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

The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/647305 doi: bioRxiv preprint changes in blood properties after bPEI nanoparticle administration could be a consequence of hepatocyte damage. [43] CXCL1 can then recruit neutrophils into circulation and aid in the clearing of unmodified bPEI nanoparticles. [44] Our discovery of heightened liver toxicity is in line with reports that demonstrate the expression of TLR4 on hepatocytes, elevated hepatocyte toxicity to PEI-coated gold nanoparticles, and PEI-induced impairment of cellular respiration in liver mitochondria. [34, 41, 45] However, our results on systemic toxicity in TLR4 knockout mice, shows that TLR4 is not the only driver of hepatic toxicity to bPEI nanoparticles. This conclusion is based on the elimination of the IL-6 response, but not the ALT response after injection with unmodified bPEI nanoparticles in TLR4 knockout mice.