Cholesterol Modification Enhances Antimetastatic Activity and siRNA Delivery Efficacy of Poly(ethylenimine)-Based CXCR4 Antagonists.

Chemokine receptor CXC receptor 4 (CXCR4) plays a crucial role in cell invasion and metastasis of multiple types of cancer. Dual-function polymeric CXCR4 antagonists based on cyclam-modified poly(ethylenimine) (C-PEI) have been shown to have potential as nucleic acid delivery vectors and antimetastatic therapeutics in recent studies. How cholesterol modification of C-PEI affects the ability of the polycation to deliver siRNA and inhibit CXCR4 is tested here. It is shown that the C-PEI with the lower content of cholesterol exhibits the highest siRNA transfection efficiency and demonstrates enhanced CXCR4 antagonism and antimetastatic activity in a breast cancer model in vivo. Overall, the cholesterol modification of C-PEI is a viable strategy to achieve efficient delivery of siRNA and simultaneous CXCR4 inhibition for combined antimetastatic therapies is validated by this study.