarkable increase in BA delivery to the liver over (99m)Tc-BA-loaded-LA-free-CL-NPs and (99m)Tc-BA oral solution. The mean area under the curve (AUC(0-24)) estimates from liver data were determined to be 11-fold and 26-fold higher from (99m)Tc-BA-loaded-LA-modified-CL-NPs relative to (99m)Tc-BA-loaded-LA-free-CL-NPs and (99m)Tc-BA solution respectively. In conclusion, the outcome of this study highlights the great potential of using LA-modified-CL-NPs for the ultrahigh encapsulation of therapeutic molecules with pH-dependent/poor water-solubility and for targeting the liver.