L-type amino acid transporter 1 targeting self-assembly polyelectrolyte nanocomplex with enhanced nose to brain...

L-type amino acid transporter 1 (LAT1) is essential for the transport of large neutral amino acids (AA) across the blood-brain barrier (BBB), which plays a crucial role and is widely employed in brain drug delivery. Thus, in this study, tryptophan (Trp), leucine (Leu) and tyrosine (Tyr) were selected and various amino acid grafted chitosan (CTS) was first synthesized and characterized by Fourier transform infrared spectroscopy (FTIR) and ¹H nuclear magnetic resonance (¹H NMR) spectrum. Furthermore, oxytocin (OT) loaded polyelectrolyte complex (PEC) based on various amino acid grafted chitosan and chondroitin sulfate (CS) as well as OT loaded chitosan-chondroitin sulfate PEC was fabricated and optimized by particle size, zeta potential and encapsulation efficiency (EE%). The morphologies and OT conformation stability of different PEC formulations were investigated by transmission electron microscopy (TEM) and circular dichroism (CD) spectroscopy respectively. Moreover, to further reveal the superiority of amino acid grafted chitosan PECs on mucosal permeation and brain targeting via LAT1 transporter, the ex vivo permeation study, in vivo pharmacokinetics behavior as well as brain distribution of OT in different PECs were also carried out by intranasal administration. It was found that both chitosan-chondroitin sulfate and amino acid grafted chitosan-chondroitin sulfate PECs exhibited comparable particle size ranging from 180 to 210 nm with a positive charge. The PEC formulation presented a sustained release behavior compared to the OT solution and better nasal mucosal permeation was observed for amino acid grafted chitosan-chondroitin sulfate PECs. Both pharmacokinetics behavior and brain distribution results demonstrated that amino acid grafted chitsaon could significantly improve the OT absorption and brain accumulation in the order of Trp > Tyr > Leu, compared to naked chitosan-chondroitin sulfate PECs and OT solution. The behavioral and immunofluorescence results also revealed that amino acid grafted chitosan-chondroitin sulfate PECs exhibited a superior inhibitory effect on oxycodone (Oxy) addiction. In conclusion, amino acid grafted chitosan-chondroitin sulfate PECs could significantly promote brain drug transportation and could be a potential vehicle for protein or peptide delivery via nasal to brain pathway.