Synthesis of KUE‐siRNA Conjugates for Prostate Cancer Cell‐Targeted Gene Silencing

Abstract

The delivery of siRNAs to selectively target cells poses a great challenge in RNAi-based cancer therapy. The lack of suitable cell-targeting methods seriously restricts the advance in delivering siRNAs to extrahepatic tissues. Based on prostate-specific membrane antigen (PSMA)-targeting ligands, we have synthesized a series of lysine-urea-glutamate (KUE)-siRNA conjugates and verified their effective cell uptake and gene silencing properties in prostate cancers. The results indicated that the KUE-siRNA conjugates could selectively enter PSMA + LNCaP cells, eventually down-regulating STAT3 expression. Based on post-synthesis modification and receptor-mediated endocytosis, this strategy of constructing ligand-siRNA conjugates might provide a general method of siRNA delivery for cell-targeted gene silencing.

Structure-activity relationship study of mesyl and busyl phosphoramidate antisense oligonucleotides for unaided and PSMA-mediated uptake into prostate cancer cells

“…Prostate-specific membrane antigen (PSMA), a prostate cancer specific cell surface biomarker, can be used for prostate cancer targeting, since it is highly overexpressed in nearly all types of prostate cancer but demonstrated only limited expression in normal tissues. To achieve highly efficient binding to PSMA for improved cellular uptake, small molecule PSMA ligands have been developed, such as DUPA for the delivery of siRNAs to PLK1 ( Abdelaal and Kasinski, 2021 ), or KUE for the delivery of siRNAs to STAT3 ( Yang et al, 2021 ). However, numerous studies on the optimization of the structure and properties of the linker in the PSMA ligand resulted in a significant improvement in the affinity and pharmacokinetic parameters of PSMA conjugates ( Baranski et al, 2017 ).…”