Liposome-polyethylenimine complexes (DPPC-PEI lipopolyplexes) for therapeutic siRNA delivery in vivo

Therapeutic applications of RNA interference (RNAi) require efficient siRNA delivery strategies in vivo. Combining lipid-based carriers with polymeric nanoparticles offers the favorable properties of both systems. This is the first study to explore polyethylenimine-based lipopolyplexes comprising a low-molecular weight PEI and the phospholipid DPPC for therapeutic siRNA use. Lipopolyplex structures are analyzed by electron microscopy. Biological efficacies are demonstrated in vitro by cellular uptake, knockdown of the target oncogene survivin, and concomitant cell growth inhibition. Upon systemic administration in tumor-bearing mice, here performed by intraperitoneal (i.p.) injection, radioactive biodistribution assays show lipopolyplex-mediated delivery of intact siRNAs. Absence of blood serum parameter alterations, erythrocyte aggregation or immunostimulation, and the observation of animal well-being and stable body weight confirm biocompatibility. Exploring therapeutic efficacies in a preclinical model, a considerable inhibition of prostate carcinoma xenograft growth is achieved, paralleled by an ~65% survivin knockdown in the tumors. We, thus, demonstrate that PEI-based lipopolyplexes represent an efficient platform for therapeutic use of small RNAs.

Graphical AbstractThe combination of lipid-based carriers with polymeric nanoparticles benefits from the favorable properties of both systems. Here, lipopolyplexes comprising a low-molecular weight polyethylenimine (PEI) and the phospholipid DPPC are explored for therapeutic siRNA delivery in tumor-bearing mice. Lipopolyplex structures and biological efficacies are analyzed. In vivo, radioactive biodistribution assays show lipopolyplex-mediated delivery of intact siRNAs upon systemic administration. A considerable inhibition of prostate carcinoma xenograft growth is achieved, paralleled by an ~65% survivin knockdown in the tumors. In conclusion, PEI-based lipopolyplexes represent a platform for efficient therapeutic use of small RNAs in the absence of adverse effects.206