Characterization and In Vivo Efficacy of Targeted Nanoparticles for Systemic siRNA Delivery to Tumors

摘要

Systemic delivery of nucleic acid molecules is one of the major hurdles limiting the application of siRNA-based therapeutics for cancer treatment. Multifunctional nanoparticles are being investigated as systemic, nonviral nucleic acid delivery systems, and here we describe the use of cyclodextrin-containing polycations (CDP) to interact with small interfering RNA (siRNA) molecules to form nanoparticles that are approximately 60-80 nm in diameter. The modular design of these nanoparticles enables modification with PEG molecules for steric stabilization and transferrin targeting ligands for uptake by tumor cells. The nanoparticles protect the nucleic acid payload from nuclease degradation, do not aggregate at physiological salt concentrations, and cause minimal erythrocyte aggregation and complement fixation at the concentrations typically used for in vivo application. These nanoparticles are able to deliver functional siRNA molecules to metastatic and subcutaneous tumors in mice after systemic administration.