Design, Stability and Efficacy of a New Targeting Peptide for Nanoparticulate Drug Delivery to SH-SY5Y Neuroblastoma Cells

In recent years, rabies virus-derived peptide (RDP) has shown promise as a specific neural cell targeting ligand, however stability of the peptide in human serum was unknown. Herein, we report the molecular modelling and design of an optimised peptide sequence based on interactions of RDP with the α7 subunit of the nicotinic acetylcholine receptor (nAChR). The new sequence, named DAS, designed around a 5-mer sequence which demonstrated optimal nAChR binding in silico, showed greatly improved stability for up to 8 hours in human serum in comparison to RDP, which degraded within 2 hours at 37 °C. In vitro analysis using SH-SY5Y neuroblastoma cells showed that DAS-conjugated nanoparticles containing the cytotoxic drug doxorubicin (DAS-Dox-NP) displayed significantly enhanced cytotoxicity compared with untargeted doxorubicin-loaded nanoparticles (Dox-NP). DAS-Dox-NP had no significant effect on non-neural cell types, confirming its neural-specific targeting properties. In this manuscript, we report the design and testing of an optimised peptide ligand, conjugated to a nanoparticulate delivery vehicle and specifically targeted to neural cells. Future impact of an innovative targeting peptide ligand combining the ability to selectively identify the target and facilitate cellular internalisation could enable the successful treatment of many neural cell disorders.