Angela Alexander-Bryant

Multifunctional Tandem Peptide Mediates Targeted siRNA Delivery to Ovarian Cancer Cells

Fusogenic peptides have been developed to enhance the delivery efficiency of nucleic acids such as small interfering RNAs (siRNAs). Fusogenic peptides can protect nucleic acids from degradation and facilitate endosomal escape, but their systemic delivery capabilities remain unrefined. Active targeting of delivery systems to overexpressed cell receptors can be used to enhance cell- and tissue-specific delivery of therapeutic payloads while reducing off-target and systemic effects. We aimed to develop a targeted fusogenic (tandem) peptide, LHRHR-DIV3W, capable of targeting the luteinizing hormone-releasing hormone receptor (LHRHR), which is overexpressed in ovarian cancer cells and tissues. Characterization studies revealed that our tandem peptide, LHRHR-DIV3W, formed monodisperse nanocomplexes that protected siRNAs in physiological environments. We also demonstrated receptor-specific internalization of peptide-siRNA nanocomplexes in ovarian cancer cell lines with upregulated LHRHR expression. Furthermore, we observed that the inclusion of both the fusogenic DIV3W sequence and the LHRHR-targeting sequences in the tandem peptide enhanced receptor-specific siRNA internalization in ovarian cancer cells by up to 40% compared with the LHRHR-targeting peptide alone, indicating the necessity of combining both peptide regions. Finally, we demonstrated significant silencing of