In this study, we prepared small interfering RNA (siRNA)/cationic liposome complexes (lipoplexes) modified with folate (FA)-polyethylene glycol (PEG, MW 2000, 3400 or 5000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to facilitate their uptake into tumor cells via folate receptor (FR), and with PEG₁₆₀₀-cholesterol (PEG₁₆₀₀-Chol) or PEG₂₀₀₀-chondroitin sulfate conjugate (PEG₂₀₀₀-CS), to enhance their systemic stability. Among the FA-PEG-modified siRNA lipoplexes, 0.5 mol% FA-PEG₅₀₀₀-DSPE-modified lipoplexes with 2.5 mol% PEG₂₀₀₀-CS or PEG₁₆₀₀-Chol (LP-0.5F₅/2.5P₂-CS and LP-0.5F₅/2.5P_1.6-CL, respectively) exhibited selective growth inhibition of human nasopharyngeal carcinoma KB cells through transduction with polo-like kinase 1 (PLK1) siRNA. Furthermore, the LP-0.5F₅/2.5P₂-CS and LP-0.5F₅/2.5P_1.6-CL lipoplexes exhibited decreased agglutination with erythrocytes through PEGylation, and markedly decreased the accumulation of siRNA in murine lungs after systemic injection. Finally, systemic injection of LP-0.5F₅/2.5P₂-CS and LP-0.5F₅/2.5P_1.6-CL lipoplexes resulted in accumulation of siRNA in KB tumor xenografts. These findings suggest that PEGylation of FA-PEG₅₀₀₀-DSPE-modified siRNA lipoplexes with PEG₂₀₀₀-CS or PEG₁₆₀₀-Chol might improve their systemic stability without the loss of selective transfection activity in tumor cells.

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