Enhancing tumor drug delivery: targeting nucleolin with liposomes for improved therapeutic efficacy

Nucleolin (NCL) is a multifunctional protein that plays a significant role in cancer development and progression. Nucleolin's expression on both endothelial and cancer cells makes it a strategic target for cancer therapy and drug delivery applications. This study aims to develop dexamethasone-loaded liposomes (LP-Dexa) coated with an affinity peptide for NCL (F3/LP-Dexa) to target cancer and endothelial cells and reduce tumor-associated inflammation. LP-Dexa were prepared using lipid film hydration followed by the extrusion method and functionalized with F3 peptide via thiol-maleimide linkage. Internalization by bEnd.3 cells (endothelial cells isolated from brain tissue derived from a mouse with endothelioma) was assessed using immunofluorescence and flow cytometry at various intervals. NCL protein and gene expression were analyzed post-treatment using immunofluorescence, flow cytometry, and real-time PCR. The anti-inflammatory effect was evaluated by measuring monocyte chemoattractant protein-1 (MCP-1) expression via Western blot. NCL expression increased two-fold in TNF-α-activated bEnd.3 cells compared to controls. F3/LP-Dexa showed efficient internalization and significantly reduced NCL mRNA and MCP-1 protein levels without inducing cytotoxicity at lower dexamethasone concentrations. Targeting NCL with F3/LP-Dexa offers a novel strategy for intracellular drug delivery to both cancer cells and activated endothelial cells, potentially reducing tumor growth and vascular inflammation while advancing therapeutic options for cancer.