Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways

Randall Toy; Pallab Pradhan; Vijayeetha Ramesh; Nelson C. Di Paolo; Blake Lash; Jiaying Liu; Emmeline L. Blanchard; Philip J. Santangelo; Dmitry M. Shayakhmetov; Krishnendu Roy

Simplified in vitro screening assays do not take into consideration that nanoparticles are internalized by a variety of cells in vivo or the potential effect of the complement response on toxicity. These in vitro screening assays also neglect the effect of acute responses from one cell type that can activate feedback mechanisms in other cell types. In the context of designing nanoparticles for nucleic acid delivery, the mismatch between in vitro cytotoxicity and in vivo systemic toxicity may falsely eliminate viable nanoparticles from further testing. Therefore, our data demonstrate that thorough in vivo toxicity analyses are essential for the advancement of cationic polymer nanoparticles for nucleic acid delivery into the clinic.