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

Moreover, the nanoparticles remained inside these organs 24 hours after administration (Supplementary Fig. 5A-B) . Although the IAA-modified chitosan nanoparticles persisted for longer in the mice, we continued to see evidence of reduced in vivo systemic toxicity with the IAA-modified chitosan. For instance, the IAA modification prevented the upregulation of CXCL1, CXCL2, and CCL2 observed in the spleens of mice treated with unmodified chitosan nanoparticles after 1 hour (Fig. 4A, Supplementary Fig. 6 ). Unmodified chitosan nanoparticles were ingested by 60% of circulating monocytes, while IAA-modified chitosan nanoparticles were only ingested by 15% of circulating monocytes (Fig. 4B) . Curiously, the circulating neutrophil uptake of chitosan nanoparticles were in agreement with the in vivo organ biodistribution data.